Clinical trial NCT02308020
Conditions: Breast Cancer Non-small Cell Lung Cancer Melanoma Brain Metastases
Sponsor: Eli Lilly and Company
Start date: 2015-04-20; Completion date: 2019-11-08
Enrollment: 162 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as abemaciclib in participants with hormone receptor positive breast cancer, non-small cell lung cancer (NSCLC), or melanoma that has spread to the brain.

Detailed description:

Arms: arm 1: Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive (HR+), HER2+ breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. arm 2: Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants in combination with endocrine therapy (ET).

Participants may continue to receive treatment until discontinuation criteria are met. arm 3: Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+, HER2+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated receiving concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours for 5-14 days prior to surgical resection. Dosing may resume following wound healing on a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. arm 4: Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. arm 5: Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. arm 6: Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Interventions: intervention 1: Abemaciclib
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_002.pdf: 
Protocol I3Y-MC-JPBO(d) 
 
A Phase 2 Study of Abemaciclib in Patients with Brain Metastasis Secondary to Hormone 
Receptor Positive Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma 
 
NCT02308020 
 
Approval Date: 08-Feb-2019 
 
 
 


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1. Protocol I3Y-MC-JPBO(d)
A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive 
Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma
Confidential Information
The information contained in this document 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 (LY2835219), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially 
confidential information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding 
release/redaction prior to any public release.  In the United States, this document is subject to Freedom of 
Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Abemaciclib (LY2835219)
This study is a global, multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain metastases 
secondary to hormone receptor positive breast cancer, non-small cell lung cancer, or melanoma.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Initial Protocol Electronically Signed and Approved by Lilly: 11 November 2014
Amendment (a) Electronically Signed and Approved by Lilly: 12 August 2015
Amendment (b) Electronically Signed and Approved by Lilly: 03 August 2016
Amendment (c) Electronically Signed and Approved by Lilly: 25 May 2017
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 08-Feb-2019 GMT


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2. Synopsis
Study Rationale
Brain metastases occur in a significant number of cancer patients, with the incidence being 
highest in lung cancer, breast cancer, and melanoma.  In the United States (US) alone, the 
incidence of brain metastases is approximately 200,000 cases per year.  Although targeted 
anticancer agents have shown promising results in treating extracranial disease, delivery of these 
agents to the central nervous system (CNS) has presented challenges.
Abemaciclib (LY2835219) is an oral, selective, and potent small molecule inhibitor of 
cyclin-dependent kinase (CDK) 4 and 6 (CDK4 and CDK6) with acceptable physical 
characteristics, pharmacokinetic (PK) properties, and safety profile in nonclinical species.  Cell-
based studies in breast cancer models indicated that abemaciclib inhibits CDK4 and CDK6 and 
induces G1 arrest, specifically in retinoblastoma (Rb) cell lines with functional Rb.  These 
studies also showed that sensitivity to CDK4 and CDK6 inhibition was greater in estrogen 
receptor positive (ER+) lines with luminal histology. In addition, abemaciclib demonstrates 
antitumor activity in multiple human xenograft models for human cancers, including, but not 
limited to non-small cell lung cancer (NSCLC) and melanoma. In radiolabeled studies in rats,
[14C]LY2835219-derived radioactivity was measurable in CNS tissues (cerebellum, cerebrum, 
medulla, and spinal cord) protected by the blood-brain barrier (BBB) through 24 hours after a 
single dose.  Abemaciclib has also been shown to inhibit glioblastoma intracranial xenografts, 
resulting in a statistically significant and dose-dependent improvement in survival.  
In the ongoing Phase 1 Study I3Y-MC-JPBA (JPBA), abemaciclib has demonstrated acceptable 
clinical safety and evidence of single-agent activity in tumor-specific cohorts of patients with 
hormone receptor positive (HR+) metastatic breast cancer (including a single patient with CNS 
target disease), NSCLC, and melanoma.  Further, cerebrospinal fluid (CSF) samples collected 
from a subset of these patients demonstrated that concentrations of abemaciclib in CSF were 
generally consistent with the unbound plasma concentrations. The preclinical results, including 
those that demonstrate that abemaciclib crosses the BBB, as well as the clinical findings from 
Study JPBA, support further investigation of abemaciclib in patients with brain metastases 
secondary to HR+ breast cancer, NSCLC, and melanoma.
Study I3Y-MC-JPBO (JPBO) is a multicenter, open-label, Phase 2 trial of abemaciclib in 
patients with brain metastases secondary to HR+ breast cancer, NSCLC, or melanoma.  This 
study will evaluate the safety and efficacy of abemaciclib in patients with HR+ metastatic breast 
cancer, NSCLC, or melanoma and new or not previously irradiated brain lesions as well as 
previously irradiated progressive brain lesions.  


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Clinical Protocol Synopsis:  Study I3Y-MC-JPBO
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  A Phase 2 Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone 
Receptor Positive Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma
Number of Planned Patients: 251
Entered: 314
Enrolled/Randomized: 251
Completed: 251
Phase of Development:  2
Length of Study:  approximately 36 months
Planned first patient visit:  April 2015
Planned last patient visit, excluding the continued access period: October 2018
Planned interim analysis:  The interim analysis of objective intracranial response rate (OIRR) for each study part 
(Part A, Part B, Part D, or Part E) will occur approximately 6 months after the 23rd evaluable patient has been 
enrolled into each respective part.  
Objectives:  The primary objective of this study is to evaluate abemaciclib with respect to OIRR (complete 
response [CR] + partial response [PR]) based on tumor assessments and Response Assessment in Neuro-Oncology 
brain metastases response assessment criteria (RANO-BM): 

in patients with brain metastases secondary to HR+, HER2+ breast cancer.  

in patients with brain metastases secondary to HR+, HER2- breast cancer.

in patients with brain metastases secondary to NSCLC. 

in patients with brain metastases secondary to melanoma.
The secondary objectives of the study are to evaluate abemaciclib with respect to:

Intracranial disease per RANO-BM
o
Best overall intracranial response (BOIR)
o
Duration of intracranial response (DOIR) (CR + PR)
o
Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
o
Intracranial clinical benefit rate (ICBR) (CR + PR + SD ≥6 months) 

Overall
o
Overall survival (OS)
o
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
and RANO-BM
o
Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and RANO-BM
o
Progression-free survival (PFS) per RECIST v1.1 and RANO-BM

Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT)

Safety and tolerability 

PK of abemaciclib and its metabolites
The exploratory objectives of the study are:

To explore change in neurocognitive function as assessed by the Trail Making Tests A and B

To explore change in neurologic signs as assessed by the Neurologic Assessment in Neuro-Oncology 
(NANO) scale

To explore the concentration of abemaciclib and its metabolites in plasma, cerebrospinal fluid (CSF), and 
brain tumor tissue collected at the time of surgical resection for patients participating in Part C, as well as 
concentrations in time-matched samples of plasma and CSF for patients participating in Part F  

To explore biomarkers related to the mechanism of action of abemaciclib, the cell cycle, and/or the 
pathogenesis of HR+ breast cancer, NSCLC, and melanoma

To assess the effect of abemaciclib on leptomeningeal metastases (LM) in patients with HR+ breast cancer, 
NSCLC, or melanoma based on proposed RANO-LM response criteria

To explore the relationship between abemaciclib exposure and response


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Study Design:  Study JPBO is a multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain 
metastases secondary to HR+ breast cancer, NSCLC, or melanoma.  The study will consist of 6 study parts; 4 of 
these parts will each accrue as few as 23 evaluable patients or as many as 56 evaluable patients with either 
metastatic breast cancer, NSCLC, or melanoma and at least 1 new or not previously irradiated brain lesion or at least 
1 progressive previously irradiated brain lesion.  These 4 parts will include patients with HR+, HER2+ breast cancer 
(Part A), HR+, HER2- breast cancer (Part B), NSCLC (Part D), and melanoma (Part E). Two study parts are 
exploratory: Part C will include approximately 8 patients (with the possibility of including up to 4 additional 
patients in order to evaluate interpatient variability) with HR+ breast cancer, NSCLC, or melanoma with intracranial 
lesions for which surgical resection is clinically indicated in order to assess concentrations of abemaciclib and its 
metabolites in plasma, CSF, and brain tumor tissue. These patients may resume abemaciclib dosing at least 15 days 
but no greater than 21 days postoperatively and continue until 1 of the criteria for discontinuation is met.  The 
second exploratory part (Part F) will include approximately 15 patients with HR+ breast cancer, NSCLC, or 
melanoma and leptomeningeal metastases. 
Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients are eligible for inclusion in the study if they 
meet all of the following criteria: 1) have brain metastases secondary to histologically or cytologically confirmed 
HR+ breast cancer, NSCLC, or melanoma; For Parts A and B:  have confirmed HR+ breast cancer.  For Part A:  
have HR+ breast cancer with confirmed HER2 overexpression (HER2+) status.  For Part B:  have HR+ breast 
cancer which does not demonstrate HER2 overexpression (HER2-) by either IHC or ISH.  
For Part C: have HR+ breast cancer, NSCLC, or melanoma with brain lesions for which surgical resection is 
clinically indicated and agree to provide posttreatment (5 to 14 days after initiating abemaciclib) brain tumor tissue.
For Part D:  have NSCLC of any subtype. For Part E:  have melanoma of any subtype. For Part F:  have HR+ 
breast cancer, NSCLC, or melanoma with leptomeningeal metastases by documented positive CSF cytology or by 
clinical signs and symptoms associated with abnormal magnetic resonance imaging (MRI) features.  Concomitant 
parenchymal brain metastases are allowed (not required), but must be stable for at least 4 weeks following whole 
brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS). 2) deleted criterion; 3) have either ≥1 new or not 
previously irradiated measurable (according to RANO-BM criteria) metastatic brain lesion ≥10 mm in the longest 
diameter (LD) or a progressive previously irradiated metastatic brain lesion (Parts A,B, D, and E) or metastatic brain 
lesion(s) for which surgical resection is clinically indicated (Part C [surgical]); 4) have completed local therapy
(surgical resection or stereotactic radiosurgery [SRS]) ≥14 days prior to initiating abemaciclib and recovered from 
all acute effects; 5) if receiving concomitant corticosteroids, must be on a stable or decreasing dose for at least 
7 days prior to the baseline gadolinium-enhanced magnetic resonance imaging (Gd-MRI); 6) have a Karnofsky 
performance status of ≥70; 7) have a life expectancy ≥12 weeks; 8) HR+ breast cancer patients in Parts A, B, and F:
if currently receiving endocrine therapy, may continue receiving the same endocrine therapy provided that 
extracranial disease is stable for at least 3 months and CNS disease progression has occurred while on this endocrine 
therapy. If these conditions are not met, patients must discontinue endocrine therapy prior to initiation of 
abemaciclib. Part C patients may continue or initiate endocrine therapy concurrently with abemaciclib; HER2+ 
breast cancer patients in Parts A, C, and F:  patients may receive concurrent treatment (ongoing or initiated 
simultaneously with abemaciclib) with trastuzumab. Concurrent treatment with trastuzumab emtansine (T-DM1) is 
not allowed; NSCLC patients in Parts D and F:  if currently receiving gemcitabine or pemetrexed (single-agent or in 
combination with another therapy), a patient may continue to receive 1 of these 2 therapies as a single agent 
provided that extracranial disease is stable for at least 6 weeks and CNS disease progression has occurred while on 
this therapy.  Combination therapies (aside from gemcitabine or pemetrexed) must be discontinued for at least 14 
days prior to initiation of abemaciclib.; Part C patients may continue or initiate gemcitabine or pemetrexed 
concurrently with abemaciclib. 9) have discontinued all previous therapies for cancer for at least 14 days prior to 
receiving abemaciclib and recovered from the acute effects of therapy (Note:  Exceptions for concurrent treatment 
are outlined in criterion [8]); 10) HER2+ breast cancer patients in Parts A, C, and F: for patients receiving 
concurrent trastuzumab, must have left ventricular ejection fraction within investigative site’s normal range; 11)
have adequate organ function; 12) are 18 years of age; 13) if a female of childbearing potential, must have a 
negative serum pregnancy test within 7 days of the first dose of abemaciclib and agree to use a medically approved 


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contraceptive method during the treatment period and for 3 months following the last dose of abemaciclib; If a male, 
agree to use a reliable method of birth control and to not donate sperm during the study and for at least 3 months 
following the last dose of abemaciclib; 14) are reliable and willing to make themselves available for the duration of 
the study and are willing to follow study procedures; and 15) are able to swallow capsules.
Patients will be excluded from the study if they meet any of the following criteria: 16) require immediate local 
therapy, including but not limited to WBRT, SRS, or surgical resection, for treatment of brain metastases; 
17) require concurrent anticancer treatment at any time during the study treatment period (except therapies outlined 
in criterion [8], or surgical resection [Part C patients only]); 18) are taking concurrent enzyme-inducing antiepileptic 
drugs (EIAED); 19) have evidence of significant (ie, symptomatic) intracranial hemorrhage; 20) Parts A, B, C, D,
and E: have evidence of leptomeningeal metastases by clinical signs and symptoms associated with abnormal MRI 
features or by previously documented CSF cytology; 21) have experienced >2 seizures within 4 weeks prior to study 
entry; 22) have visceral crisis; 23) Parts A, B, D, E, and F: have previously received treatment with any CDK4 and 
CDK6 inhibitor; Part C patients may have received prior palbociclib or ribociclib, but not abemaciclib, treatment ; 
24) have known contraindication to Gd-MRI; 25) deleted criterion; 26) are currently enrolled in a clinical trial
involving an investigational product or nonapproved use of a drug or device (other than the study drug used in this 
study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically 
compatible with this study; 27) have received treatment with a drug that has not received regulatory approval for 
any indication within 14 days of the initial dose of abemaciclib; 28) have a personal history within the last 
12 months of any ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular 
fibrillation) or sudden cardiac arrest; 29) have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study; 30) have a preexisting chronic condition resulting in 
baseline Grade 2 or higher diarrhea; 31) have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years; 32) are 
lactating; 33) have an active systemic fungal and/or known viral infection; 34) have an acute bacterial infection 
requiring intravenous (IV) antibiotics; 35) have received recent or concurrent yellow fever vaccination.  
Test Product, Dosage, and Mode of Administration:  Abemaciclib will be supplied as capsules to be 
administered at doses of 150 mg or 200 mg orally every 12 (± 2) hours on Days 1 through 21 of a 21-day cycle, for 
a total of 42 doses per cycle.
Planned Duration of Treatment:  
Treatment period:  until disease progression or other discontinuation criteria are fulfilled.
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death or overall study completion.
Criteria for Evaluation:  
Efficacy:  

OIRR (CR + PR), as defined by RANO-BM

BOIR

DOIR (CR + PR) 

IDCR (CR + PR + stable disease [SD]) 

ICBR (CR + PR + SD ≥6 months) 

OS

ORR per RECIST v1.1 and RANO-BM

DCR per RECIST v1.1 and RANO-BM

PFS per RECIST v1.1 and RANO-BM
Safety:  

Adverse events (AEs) and serious adverse events (SAEs) using Medical Dictionary for Regulatory 
Activities (MedDRA) and National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE) v4.0


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Health Outcomes:  

MDASI-BT to measure patient symptoms
Pharmacokinetics:  

Population PK parameters of abemaciclib and its metabolites
Exploratory:

Trail Making Tests A and B, to measure neurocognitive function

NANO scale to measure neurologic response or progression

Relative concentrations of abemaciclib and its metabolites in plasma, CSF, and tumor tissue

Exploratory correlative analysis of biomarkers related to the mechanism of action of abemaciclib, the cell 
cycle, and/or the pathogenesis of HR+ breast cancer, NSCLC, and melanoma.

Assess the effect of abemaciclib on leptomeningeal metastases in patients with HR+ breast cancer, 
NSCLC, or melanoma based on RANO-LM
Assess the relationship between abemaciclib exposure and response
Statistical Methods:  
Statistical:  
The primary objective of this clinical trial is to estimate the antitumor activity, measured by OIRR of abemaciclib in 
patients with brain metastases secondary to HR+ breast cancer, NSCLC, or melanoma.  
Simon 2-stage designs will be employed for this study for the following study parts: Part A (patients with HR+, 
HER2+ breast cancer), Part B (patients with HR+, HER2- breast cancer), Part D (patients with NSCLC), and Part E
(patients with melanoma).  Each design assumes a 1-sided type I error of 0.05 and 80% power.  
For Part A, up to 56 evaluable patients will be enrolled with the possibility of stopping the study early for either lack 
of efficacy or unacceptable toxicity.  Twenty-three evaluable patients will be enrolled in the first stage.  If fewer 
than 2 of the first 23 evaluable patients respond to abemaciclib, accrual will be stopped, and the conclusion will be 
drawn that abemaciclib is not worthy of further study in the Part-A population.  If at least 2 of the first 23 evaluable 
patients respond to therapy, accrual will continue until 33 additional evaluable patients have been enrolled.  A total 
of 6 responders out of 56 evaluable patients in Part A would need to be observed to warrant further investigation of 
abemaciclib in this patient population.  
The procedure described above tests the null hypothesis (H0) that the true OIRR of abemaciclib in Part A is ≤5% 
versus the alternative hypothesis (Ha) that the true OIRR is ≥15%.  The probability of early termination of the 
treatment arm under H0 is 0.68. 
Parts B, D, and E will have the identical design as Part A.  
Efficacy:
Efficacy analyses will be conducted on the full analysis set (FAS) and in the OIRR evaluable population when 
appropriate.  The FAS includes all data from all enrolled patients receiving at least 1 dose of abemaciclib.  The 
OIRR evaluable population is defined as patients receiving at least 1 dose of abemaciclib who have ≥1 measurable 
brain lesion at the time of enrollment (per RANO-BM) and for whom at least 1 post-baseline overall response 
assessment for intracranial disease is available.  OIRR will be reported along with 95% confidence intervals (CIs)
using the normal approximation.  Point estimates and 95% CIs (using the normal approximation to the binomial) 
will be calculated for BOIR, IDCR, ICBR, ORR, and DCR for Parts A B, D, and E.  Time-to-event efficacy 
endpoints (OS, PFS, and DOIR) will be summarized for Parts A, B, D, and E using Kaplan-Meier techniques if 
there is sufficient data.  If performed, Kaplan-Meier curves will be generated, and quartiles and point probabilities 
will be calculated.  Interval estimates will be calculated using 95% CIs.
Safety:
Safety analyses will be conducted on the FAS.  
Health Outcomes:
Patients with at least 1 baseline and 1 postbaseline assessment will be included in the analyses.  


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MDASI-BT data will be summarized by study part and response category (CR/PR, SD, PD); change from baseline
and time to worsening will be explored.  This summary will include mean, standard deviation, median, minimum, 
maximum, and change from baseline.  The MDASI-BT will be reported as core symptoms, brain tumor symptoms, 
symptom interference, and symptom groupings (affect, cognition, focal neurologic deficit, treatment-related 
symptoms, generalized/disease status symptoms, and gastrointestinal symptoms). 
Pharmacokinetics:  
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib and have had 
samples collected.  Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and interindividual PK variability will be computed using nonlinear mixed effect 
modeling (NONMEM).  Covariate effects (such as age, weight, sex, creatinine clearance, and plasma protein levels) 
on the PK parameters of abemaciclib in plasma will also be investigated.  
Pharmacodynamics:
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients from the above 
populations from whom a valid assay result (according to laboratory guideline) has been obtained.  
Pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood, OIRR, PFS, or OS) collected
in this study may also be analyzed by means of NONMEM and connected to the population PK model in a 
PK/pharmacodynamic model.
Exploratory:

Trail Making Tests A and B:  Summary statistics will be provided by study parts and each response 
category (CR/PR, SD, PD); change from baseline and time to worsening will be explored.

NANO Scale:  Clinical response and progression will be explored and summarized for the NANO scale 
using descriptive statistics.

Drug Concentrations in Plasma, Cerebrospinal Fluid, and Resected Tumor Tissue:  The relative 
concentrations of abemaciclib and its metabolites in plasma, CSF, and tumor tissue collected at the time of 
surgical resection for patients participating in Part C will be explored. In addition, the relative 
concentrations of abemaciclib and its metabolites in time-matched samples of plasma and CSF collected on 
Cycle 3 Day 1, as well as any other time the collection of CSF is clinically indicated, for patients 
participating in Part F will be explored.    

Biomarkers:  Summary statistics for biomarkers with continuous measures will include means, medians,
corresponding standard errors, quartiles, and ranges. Biomarkers with discrete measures will be 
summarized in frequency tables. Correlative analyses may be performed to investigate associations 
between biomarkers and clinical endpoints.


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3. Table of Contents
A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive Breast 
Cancer, Non-Small Cell Lung Cancer, or Melanoma
Section
Page
1.
Protocol I3Y-MC-JPBO(d)  A Phase 2 Study of Abemaciclib in 
Patients with Brain Metastases Secondary to Hormone Receptor 
Positive Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma...................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................20
5.1.
Rationale for Amendment (a).......................................................................................22
5.2.
Rationale for Amendment (b).......................................................................................22
5.3.
Rationale for Amendment (c).......................................................................................23
5.4.
Rationale for Amendment (d).......................................................................................23
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Study Population...............................................................................................................26
7.1.
Inclusion Criteria..........................................................................................................26
7.2.
Exclusion Criteria ........................................................................................................29
7.3.
Discontinuation............................................................................................................30
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................30
7.3.2.
Discontinuation of Investigational Product...........................................................31
7.3.3.
Discontinuation from the Study............................................................................31
7.3.4.
Patients who are Lost to Follow-Up .....................................................................31
7.3.5.
Discontinuation of Study Sites .............................................................................32
7.3.6.
Discontinuation of the Study................................................................................32
8.
Investigational Plan...........................................................................................................33
8.1.
Summary of Study Design............................................................................................33
8.1.1.
Study Completion and End of Trial......................................................................35
8.1.2.
Continued Access Period......................................................................................36
8.2.
Discussion of Design and Control ................................................................................37
9.
Treatment..........................................................................................................................38


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9.1.
Treatments Administered .............................................................................................38
9.2.
Materials and Supplies .................................................................................................38
9.3.
Method of Assignment to Treatment ............................................................................39
9.4.
Selection and Timing of Doses.....................................................................................39
9.4.1.
Special Treatment Considerations ........................................................................40
9.4.1.1.
Dose Adjustments and Delays ........................................................................40
9.4.1.1.1.
Dose Adjustments.....................................................................................41
9.4.1.1.2.
Dose Suspension (within a Cycle) and Cycle Delay ..................................41
9.4.1.1.3.
Hematologic Toxicity ...............................................................................42
9.4.1.1.4.
Nonhematologic Toxicity..........................................................................43
9.4.1.1.4.1.
Diarrhea..............................................................................................43
9.4.1.1.4.2.
Hepatic Toxicity .................................................................................43
9.5.
Blinding .......................................................................................................................43
9.6.
Concomitant Therapy...................................................................................................43
9.6.1.
Permitted Combination Therapies ........................................................................44
9.6.2.
Surgery ................................................................................................................45
9.6.3.
Supportive Care ...................................................................................................45
9.6.4.
Growth Factor......................................................................................................45
9.6.5.
Supportive Management for Diarrhea...................................................................45
9.7.
Treatment Compliance .................................................................................................46
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................47
10.1. Efficacy Measures........................................................................................................47
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................47
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................48
10.1.3.
Primary Efficacy Measure....................................................................................48
10.1.4.
Secondary Efficacy Measures...............................................................................49
10.1.5.
Exploratory Measures ..........................................................................................51
10.2. Health Outcome/Quality of Life Measures ...................................................................51
10.2.1.
Patient-Reported Outcomes..................................................................................51
10.2.1.1.
MD Anderson Symptom Inventory – Brain Tumor 
Module...........................................................................................................51
10.3. Safety Evaluations........................................................................................................52
10.3.1.
Adverse Events ....................................................................................................53
10.3.1.1.
Serious Adverse Events ..................................................................................54
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................55


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10.3.2.
Guidance for Monitoring of Renal Function in Patients on 
Abemaciclib.........................................................................................................56
10.3.3.
Other Safety Measures .........................................................................................56
10.3.3.1.
Electrocardiograms.........................................................................................56
10.3.3.2.
Echocardiograms or Multi-Gated Acquisition Scans.......................................56
10.3.4.
Safety Monitoring ................................................................................................56
10.3.4.1.
Special Hepatic Safety Data Collection...........................................................57
10.3.4.2.
Renal Function ...............................................................................................57
10.3.4.3.
Venous Thromboembolic Events (VTEs)........................................................58
10.3.5.
Complaint Handling.............................................................................................58
10.4. Sample Collection and Testing.....................................................................................58
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................59
10.4.2.
Samples for Biomarkers .......................................................................................59
10.4.2.1.
Blood Samples for Pharmacogenetic Evaluations............................................59
10.4.2.2.
Plasma Samples for Exploratory Biomarker Evaluations.................................60
10.4.2.3.
Archived Tumor Tissue ..................................................................................60
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................60
10.4.3.1.
Drug Concentrations for Parts C and F Patients ..............................................61
10.5. Appropriateness of Measurements................................................................................61
11.
Data Quality Assurance.....................................................................................................63
11.1. Data Capture System....................................................................................................63
12.
Sample Size and Statistical Methods .................................................................................64
12.1. Determination of Sample Size ......................................................................................64
12.2. Statistical and Analytical Plans.....................................................................................64
12.2.1.
General Considerations ........................................................................................64
12.2.2.
Patient Disposition...............................................................................................65
12.2.3.
Patient Characteristics..........................................................................................65
12.2.4.
Concomitant Therapy...........................................................................................65
12.2.4.1.
Postdiscontinuation Therapy...........................................................................66
12.2.5.
Treatment Compliance .........................................................................................66
12.2.6.
Primary Outcome and Methodology.....................................................................66
12.2.7.
Secondary Outcome and Methodology.................................................................66
12.2.8.
Pharmacokinetic and/or Pharmacodynamic Analyses ...........................................66
12.2.9.
Exploratory Analyses...........................................................................................67
12.2.9.1.
Trail Making Tests A and B............................................................................67
12.2.9.2.
Neurologic Assessment in Neuro-Oncology Scale ..........................................67


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12.2.9.3.
Drug Concentrations in Samples from Parts C and F 
Patients...........................................................................................................67
12.2.9.4.
Biomarker Analyses .......................................................................................67
12.2.10. Health Outcome/Quality of Life Analyses............................................................67
12.2.11. Safety Analyses....................................................................................................68
12.2.12. Interim Analyses..................................................................................................69
12.2.13. Subgroup Analyses ..............................................................................................69
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................70
13.1. Informed Consent.........................................................................................................70
13.2. Ethical Review.............................................................................................................70
13.3. Regulatory Considerations ...........................................................................................70
13.3.1.
Investigator Information.......................................................................................71
13.3.2.
Protocol Signatures ..............................................................................................71
13.3.3.
Final Report Signature .........................................................................................71
14.
References ........................................................................................................................72


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List of Tables
Table
Page
Table JPBO.1.
Treatment Regimens/Dosing Schedule ...................................................38
Table JPBO.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study
I3Y-MC-JPBO .......................................................................................40
Table JPBO.3.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBO ..................41
Table JPBO.4.
Secondary Efficacy Endpoints................................................................50
Table JPBO.5.
Exploratory Endpoints............................................................................51
Table JPBO.6.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........53


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List of Figures
Figure
Page
Figure JPBO.1.
Illustration of study design......................................................................34
Figure JPBO.2.
Study period and continued access period diagram. ................................36


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBO Study Schedule...............................................................75
Attachment 2.
Protocol JPBO Clinical Laboratory Tests................................................84
Attachment 3.
Protocol JPBO Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................85
Attachment 4.
Protocol JPBO Karnofsky Performance Status........................................86
Attachment 5.
Protocol JPBO RANO-BM and RANO-LM Criteria...............................87
Attachment 6.
Protocol JPBO RECIST 1.1....................................................................96
Attachment 7.
Protocol JPBO Electrocardiogram and Pharmacokinetic Sampling 
Schedule –
Parts A, B, D, E, and F .........................................................................103
Attachment 8.
Protocol JPBO Electrocardiogram and Pharmacokinetic Sampling 
Schedule – Part C .................................................................................104
Attachment 9.
Protocol JPBO Sampling Summary ......................................................105
Attachment 10.
Protocol JPBO Inducers and Strong Inhibitors of CYP3A or 
Substrates of CYPs with Narrow Therapeutic Range ............................106
Attachment 11.
Protocol JPBO Amendment(d) Summary  A Phase 2 Study of 
Abemaciclib in Patients with Brain Metastases Secondary to 
Hormone Receptor Positive Breast Cancer, Non-Small Cell Lung 
Cancer, or Melanoma ...........................................................................108


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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BBB
blood-brain barrier
BOIR
best overall intracranial response
CDK4 and CDK6
cyclin-dependent kinases 4 and 6
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
collection database
A computer database where clinical trial data are entered and validated.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit and no undue risks may continue to 
receive study therapy until 1 of the criteria for discontinuation is met. 
CNS
central nervous system
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.


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CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.
CR
complete response
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DCSI
Development Core Safety Information
DOIR
duration of intracranial response
EIAED
enzyme-inducing antiepileptic drugs
ECG
electrocardiogram
EDTA
ethylenediaminetetraacetic acid
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ER
estrogen receptor
ER+
estrogen receptor positive
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
ET
endocrine therapy
FAS
full analysis set
FISH
fluorescence in-situ hybridization
GCP
good clinical practice
Gd-MRI
gadolinium-enhanced magnetic resonance imaging


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H0
null hypothesis
Ha
alternative hypothesis
H&E
hematoxylin and eosin
HER2
human epidermal growth factor receptor 2
HER2+/-
human epidermal growth factor receptor 2 positive or negative
HR+
hormone receptor positive
IB
Investigator’s Brochure
ICBR
intracranial clinical benefit rate
ICF
informed consent form
ICH
International Conference on Harmonisation
IDCR
intracranial disease control rate
IHC
immunohistochemistry
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or 
3.
used to gain further information about the authorized form.
In this study, the Investigational Product is abemaciclib.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ISH
in-situ hybridization
IV
intravenous
IWRS
interactive web-response system
LC/MS/MS
liquid chromatography-tandem mass spectrometry


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LD
longest diameter
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LLT
LM
Lower Level Term
leptomeningeal metastases
MDASI-BT
MD Anderson Symptom Inventory – Brain Tumor
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition
NANO
Neurologic Assessment in Neuro-Oncology
NCI
National Cancer Institute
NONMEM
nonlinear mixed effect modeling
NSCLC
non-small cell lung cancer
OIRR
objective intracranial response rate
ORR
objective response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetic
PR
partial response
PT
Preferred Term
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis


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RANO
Response Assessment in Neuro-Oncology
RANO-BM
Response Assessment in Neuro-Oncology brain metastases
RANO-LM
Response Assessment in Neuro-Oncology leptomeningeal metastases
Rb
retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
rescreen
to screen a patient who was previously declared a screen failure for the same study
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 study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet 1 or more criteria required for participation in a trial
SD
stable disease
SOC
System Organ Class
SRS
stereotactic radiosurgery
Study completion
This study will be considered complete after the final evaluation of overall survival is 
performed.  
SUSARs
suspected unexpected serious adverse reactions 
TBL
total bilirubin
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limits of normal
US
United States
VTE
venous thromboembolic event
WBRT
whole brain radiotherapy


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A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive Breast 
Cancer, Non-Small Cell Lung Cancer, or Melanoma
5. Introduction
Brain metastases occur in a significant number of cancer patients, with the incidence being 
highest in lung cancer (40% to 50%), breast cancer (15% to 25%), and melanoma (5% to 20%).  
In the United States (US) alone, the incidence of brain metastases is approximately 200,000 
cases per year (Eichler and Loeffler 2007).  In addition, breast cancer, lung cancer, and 
melanoma are the most common primary tumors metastasizing to the leptomeninges 
(Wasserstrom et al. 1982).  Current standard-of-care treatment options for parenchymal brain 
metastases include whole brain radiotherapy (WBRT), surgical resection, and stereotactic 
radiosurgery (SRS).  Though surgery and radiotherapy are effective in palliating neurological 
symptoms, these therapies are associated with neurocognitive deficits (Lin et al. 2013), and the 
prognosis for patients remains poor. The median overall survival (OS) of patients with brain 
metastases secondary to non-small cell lung cancer (NSCLC) and melanoma is approximately 7 
months and for breast cancer is 13.8 months (Sperduto et al. 2012).  Although targeted anticancer 
agents have shown promising results in treating extracranial disease, delivery of these agents to 
the central nervous system (CNS) has presented challenges (Adamo et al. 2011). The blood-
brain barrier (BBB) arises from both a structural barrier and drug efflux transporters that may 
prevent most anticancer drugs from efficiently reaching brain tumors or metastases, though the 
BBB may be partially compromised at the metastatic site, enabling the delivery of some drugs to 
the tumor site (Deeken and Loscher 2007).
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002).  Cyclin-dependent 
kinases 4 and 6 (hereafter referred to as CDK4 and CDK6) participate in a complex with the D 
type cyclins to initiate progression through the G1 restriction point.  The CDK4 and CDK6 –
cyclin D1 complex regulates the G1 restriction point through phosphorylation and inactivation of 
the retinoblastoma (Rb) tumor suppressor protein, thereby promoting S phase entry.  Alterations 
in this pathway occur frequently in human cancers and involve 1) loss of functional CDK 
inhibitors through deletion or epigenetic silencing, 2) activating mutations and/or overexpression 
of CDK4 and CDK6 or the D type cyclins, and 3) loss of functional Rb through mutation or 
deletion.  Except for tumors with functional loss of Rb, which functions downstream of the 
CDK4 and CDK6 – cyclin D1 complex, most cancers are potentially sensitive to pharmacologic 
inhibition of CDK4 and CDK6.  From a therapeutic standpoint, the goal of inhibiting CDK4 and 
CDK6 with a small molecule is to prevent cell cycle progression through the G1 restriction point, 
thus arresting tumor growth.  
The mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) 
pathway are immediately downstream to BRAF and KRAS or NRAS. Cancers that harbor 
mutations in KRAS, NRAS and/or BRAF lead to the overactivation of this pathway. Patients with 
metastatic NSCLC that harbor KRAS mutations (25%) have a poor prognosis compared to 


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NSCLC patients who are KRAS wild-type (Guan et al. 2013). Importantly, synthetic lethal 
interaction between KRAS mutation and CDK4 inhibition indicates a potential therapeutic 
application for CDK4 and CDK6 inhibitors in NSCLC (Puyol et al. 2010). The key genetic 
alterations in melanomas [including BRAF mutation (50%), NRAS mutation (20%), and loss of 
CDKN2A (50%)] converge on the CDK4 and CDK6-CyclinD complex to enable malignant 
proliferation.
Abemaciclib (LY2835219) represents a selective and potent small molecule inhibitor of CDK4
and CDK6 with acceptable physical characteristics, pharmacokinetic (PK) properties, and safety 
profile in nonclinical species.  Cell-based studies in breast cancer models have demonstrated that 
abemaciclib inhibits CDK4 and CDK6 to induce G1 arrest specifically in cell lines with 
functional Rb versus lines which lack functional Rb.  Additional cell-based studies, which 
evaluated in vitro growth inhibition across a diverse panel of 46 breast cell lines representing the 
known molecular subgroups of breast cancer, indicated that sensitivity to CDK4 and CDK6 
inhibition was greater in ER+ lines with luminal histology. Abemaciclib demonstrates antitumor 
activity in multiple human xenograft models for human cancers including, but not limited to, 
NSCLC and melanoma. Preclinical data indicate that NSCLC models with KRAS mutations 
generally show greater sensitivity to growth inhibition by abemaciclib.
In radiolabeled studies in rats, [14C]LY2835219-derived radioactivity was measurable in CNS
tissues (cerebellum, cerebrum, medulla, and spinal cord) protected by the BBB through 24 hours 
postdose after a single dose.  Abemaciclib has also been shown to inhibit glioblastoma 
intracranial xenografts, resulting in a statistically significant and dose-dependent improvement in 
survival (Sanchez-Martinez et al. 2011).  
In the ongoing Phase 1 Study I3Y-MC-JPBA (JPBA) abemaciclib has demonstrated acceptable 
safety across 5 tumor-specific cohorts at doses up to 200 mg every 12 hours. The most common 
treatment-emergent adverse events (TEAEs) possibly related to study drug included diarrhea, 
nausea, fatigue, vomiting, and neutropenia. Results from Study JPBA suggest that abemaciclib 
has clinical activity in several distinct cancer populations. In the single agent metastatic breast 
cancer cohort, abemaciclib demonstrated evidence of clinical activity in 12 patients with 
hormone receptor positive (HR+) metastatic breast cancer, with either HER2+ or HER2 negative
(HER2-) disease, including a single patient with CNS target disease.  In the NSCLC cohort, 1 
patient with a KRAS mutation and 1 patient with KRAS wild-type showed response. The 
melanoma cohort had 1 patient with a partial response.
In Study JPBA, cerebrospinal fluid (CSF) samples were collected from a limited number of 
patients with breast cancer, NSCLC, and melanoma with brain metastases present at baseline; 
samples from 10 patients were analyzed for concentrations of abemaciclib.  In general, 
abemaciclib concentrations in CSF were consistent with unbound plasma concentrations.  The 
clinical results, as well as preclinical findings demonstrating that abemaciclib crosses the BBB, 
support further investigation of abemaciclib in patients with brain metastases secondary to HR+
breast cancer, NSCLC, and melanoma.  


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The Phase 2 Study I3Y-MC-JPBO (JPBO) will evaluate the safety and efficacy of abemaciclib in 
patients with HR+ breast cancer, NSCLC, and melanoma with new or not previously irradiated 
brain lesions as well as previously irradiated progressive brain lesions.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of abemaciclib may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to abemaciclib may be found in Section 7 
(Development Core Safety Information [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate periodically during the course of the study may be found in 
Section 6 (Effects in Humans) of the IB.  
5.1.
Rationale for Amendment (a)
The primary rationale for amendment (a) is to modify eligibility criteria to include additional 
study parts for patients with brain metastases secondary to NSCLC and melanoma, as well as an 
exploratory study part for patients with leptomeningeal metastases (LM).  Further changes for 
clarity were provided for study parts with respect to permitted concomitant therapies.  Additional 
changes include modification of language pertaining to supportive care and dose suspensions for 
patients experiencing diarrhea related to abemaciclib, as well as clarification that the study will 
use the Response Assessment in Neuro-Oncology Brain Metastases (Lin et al. 2015) criteria to 
assess intracranial response.
Minor editorial changes have been made to improve clarity and practicability of the protocol and 
secure alignment with the intended study design. 
5.2.
Rationale for Amendment (b)
The rationale for amendment (b) is primarily to clarify the abemaciclib dose to be administered 
in combination with trastuzumab.  Additional updates were made to the dosing guidance for 
cases of hematologic toxicity and on the use of blood cell growth factors. Eli Lilly and Company 
(Lilly) conducted a review across several clinical trials of abemaciclib and concluded that there 
were some inconsistencies. This amendment will harmonize the dosing guidance across 
protocols and clarify that blood cell growth factors are only to be used in a manner consistent 
with American Society of Clinical Oncology (ASCO) guidelines.
In addition, in order to evaluate interpatient variability for Part C (surgery patients), up to 
4 additional patients may be enrolled in this cohort.  Finally, the Response Assessment in Neuro-
Oncology brain metastases (RANO-BM) and Response Assessment in Neuro-Oncology 
leptomeningeal metastases (RANO-LM) assessment criteria were added to Attachment 5 rather 
than referencing a separate manual.
Minor changes have been made to improve clarity and feasibility of the protocol and secure 
alignment with the intended study design.


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5.3.
Rationale for Amendment (c)
The rationale for amendment (c) is to update the protocol to define evaluable patients for study 
Parts A, B, D, and E, and to clarify the number of patients to be enrolled. This is to ensure that 
an adequate number of evaluable patients are enrolled, since non-evaluable patients reduce the 
ability to detect a treatment effect in this study.
In addition, re-screening of patients was not previously permitted; however, in this amendment,
re-screening is allowed under certain circumstances with prior approval of the Lilly clinical 
research physician (CRP) or designee. 
5.4. Rationale for Amendment (d)
Study JPBO protocol was amended to update the dosing guidance for cases of non-
hematologic toxicity, diarrhea, and ALT increase.  This amendment will harmonize the dosing 
guidance across all clinical trials of abemaciclib in the metastatic setting.  The amendment 
updated the safety language regarding hepatic monitoring, assessment of renal function, and 
venous thromboembolic events (VTEs) for ongoing patients. Minor typographical and 
formatting edits were made throughout the document for clarity and consistency.


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6. Objectives
6.1.
Primary Objective
To evaluate abemaciclib with respect to objective intracranial response rate (OIRR; complete 
response [CR] + partial response [PR]) based on tumor assessments and Response Assessment in 
Neuro-Oncology brain metastases response assessment criteria (RANO-BM):  

in patients with brain metastases secondary to HR+, HER2+ breast cancer.

in patients with brain metastases secondary to HR+, HER2- breast cancer.

in patients with brain metastases secondary to NSCLC.

in patients with brain metastases secondary to melanoma.
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:
To evaluate abemaciclib with respect to:

Intracranial disease per RANO-BM
o
Best overall intracranial response (BOIR)
o
Duration of intracranial response (DOIR) (CR + PR)
o
Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
o
Intracranial clinical benefit rate (ICBR) (CR + PR + SD ≥6 months)

Overall
o
OS
o
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1 and RANO-BM
o
Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and RANO-BM
o
Progression-free survival (PFS) per RECIST v1.1 and RANO-BM

Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor 
(MDASI-BT)

Safety and tolerability 

PK of abemaciclib and its metabolites
6.3.
Exploratory Objectives 

To explore change in neurocognitive function as assessed by Trail Making Tests A and B

To explore change in neurologic signs as assessed by the Neurologic Assessment in 
Neuro-Oncology (NANO) scale

To explore the concentration of abemaciclib and its metabolites in plasma, CSF and brain 
tumor tissue collected at the time of surgical resection for patients participating in Part C, 
as well as concentrations in time-matched samples of plasma and CSF for patients 
participating in Part F  

To explore biomarkers related to the mechanism of action of abemaciclib, the cell cycle, 
and/or the pathogenesis of HR+ breast cancer, NSCLC, and melanoma

To assess the effect of abemaciclib on LM in patients with HR+ breast cancer, NSCLC, 
or melanoma based on proposed RANO-LM response criteria


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
To explore the relationship between abemaciclib exposure and response


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7. Study Population
Rescreening of individuals who do not meet the criteria for participation in this study is 
permitted only after discussion with and permission from the Lilly CRP or designee.  
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have brain metastases secondary to histologically or cytologically confirmed 
HR+ breast cancer, NSCLC, or melanoma. 
For Parts A and B:  have confirmed HR+ breast cancer. To fulfill the 
requirement for HR+ disease, a breast cancer must express, at least 1 of the
hormone receptors (ER or progesterone receptor [PgR]).  For ER and PgR 
assays to be considered positive, ≥1% of tumor cell nuclei must be 
immunoreactive by immunohistochemistry (IHC) (Hammond et al. 2010).
For Part A:  have HR+ breast cancer with confirmed HER2 overexpression 
(HER2+) status.  To fulfill the requirement for HER2+ disease, tumor tissue 
must demonstrate 3+ by IHC or gene amplification by in-situ hybridization 
(ISH) (Wolff et al. 2013).
For Part B:  have HR+ breast cancer which does not demonstrate HER2 
overexpression (HER2-) by either IHC or ISH.  
For Part C: have HR+ breast cancer, NSCLC, or melanoma with brain lesions 
for which surgical resection is clinically indicated and agree to provide 
posttreatment (5 to 14 days after initiating abemaciclib) brain tumor tissue.
For Part D:  have NSCLC of any subtype.
For Part E:  have melanoma of any subtype
For Part F:  have HR+ breast cancer, NSCLC, or melanoma with
leptomeningeal metastases by documented positive CSF cytology or by 
clinical signs and symptoms associated with abnormal magnetic resonance 
imaging (MRI) features. Concomitant parenchymal brain metastases are 
allowed (not required), but must be stable for at least 4 weeks following whole 
brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS).
[2]
Deleted criterion.


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[3]
For Parts A,B, D and E:  have ≥1 new or not previously irradiated measurable 
metastatic brain lesion ≥10 mm in the longest diameter (LD) and ≥5 mm in 
the perpendicular plane (refer to RANO-BM criteria in Attachment 5) or a
progressive previously irradiated metastatic brain lesion on radiographic 
imaging by gadolinium-enhanced magnetic resonance imaging (Gd-MRI).  
Note:  for patients with prior WBRT or SRS, previously irradiated lesion(s) 
must be measurable (≥10 mm in LD and ≥5 mm in the perpendicular plane) 
and demonstrate unequivocal progression in the opinion of the treating 
investigator.  Otherwise new or not previously irradiated lesions must be 
present. Previously untreated lesions are preferred target lesions (see 
Attachment 5).
For Part C (surgical):  have metastatic brain lesion(s) for which surgical 
resection is clinically indicated.
[4]
have completed local therapy (surgical resection or SRS) ≥14 days prior to 
initiating abemaciclib and recovered from all acute effects. Patients are not 
required to have received prior local therapy for study participation.
[5]
if receiving concomitant corticosteroids, must be on a stable or decreasing 
dose for at least 7 days prior to the baseline Gd-MRI.  
[6]
have a Karnofsky performance status of ≥70 (see Attachment 4).  
[7]
have a life expectancy ≥12 weeks.


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[8]
for HR+ breast cancer patients in Parts A, B, and F:  if currently receiving 
endocrine therapy, a patient may continue to receive the same endocrine 
therapy provided that extracranial disease is stable for at least 3 months and 
CNS disease progression has occurred while on this endocrine therapy.  If 
these conditions are not met, patients must discontinue endocrine therapy 
prior to initiation of abemaciclib. Part C patients may continue or initiate 
endocrine therapy concurrently with abemaciclib and need not meet the above 
conditions.
For HER2+ breast cancer patients in Parts A, C, and F:  patients may receive 
concurrent treatment (ongoing or initiated simultaneously with abemaciclib)
with trastuzumab.  Concurrent treatment with trastuzumab emtansine (T-
DM1) is not allowed.
For NSCLC patients in Parts D and F:  if currently receiving gemcitabine or
pemetrexed (single-agent or in combination with another therapy), a patient 
may continue to receive 1 of these 2 therapies as a single agent provided that 
extracranial disease is stable for at least 6 weeks and CNS disease progression 
has occurred while on this therapy.  Combination therapies (aside from 
gemcitabine or pemetrexed) must be discontinued for at least 14 days prior to 
initiation of abemaciclib. Part C patients may continue or initiate gemcitabine 
or pemetrexed (as single agents) concurrently with abemaciclib and need not 
meet the above conditions.
[9]
have discontinued all previous therapies for cancer (including cytotoxic 
chemotherapy, targeted therapy [including, but not limited to, everolimus], 
radiotherapy, immunotherapy, and investigational therapy) for at least 14 days 
prior to receiving abemaciclib and recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) except for residual alopecia or 
peripheral neuropathy.
Note:  Exceptions for concurrent treatment are outlined in criterion [8].
[10] for HER2+ breast cancer patients in Parts A, C, and F: patients receiving 
concurrent trastuzumab, must have left ventricular ejection fraction within 
investigative site’s normal range.
[11] 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 aminotransferase (AST) 3.0 times 
ULN (or ALT and AST ≤5.0 times ULN if liver metastases are present).  

Renal:  Serum creatinine 1.5 times ULN.


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[12] are 18 years of age.  
[13] if a female of childbearing potential, must have a negative serum pregnancy 
test within 7 days of the first dose of abemaciclib and agree to use a medically 
approved contraceptive method during the treatment period and for 3 months 
following the last dose of abemaciclib. If a male, agree to use a reliable 
method of birth control and to not donate sperm during the study and for at 
least 3 months following the last dose of abemaciclib. Contraceptive methods 
may include an intrauterine device [IUD] or barrier method. If condoms are 
used as a barrier method, a spermicidal agent should be added as a double 
barrier protection.  
[14] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[15] are able to swallow capsules.  
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[16] require immediate local therapy, including but not limited to WBRT, SRS, or 
surgical resection, for treatment of brain metastases.  
[17] require concurrent anticancer treatment at any time during the study treatment 
period.  
Note:  exceptions are therapies outlined in criterion [8] or surgical resection 
(Part C patients only).  
[18] are taking concurrent enzyme-inducing antiepileptic drugs (EIAED).
[19] have evidence of significant (ie, symptomatic) intracranial hemorrhage.  
[20] for Parts A, B, C, D, and E:  have evidence of leptomeningeal metastases by 
clinical signs and symptoms associated with abnormal MRI features or by 
documented CSF cytology.  
Note:  discrete dural metastases are permitted.  
[21] have experienced >2 seizures within 4 weeks prior to study entry.  
[22] have visceral crisis. Visceral crisis is not the mere presence of visceral 
metastases but implies severe organ dysfunction as assessed by symptoms and 
signs, laboratory studies, and rapid progression of the disease.  
[23] for Parts A, B, D, E, and F:  have previously received treatment with any 
CDK4 and CDK6 inhibitor.  Part C patients may have received prior 
palbociclib or ribociclib, but not abemaciclib, treatment.
[24] have known contraindication to Gd-MRI.  
[25] deleted criterion.


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[26] are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the study drug used in this 
study), or concurrently enrolled in any other type of medical research judged 
not to be scientifically or medically compatible with this study.
[27] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 days of the initial dose of abemaciclib.  
[28] have a personal history within the last 12 months of any ventricular 
arrhythmia (including but not limited to ventricular tachycardia and 
ventricular fibrillation) or sudden cardiac arrest.  
[29] 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).  
[30] have a preexisting chronic condition resulting in baseline Grade 2 or higher 
diarrhea.  
[31] have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years.  
[32] are lactating.  
[33] have an active systemic fungal and/or known viral infection (for example, 
human immunodeficiency virus antibodies, hepatitis B surface antigen, or 
hepatitis C antibodies).  Screening is not required for enrollment.  
[34] have an acute bacterial infection requiring intravenous (IV) antibiotics.
[35] have received recent (within 28 days of initial dose of abemaciclib) or
concurrent yellow fever vaccination.  
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
Patients who are discontinued from abemaciclib early will have follow-up procedures performed 
as shown in the Study Schedule (Attachment 1).  
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.  
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 


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with or without abemaciclib.  Inadvertently enrolled patients may be maintained in the study and 
on abemaciclib 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 abemaciclib if the 
Lilly CRP does not agree with the investigator’s determination it is medically appropriate for the 
patient to continue. The investigator must obtain documented approval from the Lilly CRP to 
allow the inadvertently enrolled patient to continue in the study with or without abemaciclib.  
7.3.2. Discontinuation of Investigational Product
Patients will be discontinued from abemaciclib in the following circumstances:  

the patient has intracranial (parenchymal) disease progression according to RANO-BM or 
extracranial disease progression according to RECIST v1.1. For patients in Part F, 
evidence of leptomeningeal disease progression based upon radiography, cytology,
and/or clinical neurological assessment will also result in discontinuation from 
abemaciclib. In exceptional circumstances, if discordant disease progression and 
response (intracranial vs. extracranial or vice versa) occur and the patient has exhausted 
all other treatment options, the investigator must contact the Lilly CRP to discuss the 
possibility of continuing the patient on abemaciclib.

the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication (except those 
noted as allowable in the inclusion/exclusion criteria and Section 9.6); discontinuation of 
abemaciclib occurs prior to introduction of the new agent.

the patient experiences unacceptable toxicity 

the patient is noncompliant with study procedures and/or treatment  

if further dose reduction is required beyond 100 mg every 12 hours.

the investigator decides that the patient should be discontinued from abemaciclib.

the patient or the patient’s designee (for example, legal guardian) requests that the patient 
be withdrawn from abemaciclib.  

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.  
7.3.3. Discontinuation from the Study 
Patients will be discontinued from the study in the following circumstances:

the patient or the patient’s designee (for example, legal guardian) requests that the patient 
be withdrawn from the study.  

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice (GCP).  
7.3.4. Patients who are Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 


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3 diligent attempts (by telephone and/or email) to contact patients who fail to return for a 
scheduled visit or who the site is otherwise unable to follow.  
7.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.  
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.  


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8. Investigational Plan
8.1.
Summary of Study Design
Study JPBO is a multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain 
metastases secondary to HR+ breast cancer, NSCLC or melanoma.
The study will consist of a total of 6 parts; 4 of these parts will each accrue as few as 
23 evaluable patients or as many as 56 evaluable patients with metastatic cancer (breast cancer,
NSCLC or melanoma) and at least 1 new or not previously irradiated measurable brain lesion or 
at least 1 progressive previously irradiated measurable brain lesion. The Part D (NSCLC) and 
Part E (melanoma) populations will be monitored upon enrollment and may be adjusted to 
achieve adequate numbers of patients with wild type versus mutant biomarker (KRAS for 
NSCLC and BRAF for melanoma) status.
Part C will initially include approximately 8 patients with any of the 3 tumor types (breast
cancer, NSCLC, or melanoma) who have intracranial lesions for which surgical resection is 
clinically indicated in order to assess concentrations of abemaciclib and its metabolites in 
plasma, CSF, and brain tumor tissue.  Up to 4 additional patients may be added to Part C in order 
to evaluate interpatient variability.  Part C patients may resume abemaciclib dosing at least 15 
days but no greater than 21 days postoperatively and continue until 1 of the criteria for 
discontinuation is met (refer to Section 7.3).  The day the patient resumes treatment with 
abemaciclib will be considered as Cycle 2 Day 1 and all pertinent study procedures (Attachment 
1) must be completed.  In exceptional cases, in consultation with the Lilly CRP, a patient may 
resume dosing more than 21 days postoperatively.  These exceptional cases will not be 
considered protocol violations.
Part F will include approximately 15 patients with any of the 3 tumor types (breast cancer, 
NSCLC, or melanoma) and leptomeningeal metastases.
Figure JPBO.1 illustrates the study design.


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* All patients in Parts A, B, D, E, and F will receive abemaciclib PO Q12H until PD, 
unacceptable toxicity, or withdrawal from the study.  Patients in Part C will receive 
abemaciclib PO Q12H for 5 to 14 days prior to surgical resection; dosing may resume 
after a wound healing period and continue until PD, unacceptable toxicity or 
withdrawal.
Abbreviations: HER2+ = HER2 positive; HER2-=HER2 negative; HR+ = hormone 
receptor positive; mg = milligrams; NSCLC = Non-small cell lung cancer; 
PD = progressive disease; PO = orally; pts = patients; Q12H = every 12 hours.
Figure JPBO.1.
Illustration of study design.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form (ICF) is signed and ends at the first 
study treatment (or at discontinuation, if no treatment is given).  

Study Period:  begins at the first study treatment and ends at study completion. The 
study period does not include the continued access period.  
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue 
abemaciclib.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from abemaciclib.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue abemaciclib.
Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue abemaciclib and lasts 
approximately 30 days.  
Long-term follow-up begins the day after short-term follow-up is 
completed and continues until the patient’s death or overall study 
completion.


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
Continued Access Period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on abemaciclib who continue to experience 
clinical benefit and no undue risks may continue to receive abemaciclib until 1 of the 
criteria for discontinuation is met.  The continued access period includes continued 
access follow-up.
o
Continued Access Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue abemaciclib in the 
continued access period and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
The primary analysis of OIRR for each study Part (A, B, D, or E) will occur approximately 6 
months after up to 56 evaluable patients have been enrolled into each respective part. This is to 
ensure that adequate durability of response data is available at the time of analysis. Investigators 
will continue to follow the study schedule for all patients until notified by Lilly that study 
completion has occurred.  
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up (Figure JPBO.2).


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Abbreviations:  OIRR = objective intracranial response rate; OS = overall survival.
Figure JPBO.2.
Study period and continued access period diagram.
8.1.2. Continued Access Period 
The continued access period will apply to this study only if at least 1 patient is still on 
abemaciclib when study completion occurs.
Patients receiving abemaciclib and experiencing ongoing clinical benefit and no undue risks may 
continue to receive abemaciclib in the continued access period until 1 of the criteria for 
discontinuation is met (Section 7.3).  Lilly will notify investigators when the continued access
period begins.  
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.  
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.  
During the continued access period, all AEs, SAEs, and abemaciclib exposure will be reported 
on the eCRF.  SAEs will also be reported to Lilly Global Patient Safety (see Section 10.3.1).  In 
Continued Collection of OS Data
End of 
Trial
Study 
Completion
Patients 
on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
a Lilly will notify sites when this begins and ends.  
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Accesss 
Follow-Up
Primary Analysis 
of OIRR
Final Analysis 
of OS Data
Long-Term 
Follow-Up
Patient on 
Study 
Treatment
Short-Term 
Follow-Up 
Patient 
Discontinues 
Study 
Treatment
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment


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the event that an SAE occurs, Lilly may request additional information (such as local laboratory 
results, concomitant medications, and hospitalizations) in order to evaluate the reported SAE.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly
will not routinely collect the results of these assessments.
8.2.
Discussion of Design and Control
A nonrandomized, uncontrolled design is being used in this study.  Although this design has 
known inferential deficiencies, this design is justified for this study for the following reasons:
1. There is no approved chemotherapeutic option for these patients.
2. The primary endpoint in this study is intracranial tumor response, observation of which is 
putative evidence of antitumor effect of abemaciclib.


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9. Treatment
9.1.
Treatments Administered
Abemaciclib 200 mg will be administered orally every 12 (± 2) hours on Days 1 through 21 of a 
21-day cycle when administered as a single agent or for breast cancer patients in combination 
with endocrine therapy.  For HER2+ breast cancer patients receiving concurrent trastuzumab or 
for NSCLC patients receiving concurrent gemcitabine or pemetrexed, abemaciclib will be 
administered at a starting dose of 150 mg orally every 12 (± 2) hours on Days 1 through 21 of a 
21-day cycle.
Table JPBO.1 shows the treatment regimen.
Table JPBO.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose 
Abemaciclib
(single agent or in 
combination with ET)
Treatment/21-day cycle
200 mg Q12H PO on Days 1 – 21 of a 
21-day cycle
Abemaciclib (in 
combination with 
trastuzumab, 
gemcitabine, or 
pemetrexed)
Treatment/21-day cycle
150 mg Q12H PO on Days 1 – 21 of a 
21-day cycle
Abbreviations:  ET = endocrine therapy; PO = orally; Q12H = once every 12 (± 2) hours.
The investigator or his/her designee is responsible for the following:  

explaining the correct use of abemaciclib and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of abemaciclib dispensing and collection, 

and returning all unused abemaciclib to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with abemaciclib so that the situation can be assessed.  
9.2.
Materials and Supplies
Abemaciclib will be supplied by Lilly as capsules for oral administration. The capsules 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 in the 
original package and in a location inaccessible to children. Abemaciclib will be labeled 
according to country regulatory requirements.


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9.3.
Method of Assignment to Treatment
Upon obtaining informed consent, site personnel should access the interactive web-response 
system (IWRS) which will assign a patient number.  The IWRS will be used to assign 
abemaciclib to patients who meet all criteria for enrollment in 1 of 6 study parts:

Part A: patients with HR+, HER2+ breast cancer

Part B: patients with HR+, HER2- breast cancer

Part C:  patients with HR+ breast cancer, NSCLC or melanoma and intracranial 
lesions for which surgical resection is clinically indicated.

Part D: patients with NSCLC

Part E:  patients with melanoma

Part F:  patients with HR+ breast cancer, NSCLC, or melanoma and LM
The period between assignment to abemaciclib in IWRS and the first dose (Cycle 1, Day 1) 
should not exceed 7 days.
9.4.
Selection and Timing of Doses
Abemaciclib will be taken orally every 12 (± 2) hours on Days 1 through 21 of a 21-day cycle
according to Table JPBO.1, for a total of 42 doses per cycle. During all cycles, abemaciclib 
should be taken at approximately the same times each day. If a patient misses or vomits a dose, 
that dose should be omitted.
A cycle is defined as an interval of 21 days plus any subsequent delay prior to start of the next 
cycle. A delay in the start of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances will be permitted up to 7 days and not counted as a protocol deviation. 
In exceptional cases, for planned delays (including but not limited to vacation or holidays), 
additional abemaciclib may be dispensed.  
A patient may continue to receive abemaciclib until meeting 1 or more of the specified reasons 
for discontinuation (as described in Section 7.3).


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9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
Table JPBO.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study
I3Y-MC-JPBO
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 9.4.1.1.3
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 9.4.1.1.3
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 9.4.1.1.3
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
Sections 9.4.1.1.3 and 9.6.4
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 
led to the use of growth 
factor.
Nonhematologic Toxicitya
(except diarrhea and ALT 
increased)
Section 9.4.1.1.4
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 9.4.1.1.4
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 9.4.1.1.4.1 and 9.6.5
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 9.4.1.1.4.1 and 9.6.5
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 9.4.1.1.4.1 and 9.6.5
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-JPBO
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
ALT Increased 
(Sections 9.4.1.1.4.2 and 
10.3.4.1)
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 9.4.1.1.4.2 and 
10.3.4.1)
Grade 4 (>20.0×ULN)
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST be 
discontinued.
ALT Increased with increased 
total bilirubin, in the absence 
of cholestasis
(Sections 9.4.1.1.4.2 and 
10.3.4.1)
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
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 renal and hepatic monitoring is in Sections 10.3.3.1 and 10.3.3.2.
b Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:
•
shows stable hematological counts (Grade ≤2) during that timeframe
•
has absence of any signs or risk of infection 
•
is benefiting from study treatment
c
Note: the patient who presents with no liver metastases at baseline.
d Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
10.3.4.1 for additional guidance for hepatic monitoring
9.4.1.1.1. Dose Adjustments
Abemaciclib dose adjustments, as outlined in Table JPBO.3 are allowed both within a cycle and 
between cycles.  Abemaciclib must be reduced sequentially by 1 dose level.  
For patients requiring dose reduction(s), any reescalation to a prior dose level is permitted only 
after consultation with the Lilly CRP.  
Table JPBO.3.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBO
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
Abemaciclib must be discontinued if further dose reduction is required beyond 100 mg every 
12 hours.  
9.4.1.1.2. Dose Suspension (within a Cycle) and Cycle Delay
Both abemaciclib dose suspension (within a cycle) and cycle delay are permitted up to 14 days to 
allow sufficient time for recovery from a toxicity (defined as an AE possibly related to 


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abemaciclib per the investigator’s judgment).  Patients not recovering from toxicity within 
14 days should be considered for discontinuation of abemaciclib.  In exceptional circumstances, 
a delay >14 days is permitted upon agreement between the investigator and the Lilly CRP, and 
abemaciclib dose adjustment is to be considered.  
In the event of a cycle delay due to logistical reasons (for example, due to patient availability), 
the patient should continue on abemaciclib if the patient has adequate drug supply.  If a patient’s 
treatment is interrupted as a result of not having sufficient drug supply, the cycle may be delayed 
up to 7 days (and not be considered a protocol violation). In exceptional circumstances, a delay 
>7 days is permitted upon agreement between the investigator and the Lilly CRP. 
An interruption in Cycle 1 dosing or a delay in the initiation of Cycle 2 may occur in order to 
allow patients participating in Part C to undergo surgical resection.  For additional information, 
refer to Section 9.6.2.  
9.4.1.1.3. Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2), and the dose of abemaciclib must be reduced by 1 dose 
level as outlined in Table JPBO.3.
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of abemaciclib may be reduced by 1 dose level
as outlined in Table JPBO.3 at the discretion of the investigator.  If the patient experiences a 
recurrent episode of Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of abemaciclib must be reduced by 1 dose 
level.
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
The patient showed stable hematological counts (Grade ≤2) during that timeframe
•
In the absence of any signs or risk of infection 
•
The patient is benefiting from study treatment
If a patient requires administration of blood cell growth factors, the dose of abemaciclib must be 
suspended for at least 48 hours after the last dose of blood cell growth factors was administered 
and until toxicity resolves to at least Grade 2, then must be reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
Before re-initiation of abemaciclib, hematologic toxicity must resolve to either baseline or at 
least Grade 2.  


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9.4.1.1.4. Nonhematologic Toxicity
If a patient experiences ≥Grade 3 nonhematologic toxicity, 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 by 1 dose level as outlined in Table JPBO.3.  
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea, 
refer to Section 9.4.1.1.4.1 or ALT increased, refer to Section 10.3.4.1) that does not resolve with 
maximal supportive measures within 7 days to either baseline or Grade 1, then dosing of 
abemaciclib must be suspended (until the toxicity resolves to either baseline or Grade 1), and the 
dose of abemaciclib must be reduced by 1 dose level as outlined in Table JPBO.3 at the 
discretion of the investigator.  
Before re-initiation of abemaciclib, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or Grade 1.
9.4.1.1.4.1.
Diarrhea
A patient experiencing diarrhea requiring hospitalization (irrespective of grade; that is, requiring 
IV rehydration) or severe diarrhea (Grade 3 or 4) must have dosing suspended (until the toxicity 
resolves to at least Grade 1) and must have the abemaciclib dose reduced by 1 dose level as 
outlined in Table JPBO.3.  
If a patient experiences Grade 2 diarrhea that does not resolve with maximal supportive measures 
(refer to Section 9.6.5) within 24 hours to at least Grade 1, the study drug must be suspended 
(until the toxicity resolves to at least Grade 1) but abemaciclib dose reduction is not required. 
However, if a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve 
with maximal supportive measures (refer to Section 9.6.5) within 24 hours to at least Grade 1, 
then dosing must be suspended (until the toxicity resolves to at least Grade 1), and the dose of 
abemaciclib must be reduced by 1 dose level as outlined in Table JPBO.3.
9.4.1.1.4.2.
Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBO.3. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, abemaciclib must be 
suspended until the toxicity has resolved to at least Grade 1 and the dose must be reduced by 1 
dose level. Discontinue abemaciclib for Grade 3 increased ALT (˃5.0 x ULN) with total 
bilirubin (TBL) >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, the patient 
must be discontinued from abemaciclib.  Refer to Section 10.3.4.1 for additional hepatic 
monitoring guidance.
9.5.
Blinding
This is an open-label study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRF.  Concomitant medications and 


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supportive care therapies must also be documented at the time of discontinuation and at the 
30-day short-term follow-up visit.  
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, radiation, surgery for cancer, or 
experimental medications will be permitted while patients are on abemaciclib.  Use of megestrol 
acetate as an appetite stimulant is not permitted for patients with breast cancer.
In vivo in humans, abemaciclib is extensively metabolized through oxidation.  Additionally, the 
results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study indicate 
that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4. Based on these
findings, grapefruit juice as well as inducers and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 10).  Concurrent treatment with EIAED is not 
permitted while on abemaciclib.  Patients requiring treatment with antiepileptic drugs should be 
prescribed a non-EIAED (eg, levetiracetam, lacosamide, lamotrigine, etc).  Although 
dexamethasone is a CYP3A4 inducer, use during the study is allowed.  The dose of 
corticosteroids, including dexamethasone, will be captured throughout the study, with an 
emphasis on recording changes in dose at the time of intracranial tumor assessments.  
In addition, in vitro studies in primary cultures of human hepatocytes indicate that abemaciclib 
and its significant metabolites LSN2839567 and LSN3106726 down regulate mRNA of 1 or 
more CYPs including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A at 
clinically relevant concentrations.  The mechanism of down regulation and its clinical relevance 
are presently not understood.  Therefore, caution should be exercised when coadministering 
substrate drugs of the above CYPs with narrow therapeutic margin (see Attachment 10).
9.6.1. Permitted Combination Therapies
Patients with HR+ breast cancer in Parts A, B, and F receiving endocrine therapy prior to study 
entry may continue to receive the same endocrine therapy throughout the study treatment period 
per the respective label provided that extracranial disease is stable for at least 3 months and CNS
disease progression has occurred while on this endocrine therapy.  If these conditions are not 
met, patients must discontinue endocrine therapy prior to initiation of abemaciclib.  These 
patients may not initiate endocrine therapy immediately prior to study entry or at any time during 
the study.  Part C patients may continue or initiate endocrine therapy concurrently with 
abemaciclib and need not meet the above conditions. Additionally, patients with HER2+ breast 
cancer in Parts A, C, and F may receive concurrent trastuzumab per the label throughout the 
study treatment period provided trastuzumab is initiated prior to or concurrently with the 
initiation of abemaciclib.  
For NSCLC patients in Parts D and F who are receiving gemcitabine or pemetrexed (single-
agent or in combination with another therapy) prior to study entry, these patients may continue to 
receive 1 of these 2 therapies as a single-agent provided that extracranial disease is stable for at 
least 6 weeks and CNS disease progression has occurred while on this therapy.  Combination 
therapies (aside from gemcitabine or pemetrexed) must be discontinued at least 14 days prior to 


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initiation of abemaciclib.  Part C patients may continue or initiate gemcitabine or pemetrexed (as 
single agents) concurrently with abemaciclib and need not meet the above conditions.
Changes (i.e., switching from one therapy to another) in concomitant therapy after study entry 
are not permitted.  Patients requiring a change in concomitant therapy should be assessed for PD 
and be discontinued from abemaciclib. However, in the absence of PD, patients may discontinue 
concomitant therapy (i.e., in cases of intolerable toxicity) and continue abemaciclib.
9.6.2. Surgery
A patient in Part C with brain lesions for which surgical resection is clinically indicated may 
undergo surgery following 5 to 14 days of treatment with abemaciclib. Abemaciclib should be 
taken 6 to 12 hours prior to surgical resection of brain lesions in order to accommodate 
assessment of drug concentrations in tumor tissue.  These patients may resume abemaciclib 
dosing at least 15 days but no greater than 21 days postoperatively to allow adequate time for 
wound healing.  Patients requiring WBRT or SRS following surgery must be permanently 
discontinued from abemaciclib.  
9.6.3. Supportive Care
Patients should receive full supportive care to maximize quality of life.  Patients will receive 
supportive care as judged by their treating physician.  If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported on the eCRFs.  
9.6.4. Growth Factor
Growth factors should not be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).
Dosing of abemaciclib must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered. Following the administration of growth factors, the dose of abemaciclib must be 
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.  
9.6.5. Supportive Management for Diarrhea
At enrollment, patients should receive instructions on the management of diarrhea. 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 (eg,
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up.

Patients should also be encouraged to drink fluids (eg, 8 to 10 glasses of clear liquids per 
day).

Site personnel should assess response within 24 hours.


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
If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least Grade 1, 
then dosing of abemaciclib should be suspended until diarrhea is resolved to at least
Grade 1.

When abemaciclib recommences dosing should be adjusted as outlined in 
Sections 9.4.1.1.1, 9.4.1.1.2, and 9.4.1.1.4.1.
9.7.
Treatment Compliance
Patient compliance with abemaciclib dosing will be assessed by capsule counts at each visit, with 
the number of capsules taken relative to the number expected to be taken summarized for each 
cycle. The patient must take ≥75% of the planned doses of abemaciclib in a cycle to be deemed 
compliant. As outlined in Section 9.4.1.1.2, dose suspensions or delays may occur and will not 
result in a patient being considered as noncompliant. A patient may be considered noncompliant 
if he or she is judged by the investigator to have intentionally or repeatedly taken ≥125% of the 
planned doses of abemaciclib in a cycle.
A patient enrolled in Part C who undergoes resection of brain metastases will not be considered 
noncompliant for doses of abemaciclib withheld in conjunction with surgery and will not incur a 
protocol deviation. For additional information, refer to Section 9.6.2. 


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10.
Efficacy, Health Outcome/Quality of Life Measures, 
Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations. 
Study procedures related to efficacy, safety, health outcome/quality of life measures, sample 
collection, and testing assessments and their timing are described in the sections below and 
shown in the Study Schedule (Attachment 1).  
10.1. Efficacy Measures 
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 28 days before the first dose of abemaciclib, baseline tumor measurements will be 
performed for each patient.  Intracranial tumor assessments will be performed by Gd-MRI 
according to RANO-BM (Attachment 5). Extracranial tumor assessments will be performed 
according to RECIST v1.1 (Attachment 6).  Computed tomography (CT) scans, including spiral 
CT scans, and MRI are the preferred methods of measurement of extracranial disease. For 
melanoma patients with visible lesions, photography will be performed at baseline and each 
photographic image of the lesion should include a ruler.  In addition, for Part F patients only, Gd-
MRI of the spine should be performed (see Attachment 1).
For patients with progressive intracranial disease, Gd-MRI acquired prior to study screening 
must be provided to confirm PD on the baseline intracranial tumor assessment.  Additionally, in 
order to document stable extracranial disease for patients receiving concomitant therapies 
outlined in Section 9.6.1, CT scan or MRI of extracranial lesions acquired at least 3 months
(endocrine therapy) or 6 weeks (gemcitabine or pemetrexed) prior to study screening must be 
provided.  
The method of radiological assessment used at baseline must be used consistently for tumor 
assessment and will be repeated between Day 14 and Day 21 of every other cycle beginning with 
Cycle 2 and continuing through Cycle 8; thereafter, tumor assessments will be repeated between 
Day 14 and Day 21 of every fourth cycle (beginning with Cycle 12). Visible lesions will be 
assessed on Day 1 of every other cycle beginning with Cycle 3, or more frequently as clinically 
indicated.
Intracranial and extracranial responses (CR or PR) must be confirmed no less than 28 days from 
the first evidence of response.
During the continued access period, efficacy assessments (frequency and type of assessments) 
will be completed at the discretion of the investigator.  


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10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1). 
For those patients who discontinue abemaciclib without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response 
approximately every 6 weeks for the first 6 months following initiation of abemaciclib and 
thereafter approximately every 12 weeks by the same method used at baseline and throughout the 
study until the patient has objective disease progression, or until the final analysis of OS.  If a 
patient’s most recent response prior to discontinuation is a PR or CR, an additional radiological 
assessment should be performed during the 30-day follow-up period to confirm the response, at 
least 28 days after the previous radiological assessment.  Response should be confirmed before 
the initiation of additional anticancer therapy.  However, initiation of new therapy should not be 
delayed solely to confirm response.  After the patient has objective disease progression, 
radiologic tests are no longer required, and the patient will be followed up approximately every 
90 days until the patient’s death or overall study completion.  
Lilly will continue to collect survival data on all patients but may reduce data collection for other 
efficacy data.  Lilly will notify investigators when this reduced data collection can begin.  
10.1.3. Primary Efficacy Measure
The primary efficacy measure is OIRR (CR + PR) as defined by RANO-BM (see Attachment 5).
A partial intracranial response is defined as ≥30% decrease in sum of LD of up to 5 target brain
lesions sustained for at least 4 weeks in the absence of progression of nonmeasurable brain 
lesions, new brain lesions, increased corticosteroid dose, or clinical worsening.  
Best response is determined from the sequence of responses assessed.  
A second assessment must be performed ≥28 days after the first evidence of response.  
Two objective status determinations of CR before progression are required for a best response of 
CR.  Two determinations of PR or better before progression, but not qualifying as a CR, are 
required for a best response of PR.  Best response of SD is defined as disease that does not meet 
the criteria for CR, PR, or PD and has been evaluated at least 1 time, at least 35 days after the 
start of abemaciclib. 
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
of objective progression or start of new anticancer therapy.  Any responses observed after 
objective progression or the start of new anticancer therapy are excluded from the determination 
of best response.  
The date of first documented objective disease progression must be recorded on the eCRF even if 
it occurs after the patient has started a new therapy.  


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Lilly or its designee will collect and store tumor assessment images (including photographs of 
visible lesions), and an independent review of imaging scans may be performed by Lilly or its 
designee. 
The OIRR is estimated as the total number of confirmed CRs and PRs divided by the total 
number of evaluable patients enrolled. The primary analysis of OIRR for each study Part (A, B, 
D, or E) will occur approximately 6 months after up to 56 evaluable patients have been enrolled 
into each respective part. This is to ensure adequate durability of response data is available at the 
time of analysis. An evaluable patient is defined as a patient who has ≥1 measurable brain lesion 
at the time of enrollment (per RANO-BM) and for whom at least 1 post-baseline overall 
response assessment for intracranial disease is available. 
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBO.4) will be collected at the times shown 
in the Study Schedule (Attachment 1).  


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Table JPBO.4.
Secondary Efficacy Endpoints
Endpoint
Definition
Best overall intracranial 
response (BOIR)
Derived to encompass all tumor assessments (according to RANO-BM) from 
baseline until the earliest of objective progression (intracranial or extracranial 
according to brain metastases response criteria or RECIST v1.1, respectively) or 
start of new anticancer therapy. Any responses observed after objective 
progression (intracranial or extracranial) or the start of new anticancer therapy are 
excluded from the determination of best response.  Each patient’s BOIR will be 
categorized as CR, PR, SD, PD, or NE.
Duration of intracranial 
response (DOIR) (CR + PR) 
Defined only for responders (patients with a confirmed CR or PR, as defined in 
Section 10.1.3). It is measured from the date of first evidence of a confirmed 
response (CR or PR as defined by brain metastases response criteria) to the date 
of investigator-determined objective progression (intracranial or extracranial as 
defined by RANO-BM or RECIST v1.1, respectively) or death from any cause. 
Patients who have neither progressed nor died will be censored on the day of their 
last radiographic tumor assessment (if available) or on the date of response (CR or 
PR as defined by brain metastases response criteria) if no radiographic assessment 
is available.
Intracranial disease control 
rate (IDCR) 
Defined as the proportion of patients with BOIR of CR, PR, or SD (according to
RANO-BM).
Intracranial clinical benefit 
rate (ICBR)
Defined as the proportion of patients with BOIR of CR, PR, or SD with duration 
of SD for at least 6 months (according to RANO-BM).
Overall survival (OS)
Measured from the date of enrollment to the date of death from any cause. For 
each patient who is not known to have died as of the data-inclusion cutoff date for
a particular analysis, OS will be censored for that analysis at the date of last 
contact prior to the data inclusion cutoff date (contacts considered in the 
determination of last contact date include AE date, tumor assessment date, visit 
date, and last known alive date).  Patients will be followed for OS for 18 months 
following the last patient entering treatment in each study part (Parts A or B).
Objective response rate
(ORR) per RECIST v1.1
and brain metastases 
response criteria
The percentage of patients with a best response of CR or PR as defined by 
RECIST v1.1 and RANO-BM.
Disease control rate (DCR)
Defined as the proportion of patients with best overall response of CR, PR, or SD 
(according to RECIST v1.1 and RANO-BM).
Progression-free survival
(PFS)
Measured from the date of enrollment to the date of investigator-determined
objective progression (intracranial or extracranial as defined by RANO-BM or 
RECIST v1.1, respectively) or death from any cause. Patients who have neither 
progressed nor died will be censored at the day of their last radiographic tumor
assessment (if available) or date of enrollment if no postinitiation (that is, 
postbaseline) radiographic assessment is available.
Abbreviations:  AE = adverse event; CR = complete response; NE =not evaluable; PD = progressive disease; 
PR = partial response; RANO-BM = Response Assessment in Neuro-Oncology brain metastases 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.  


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10.1.5. Exploratory Measures
The following exploratory measures (Table JPBO.5) will be collected at the times shown in the 
Study Schedule (Attachment 1).
Table JPBO.5.
Exploratory Endpoints
Endpoint
Definition
Trail Making Test
To assess neurocognitive function using Trail Making Tests A and B. Each test is 
administered by trained site staff and has a time limit (180 seconds for Test Part A 
and 300 seconds for Test Part B).  The score for each test is determined by either 
the time in seconds to complete the test or the last number or letter reached at the 
time limit (Reitan 1992; Wefel et al. 2011).
NANO scale
Clinical assessment of change in neurological signs using the NANO scale, which 
consists of 9 domains (gait, strength, ataxia, sensation, visual fields, facial 
strength, language, level of consciousness, and behavior).  A modified version of 
the NANO scale (consisting of 11 domains, including gait, strength, sensation, 
vision, eye movements, facial strength, hearing, swallowing, level of 
consciousness, behavior, and other) has been adapted for patients with LM and 
will be used to assess all Part F patients.
Concentration of 
abemaciclib and its 
metabolites 
To explore the concentration of abemaciclib and its metabolites in plasma, CSF, 
and brain tumor tissue collected at the time of surgical resection for patients 
participating in Part C, as well as patients in Parts A and B with PD and planned 
surgical resection.
Biomarkers
To explore biomarkers related to the mechanism of action of abemaciclib, the cell 
cycle, and/or the pathogenesis of breast cancer, NSCLC, and melanoma.
Effect in patients with
leptomeningeal metastases
To assess response of patients with LM by applying proposed RANO-LM 
assessment criteria.
Abbreviations:  CSF = cerebrospinal fluid; NANO = Neurologic Assessment in Neuro-Oncology; NSCLC = non-
small cell lung cancer; PD = progressive disease, RANO-LM = Response Assessment in Neuro-Oncology 
leptomeningeal metastases
10.2. Health Outcome/Quality of Life Measures
Patient-reported symptoms will be assessed with the self-administered MDASI-BT on paper.  
The MDASI-BT assessment will be completed per the Study Schedule (Attachment 1). 
The MDASI-BT should be completed at the beginning of office visits, before any extensive 
contact and consultation with the clinician/study investigator in regards to the tumor 
assessments. Discussion with the clinician may bias perceptions about symptoms and thus affect 
assessments.  
The MDASI-BT will only be completed by patients for whom there is a valid translation in a 
language in which the patient is fluent.  
10.2.1. Patient-Reported Outcomes
10.2.1.1. MD Anderson Symptom Inventory – Brain Tumor Module
The MDASI-BT is a reliable and valid instrument to assess symptoms in patients with brain
metastases (Armstrong et al. 2009; Meyers and Brown 2006).  The MDASI-BT consists of 


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22 symptom items (13 items of the core MDASI plus 9 items specific to brain tumors) plus 6 
interference items, all with 11-point rating scales.  For the symptom items, 0 equals “not present” 
and 10 equals “as bad as you can imagine.”  For the interference items, 0 equals “did not 
interfere” and 10 equals “interfered completely.”  The MDASI-BT may be scored by reporting
the individual items or by calculating the means of all symptom items and of all interference 
items.  The means of the core and brain tumor items may be reported separately. The
22 symptom items may also be grouped by their underlying constructs:  (1) affect; (2) cognition; 
(3) focal neurologic deficit; (4) treatment-related symptoms; (5) generalized/disease status 
symptoms; and (6) gastrointestinal symptoms.  
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of patients during the study.  
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator.  
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JPBO.6 presents a summary of AE and SAE reporting guidelines and also shows which 
database or system is used to store AE and SAE data.  


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Table JPBO.6.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or abemaciclib
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving abemaciclib and no 
longer in follow-up)
All SAEs related to protocol procedures 
or abemaciclib that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.  
Lack of drug effect is not an AE in clinical trials because the purpose of the clinical trial is to 
establish drug effect.  
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, and other study procedures that result in a diagnosis should be reported to Lilly or 
its designee.  
Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported.  If a 
patient is determined to be pregnant following abemaciclib initiation, she must discontinue 
treatment immediately.  Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation.  
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.  
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.  


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In addition, the investigator will record all relevant AE/SAE information in the CRF.  
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drug via eCRF.  
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study drug, study procedure, or other concomitant treatment or pathologies.  To assess the 
relationship of the AE to study drug or study procedure, the following terminologies are defined:  

Probably related:  a direct cause and effect relationship between the study drug and the 
AE is likely

Possibly related:  a cause and effect relationship between the study drug and the AE has 
not been demonstrated at this time and is not probable but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study drug
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug or study procedure.  
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.  
The National Cancer Institute (NCI)- Common Terminology Criteria for Adverse Events
(CTCAE) v4.0 will serve as the reference document for choosing appropriate terminology for, 
and grading the severity of, all AEs and other symptoms.  For AEs without matching 
terminology within the NCI-CTCAE v4.0 criteria, the investigator will be responsible for 
selecting the appropriate System Organ Class (SOC) and assessing severity grade based on the 
intensity of the event.  
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary.  
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.  
10.3.1.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:  

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 


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medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition.  
SAE collection begins after the patient has signed informed consent and has received 
abemaciclib.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving abemaciclib, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.  
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.  
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If study site personnel contact Lilly or 
its designee by telephone regarding an SAE, study site personnel must also immediately provide 
official notification on study-specific SAE forms.  
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.  
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.  
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of abemaciclib or other protocol-required procedure) should not 
be considered SAEs.  
SAEs due to disease progression, including death, should not be reported unless the investigator 
deems them to be possibly related to the study drug.  
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study drug, the investigator should report the SAE 
to the sponsor, and the SAE will be entered in the Lilly Safety System.  
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the DCSI in the IB and that the investigator identifies as related to the study drug or study 
procedure.  US 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 


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and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.
10.3.2. 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 (See 
Section 3.2.4 of the abemaciclib IB for additional background).  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, discontinuation) should not solely be based on interpretation of 
serum creatinine values because these may not reflect renal function.
10.3.3. Other Safety Measures
10.3.3.1. Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule (see
Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. ECGs may be obtained at 
additional times, if clinically indicated.  
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 for immediate patient management, should any clinically relevant findings be identified. 
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.  
10.3.3.2. Echocardiograms or Multi-Gated Acquisition Scans
For only those HER2+ breast cancer patients receiving concurrent IV trastuzumab during the 
study, an echocardiogram or multi-gated acquisition (MUGA) scan is required within 28 days of 
initiation of abemaciclib (Attachment 1).  Per the trastuzumab prescribing information
(Herceptin [trastuzumab] highlights of prescribing information, 2014 and Herceptin 
[trastuzumab] summary of product characteristics, 2014), continued cardiac function monitoring
throughout treatment is recommended but is not required as a protocol procedure.
10.3.4. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.  


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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist and review:  

trends in safety data

laboratory analytes 

AEs

If a patient experiences elevated ALT or AST >5× ULN and elevated total bilirubin 
>2× ULN, clinical and laboratory monitoring should be initiated by the investigator. For 
patients entering the study with ALT or AST >3× ULN in the presence of liver 
metastases, monitoring should be triggered at ALT >2× baseline.  

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests (See Attachment 3).
10.3.4.1. 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 with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
10.3.4.2. Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.


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Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPBO.3).
10.3.4.3. Venous Thromboembolic Events (VTEs)
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (e.g., deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice. In studies with single-
agent abemaciclib use in the mBC population or other tumor types, including NSCLC, no 
increased rates of VTEs were observed as compared to the incidence of VTEs for these particular 
patient populations who were treated with other anticancer agents.  
10.3.5. Complaint Handling
Lilly collects product complaints on study drug used in clinical trials in order to ensure the safety 
of study participants, monitor quality, and to facilitate process and product improvements.  
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.  
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.  
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.  
Attachment 7 provides a schedule of ECG collection and PK sampling during the study for 
patients in Parts A and B.  
Attachment 8 provides a schedule of ECG collection and PK sampling during the study for 
patients in Part C.
Attachment 9 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.  


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10.4.1. 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.
10.4.2. Samples for Biomarkers 
Required samples for biomarker research to be collected from all patients enrolled in this study 
are the following:

whole blood

plasma

archived tumor tissue
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.  Similar analyses may be 
performed with brain tumor tissue and CSF collected from patients undergoing surgical resection
(Section 10.4.3.1).
These samples are described in the following sections.
10.4.2.1. Blood Samples for Pharmacogenetic Evaluations
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Samples may be genotyped and analysis may be performed to evaluate a genetic association with 
response or lack of response to abemaciclib.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to 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 abemaciclib.
Samples will be destroyed according to a process consistent with local regulation.


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10.4.2.2. Plasma Samples for Exploratory Biomarker Evaluations
Ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma samples will be collected and 
analysis may be performed on biomarkers that may play a role in the abemaciclib mechanism of 
action (refer to Attachment 1).  The evaluation of these samples may involve analysis of DNA, 
RNA, and proteins (including any of these components derived from exosomes) to investigate 
their association with observed clinical outcomes to abemaciclib.  The samples will be coded 
with the patient number and stored for up to 15 years.  Details for collecting, processing, and 
storing the samples are similar those provided in Section 10.4.2.1.
10.4.2.3. Archived Tumor Tissue
For patients in the study, a small amount of archival, preserved tumor tissue is required to be 
provided by sites upon patient assignment to abemaciclib for biomarker research. However, if 
this sample is not available for a patient, this should be discussed with the sponsor.  A protocol 
deviation will not be incurred, and the patient is still eligible for the study.
Available formalin-fixed, paraffin-embedded archived primary and/or metastatic tumor tissue 
should be in a whole block, partial block, or 20 unstained slides, cut at 5 microns, and 
1 hematoxylin and eosin (H&E) slide containing tumor specimen will be requested, if available,
to be used for exploratory analysis.  Due diligence should be used to make sure that a 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. 
In tumor tissue samples, the CDK4 and CDK6 pathway components (for example, Rb and its 
targets) and markers relevant to breast cancer pathogenesis may be evaluated to assess any 
potential correlation with response to abemaciclib.  These studies will be performed in a 
laboratory designated by the sponsor and may include, but are not limited to, IHC of proteins, 
fluorescence in-situ hybridization (FISH) for copy number alterations, mRNA gene-expression 
profiling, and/or genetic analyses of the tumor DNA.  Such analyses may employ targeted or 
high-throughput sequencing approaches.  For this purpose, the results of this analysis will be 
correlated with clinical efficacy data.  
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics 
PK samples will be collected for Parts A B, D, E, and F as specified in the Pharmacokinetic 
Sampling Schedule (Attachment 7). A separate Pharmacokinetic Sampling Schedule 
(Attachment 8) is provided for patients participating in Part C.
At the visits and times specified in the Pharmacokinetic Sampling Schedules (Attachment 7 and 
Attachment 8), venous blood samples of approximately 2 mL each will be collected to determine 
the plasma concentrations of abemaciclib and its metabolites.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  It 
is preferred that the blood samples be obtained from a peripheral location.  Blood samples will 
be allowed from central access devices, but precautions must be taken to prevent obtaining a 


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dilute sample when the sample is drawn for PK from a central catheter of any type.  If multiple 
samples are obtained centrally, the PK sample should be the last specimen drawn to reduce the 
potential for a diluted or improperly drawn sample.  The actual date and time (24-hour clock 
time) of each sampling will be recorded. A maximum of 5 samples may be drawn at additional 
time points during the study if warranted and agreed upon between both the investigator and 
Lilly.  
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 the
study site.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib and its metabolites will be assayed using a validated liquid 
chromatography-tandem mass spectrometry (LC/MS/MS) method.
Bioanalytical samples collected to measure abemaciclib concentration and metabolism and/or 
protein binding will be retained for a maximum of 1 year following last patient visit for the 
study.  The PK samples will be stored at a facility designated by the sponsor.
10.4.3.1. Drug Concentrations for Parts C and F Patients
Time-matched blood and CSF samples will be collected for exploratory measurement of 
abemaciclib and, if deemed necessary, the concentrations of its metabolites. These samples will 
be collected at the time of surgery for patients participating in Part C, and on Cycle 3 Day 1 and 
as clinically indicated for patients participating in Part F.  In addition, resected brain tumor 
samples will be collected from patients participating in Part C for exploratory measurement of 
abemaciclib and, if deemed necessary, the concentrations of its metabolites.  Separate samples 
are not required for the parent and its metabolites. Supplies and instructions for the collection 
and handling of blood, CSF, and tumor samples will be provided by the sponsor.  In cases where 
collection of CSF is not feasible, a missing sample will not be considered a protocol deviation.  
Plasma, CSF, and resected tumor samples will be analyzed at a laboratory designated by the 
sponsor.  Concentrations of abemaciclib and, if deemed necessary, its metabolites will be 
explored using an LC/MS/MS method. .
Local histopathology results for resected tissue should confirm the presence of tumor tissue.  In 
cases where tumor tissue is not confirmed by histopathology report, the Sponsor must be 
notified.  The remaining submitted tumor tissue and CSF samples after drug concentration 
measurements may be used for additional analyses including, but not limited to, nucleic acid and 
protein profiles to better understand the disease process and to develop predictive biomarkers.
10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between effective and ineffective 
agents.


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Safety measurements by laboratory monitoring are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between agents with acceptable and 
unacceptable safety profiles.


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11.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the 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 use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.  
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.  
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
eCRF data will be encoded and stored in a clinical trial database.  Data managed by a central 
vendor, such as laboratory test data, will be stored electronically in the central vendor’s database 
system.  Data will subsequently be transferred from the central vendor to Lilly.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this clinical trial is to estimate the antitumor activity, measured by 
OIRR of abemaciclib in patients with brain metastases secondary to HR+ breast cancer, NSCLC 
or melanoma.  
Separate Simon 2-stage designs (Simon 1989) will be employed for this study, including; Part A 
(patients with HR+, HER2+ breast cancer), Part B (patients with HR+, HER2- breast cancer), 
Part D (patients with NSCLC), and Part E (patients with melanoma). Each design assumes a 1-
sided type-I error of 0.05 and 80% power.
For Part A, up to 56 evaluable patients will be enrolled with the possibility of stopping the study 
early for either lack of efficacy or unacceptable toxicity. Twenty-three evaluable patients will be 
enrolled in the first stage. If fewer than 2 of the first 23 evaluable patients respond to 
abemaciclib, accrual will be stopped, and the conclusion will be drawn that abemaciclib is not 
worthy of further study in the Part-A population. If at least 2 of the first 23 evaluable patients 
respond to therapy, accrual will continue until 33 additional evaluable patients have been 
enrolled. A total of 6 responders out of 56 evaluable patients in Part A would need to be 
observed to warrant further investigation of abemaciclib in this patient population.  
The procedure described above tests the null hypothesis (H0) that the true OIRR of abemaciclib 
in Part A is ≤5% versus the alternative hypothesis (Ha) that the true OIRR is 15%.  The 
probability of early termination of the treatment arm under H0 is 0.68.  
Parts B, D, and E will have the identical design as Part A.
Assuming approximately 20% screening failure, the study will enter approximately 309 patients.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.  
Safety analyses will be conducted on the full analysis set (FAS).  This set includes all data from 
all enrolled patients receiving at least 1 dose of abemaciclib.  
Efficacy analyses will be conducted on the FAS population and in the OIRR evaluable 
population when appropriate.  The FAS includes all data from all enrolled patients receiving at 
least 1 dose of abemaciclib.  The OIRR evaluable population is defined as patients receiving at 
least 1 dose of abemaciclib who have ≥1 measurable brain lesion at the time of enrollment (per 
RANO-BM) and for whom at least 1 post-baseline overall response assessment for intracranial 
disease is available.
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected.


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Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.  
All tests will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.  All tests of 
interactions will be conducted at a 2-sided alpha level of 0.1, and all confidence intervals (CIs)
will be given at a 2-sided 95% level, unless otherwise stated.  
Unless otherwise stated, all analyses will be conducted on each study part separately. Pooled 
analyses including patients from all 3 parts will be conducted when applicable.  
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.  
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided. 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 discontinuation will be given.
A summary of all important protocol deviations will be provided.  
12.2.3. Patient Characteristics
Patient demographics including age, sex, screening height and weight, and screening body mass
index will be reported using descriptive statistics.  
Baseline disease characteristics will be summarized by presenting frequency counts and
percentages for pathological diagnosis (histological or cytological), disease stage, or
performance status.  
Preexisting conditions, historical illnesses, and prior chemotherapy (including both cytotoxic and 
targeted agents) will be summarized.  
Other patient characteristics will be summarized as deemed appropriate.  
12.2.4. Concomitant Therapy
Concomitant medication will be summarized in a frequency table listing the terms recorded on 
the eCRF.  


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12.2.4.1.Postdiscontinuation Therapy 
The numbers and percentages of patients reporting postdiscontinuationanticancertherapies will 
be provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.  
12.2.5.Treatment Compliance 
The number of dose omissions, reductions, delays, cycles received, and dose intensity will be 
summarized for all treated patients.  
Treatment compliance information for abemaciclibwill be collected through pill counts at each 
visit.  The estimate of percent compliance will be given by:
Percent Compliance=
Actual cumulative dose taken
Expected cumulative dose to be takenx100
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed.  The 
expected cumulative dose to be taken will be determined based on the assigned dose and will 
take into account any dose reductions or omissions.  
12.2.6.Primary Outcome and Methodology
The primary endpoint of this study is OIRR assessed using RANO-BM(see Attachment 5)in the 
OIRR evaluable population. The OIRR will be reported along with 95% CIsusing the normal 
approximation. 
12.2.7.Secondary Outcome and Methodology
The secondary objectives for this study are stated in Section6.2; secondary efficacy measures
aredefined in Section10.1.4.  
Point estimates and 95% CIs(using the normal approximation to the binomial) will be calculated 
for BOIR, IDCR, ICBR, ORR, and DCRfor PartsA,B, D,and E.  
Time-to-event efficacy endpoints (OS, PFS, and DOIR) will be summarized for PartsA,B, D,
and Eusing Kaplan-Meier techniques (Kaplan and Meier 1958) if there is sufficient data. If 
performed, Kaplan-Meier curves will be generated, and quartiles and point probabilities will be 
calculated. Interval estimates will be calculated using 95% CIs (Brookmeyer and Crowley 
1982).  
12.2.8.Pharmacokinetic and/or Pharmacodynamic Analyses
PKanalyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected (seePharmacokineticSampling SchedulesinAttachment 7and 
Attachment 8).  
Mean population PK parameters for abemaciclibin plasma (clearance, exposure, volume of 
distribution, and half-lives) and interindividual PK variability will be computed using nonlinear 
mixed effect modeling (NONMEM).  The current PK model for abemaciclib, which has been 


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developed using plasma concentration data available from the Phase 1 Study JPBA, will be 
updated using the plasma data collected in this study.  Covariate effects (such as age, weight, 
sex, creatinine clearance, and plasma protein levels) on the PK parameters of abemaciclib in 
plasma will also be investigated.
Finally, pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood, 
OIRR, PFS, or OS ) collected in this study may also be analyzed by means of NONMEM and 
connected to the population PK model in a PK/pharmacodynamic model.  
The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.9. Exploratory Analyses
12.2.9.1. Trail Making Tests A and B
Neurocognitive function will be assessed using Trail Making Tests A and B.  Summary statistics 
will be provided by study part and each response category (CR/PR, SD, and PD). Change from 
baseline and time to worsening will be explored. 
12.2.9.2. Neurologic Assessment in Neuro-Oncology Scale
Clinical response and progression will be explored and summarized for the NANO scale using 
descriptive statistics.  Neurologic response will be defined as an improvement of ≥2 on any 
single domain in the absence of deterioration in other domains.  Neurologic progression will be 
defined as worsening of ≥2 from baseline on any single domain.  These results may be compared 
with objective tumor assessment results.  
12.2.9.3. Drug Concentrations in Samples from Parts C and F Patients
The relative concentrations of abemaciclib and its metabolites in time-matched samples of
plasma, CSF, and tumor tissue collected at the time of surgical resection for patients participating 
in Part C will be explored. In addition, the relative concentrations of abemaciclib and its 
metabolites in time-matched samples of plasma and CSF collected on Cycle 3 Day 1, as well as 
any other time the collection of CSF is clinically indicated, for patients participating in Part F 
will be explored. 
12.2.9.4. Biomarker Analyses
The distributions of biomarkers with continuous measures, such as gene or protein expression, 
will be described.  Summary statistics will include means, medians, corresponding standard 
errors, quartiles, and ranges.  Biomarkers with discrete measures, such as genotype locus, will be 
summarized in frequency tables.  Correlative analyses may be performed to investigate 
associations between biomarkers and clinical endpoints as deemed appropriate.
12.2.10.
Health Outcome/Quality of Life Analyses 
Patients with at least 1 baseline and at least 1 postbaseline assessment will be included in 
the analyses. Compliance with completing the questionnaires will be summarized at the 
group-level at each assessment period (defined as the number of completed 


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questionnaires/number expected questionnaires given those that are still on study).
Reason for missing questionnaires will be assessed.
Relationships among MDASI-BT, Trail Making Tests, and other clinical parameters such 
as performance status, OS, and disease assessments may be explored.
Data will be summarized by study part and each response category (CR/PR, SD, PD). 
Change from baseline and time to worsening will be explored. This summary will 
include mean, standard deviation, median, minimum, maximum, and change from
baseline.  The MDASI-BT will be reported as core symptoms, brain tumor symptoms, 
symptom interference, and symptom groupings (affect, cognition, focal neurologic 
deficit, treatment-related symptoms, generalized/disease status symptoms, and 
gastrointestinal symptoms). Time to worsening will be described for these categories.
Further analyses will be specified in the statistical analysis plan.  
12.2.11.
Safety Analyses
All safety summaries and analyses will be based upon the FAS as defined in Section 12.2.1. 
Overall exposure to abemaciclib, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments. 
AEs will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and SOC of the corresponding MedDRA Lower Level Term (LLT), 
unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as AEs that begin prior to the first dose of abemaciclib. A 
TEAE is defined as an event that first occurred or worsened in severity after baseline.
Comparisons of preexisting conditions to on-treatment events at the LLT level will be used in the 
treatment-emergent computation.  
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to abemaciclib and repeated for events regardless of abemaciclib causality.  
The following summaries will be produced by PT within SOC:  preexisting conditions, SAEs, 
TEAEs, drug-related TEAEs, and procedure-related TEAEs.  
The following summaries will be produced by PT within SOC and maximum CTCAE grade:  
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs, 
and drug-related nonlaboratory-based TEAEs.  


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Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation. 
Hospitalizations and transfusions during the study treatment period or during the 30-day 
short-term follow-up period will be summarized by treatment group.  
12.2.12.
Interim Analyses
The Simon 2-stage design has a built-in interim analysis to analyze OIRR and to meet threshold 
continuation criteria. The interim analysis of OIRR for each study part (A, B, D, or E) will occur 
approximately 6 months after the 23rd evaluable patient is enrolled into each respective part.  
This is to ensure adequate durability of response data is available at the time of analysis. This 
interim analysis for response must be strictly followed to preserve the statistical properties of the 
Simon 2-stage design. Due to this requirement, objective data will be obtained to document 
response and to determine if the trial is to continue based on the OIRR. Because of this, no 
Assessment Committee or Data Monitoring Committee will be convened to oversee this trial. 
Additional interim analyses will be planned if deemed necessary.
12.2.13.
Subgroup Analyses
Subgroup analyses will be performed for potential prognostic subgroup variables.


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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or, 
where permitted by local law or regulation, by the patient's legal representative.  This includes 
obtaining the appropriate signatures and dates on the ICF prior to the performance of any 
protocol procedures and prior to the administration of study drug.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative sites.  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites. 
The study site’s ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

ICH GCP Guideline (E6)

applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
Lilly will select an investigator to serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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Attachment 1.Protocol JPBO Study Schedule
Baseline Assessments
Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Informed consent 
X
Informed consent form signed (prior to performance of any 
protocol-specific tests/procedures).
Pregnancy test 
X
Women with childbearing potential must have a negative serum 
pregnancy test within 7 days of the first dose of abemaciclib.
Medical history
X
Including alcohol/tobacco use and other relevant habits 
assessments.
Physical exam, vital 
signs, height, and 
weight
X
Vital signs include temperature, blood pressure, pulse rate, and 
respiration rate.
Neurologic assessment 
using the NANO scale
X
A modified version of NANO scale will be used to assess Part F 
patients.
Karnofsky 
Performance Status
X
Concomitant 
medications
X
CTCAE v4.0 grading 
(preexisting 
conditions)
X
To be reported only after study eligibility is confirmed.  
Brain Gd-MRI
assessment according 
to RANO-BM
X
Required for all patients.  Performed locally (Day -28 to Day -1) at 
baseline.
Radiological tumor 
assessment according 
to RECIST v1.1
X
Imaging studies to assess extracranial disease (CT scan or Gd-MRI) 
are performed locally (Day -28 to Day -1) at baseline.  It is 
recommended that CT imaging of the abdomen and pelvis be 
performed with IV contrast, whenever possible.  For patients with 
known hypersensitivity to CT contrast material, a CT scan of the 
chest without contrast and Gd-MRI of the abdomen/pelvis are 
encouraged.  Imaging based evaluation should be done rather than 
clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical tumor 
assessment
X
Melanoma patients only: For visible lesions, clinical tumor 
assessments are performed at baseline and photographs taken 
(including a ruler).
Gd-MRI of spine
X
Part F only
Echocardiogram or 
MUGA
X
Parts A, C, or F (HER2+ breast cancer patients only): 
Echocardiogram or MUGA is required at baseline only for patients 
receiving concurrent trastuzumab.  Per the trastuzumab prescribing 
information, continued cardiac function monitoring throughout 
treatment is recommended but is not required as a protocol 
procedure.


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ECG 
X
ECGs will be performed locally.  
Central hematology
X
Enrollment and treatment decisions may be based upon results of 
tests performed locally. If local laboratory tests are used for this 
purpose, then a duplicate specimen must be submitted to the central 
laboratory. Discrepancies between the local and central laboratory 
that may have an impact on eligibility or treatment decisions will 
not be considered protocol deviations.
Central chemistry 
X
Enrollment and treatment decisions may be based upon results of 
tests performed locally. If local laboratory tests are used for this 
purpose, then a duplicate specimen must be submitted to the central 
laboratory. Discrepancies between local and central laboratory that 
may have an impact on eligibility or treatment decisions will not be 
considered protocol deviations.
Cerebrospinal Fluid
(CSF) via lumbar 
puncture
X
Part F only:  CSF cytology will be assessed locally at baseline for 
patients with leptomeningeal metastases. Previously documented 
CSF cytology results may be used if collected within 28 days prior 
to initiation of abemaciclib. If patient refuses lumbar puncture, the 
lack of CSF sample will not be considered a protocol deviation.
MDASI-BT 
X
To be completed prior to physical exam and preferably prior to 
administration of the Trail Making Tests.
Trail Making Tests A 
and B
X
To be completed prior to physical exam and administered by trained 
site staff.
Abbreviations:  CSF = Cerebrospinal fluid; CT = computed tomography; CTCAE = Common Terminology Criteria 
for Adverse Events; ECG = electrocardiogram; Gd-MRI = gadolinium-enhanced magnetic resonance imaging; 
IV = intravenous; MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; MUGA = multi-gated
acquisition scan; NANO = Neurologic Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria 
in Solid Tumors.


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Study Schedule, Protocol I3Y-MC-JPBO
During Treatment Study Schedule
Study Period
Study Treatment Period a
Cycle/Visit
1
2
3
4-X
Duration
21 ±3 days
21 ±3 days
21 ±3 days
21 ±3 days
A cycle is defined as the planned treatment interval of 21 days plus 
any subsequent delay prior to the start of the next cycle. A delay of 
a cycle due to logistical reasons (i.e. holidays, planned vacations)
will be permitted up to 7 days and not constituted as a protocol 
violation.  Additionally, a cycle delay up to 14 days to allow 
sufficient time for recovery from a toxicity is permitted.
Relative Day within 
Dosing Cycle
1
1
14-
21
1
1
14-
21
Procedure 
Category
Procedure
Comments
Physical 
examination
Physical exam
X
X
X
X
Neurologic assessment using 
NANO scale
X
X
X
X
A modified version of NANO scale will be used to assess Part F 
patients.
Weight 
X
X
X
X
Vital signs
X
X
X
X
Includes blood pressure, pulse, respiratory rate, and temperature. 
Karnofsky Performance 
Status
X
X
X
X
Archived tumor tissue
X
Formalin-fixed paraffin-embedded archived tumor tissue must be 
requested after study eligibility is confirmed.  The absence of an 
available specimen of the patient’s tumor does not constitute a 
protocol deviation (see Section 10.4.2.3).
Adverse events collection/CTCAE grading
X
X
X
X
Concomitant medication notation
X
X
X
X
Lab/
diagnostic tests
Central hematology
X
X
X
X
Central hematology labs may be drawn up to 3 days prior to Day 1 
of each cycle. Additional local hematology labs may be drawn for 
treatment adjustment and patient management purposes.  Duplicate 
central labs should be submitted for assessment.
Central chemistry
X
X
X
X
Central chemistry labs may be drawn up to 3 days prior to Day 1 of
each cycle. Additional local chemistry labs may be drawn for 
treatment adjustment and patient management purposes. Duplicate 
central labs should be submitted for assessment.
CSF via lumbar puncture
X
For Part F only:  Additional CSF collection to be performed only as 
clinically indicated based upon evidence of response by MRI and 
neurologic assessment.  CSF to be assessed locally for cytology, as 


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Study Period
Study Treatment Period a
Cycle/Visit
1
2
3
4-X
Duration
21 ±3 days
21 ±3 days
21 ±3 days
21 ±3 days
A cycle is defined as the planned treatment interval of 21 days plus 
any subsequent delay prior to the start of the next cycle. A delay of 
a cycle due to logistical reasons (i.e. holidays, planned vacations)
will be permitted up to 7 days and not constituted as a protocol 
violation.  Additionally, a cycle delay up to 14 days to allow 
sufficient time for recovery from a toxicity is permitted.
Relative Day within 
Dosing Cycle
1
1
14-
21
1
1
14-
21
Procedure 
Category
Procedure
Comments
well as submitting a sample centrally for assessment of drug 
concentration.  If patient refuses lumbar puncture, the lack of CSF 
sample will not be considered a protocol deviation.  CSF will be 
collected for Part C (surgery) patients at the time of surgical 
resection (during Cycle 1) and does not require a lumbar puncture.
PK sampling 
X
X
X
See Pharmacokinetic Sampling Schedule (Attachment 7 and 
Attachment 8)
Pharmacogenetic blood 
sample
X
Draw sample before patient is dosed on C1D1. 
Biomarker plasma sample
X
X
Draw sample before patient is dosed on C1D1 and upon arrival at 
site on C2D1. 
Local ECG
X
X
X
X
ECGs will be performed according to separate schedule (see 
Attachment 7 and Attachment 8).
Tumor 
assessment
Brain Gd-MRI assessment 
according to RANO-BM
X
X
Performed locally.  Repeat between D14 and D21 of every other 
cycle beginning with C2 and continuing through C8; thereafter,
tumor assessments will be repeated between D14 and D21 of every 
fourth cycle (beginning with C12).
Radiologic imaging according 
to RECIST v1.1
X
X
Performed locally.  Imaging studies to assess extracranial disease
should be repeated between D14 and D21 of every other cycle 
beginning with C2 and continuing through C8; thereafter, tumor 
assessments will be repeated between D14 and D21 of every fourth 
cycle (beginning with C12). The same method of imaging used at 
baseline should be used for each subsequent assessment.
Clinical tumor assessment
X
X
Melanoma patients only: For visible lesions, assessments are 
performed and photographs taken (including a ruler) on Day 1 of 
every other cycle beginning with Cycle 3 or as clinically indicated.
Gd-MRI of spine
X
X
For Part F only:  Performed locally.  Repeat between D14 and D21 
of every other cycle beginning with C2 and continuing through C8; 
thereafter, tumor assessments will be repeated between D14 and 
D21 of every fourth cycle (beginning with C12).


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Study Period
Study Treatment Period a
Cycle/Visit
1
2
3
4-X
Duration
21 ±3 days
21 ±3 days
21 ±3 days
21 ±3 days
A cycle is defined as the planned treatment interval of 21 days plus 
any subsequent delay prior to the start of the next cycle. A delay of 
a cycle due to logistical reasons (i.e. holidays, planned vacations)
will be permitted up to 7 days and not constituted as a protocol 
violation.  Additionally, a cycle delay up to 14 days to allow 
sufficient time for recovery from a toxicity is permitted.
Relative Day within 
Dosing Cycle
1
1
14-
21
1
1
14-
21
Procedure 
Category
Procedure
Comments
Health 
outcomes
MDASI-BT
X
X
X
X
MDASI-BT will be administered on D1 of each cycle prior to
physical exam, administration of the Trail Making Tests, and
extensive interaction with site staff.  On C1D1, MDASI-BT is to be 
administered before the first dose of abemaciclib in the clinic.
Trail Making Tests A and B
X
X 
X
X
Tests A and B will be completed on D1 of each cycle prior to 
physical exam and administered by trained site staff.  On C1D1, 
Tests A and B are to be administered before the first dose of 
abemaciclib in the clinic.
Investigational 
product
Abemaciclib 
Take 200 mg or prescribed dose orally every 12 hours on Days 1 
through 21 of every cycle.
The period between assignment to abemaciclib in IWRS and the 
first dose (C1D1) should not exceed 7 days.
Abbreviations:  C = cycle; CSF = Cerebrospinal fluid; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; IWRS 
= interactive web-response system; MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; Gd-MRI = gadolinium-enhanced magnetic resonance 
imaging; NANO = Neurologic Assessment in Neuro-Oncology; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors.


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Study Schedule, Protocol I3Y-MC-JPBO
Post Treatment Discontinuation Study Schedule
Study Period
Postdiscontinua
tion Follow-Up
Long-Term 
Follow-Up 
Visit 
801
802-X
Posttreatment Discontinuation Follow-Up should begin the day after the last dose of 
abemaciclib or, if abemaciclib has been omitted for an extended period, the date it is decided 
that the patient will not restart abemaciclib.
Duration
30 +/-  5 days
Variable
Long-term follow-up begins the day after the short-term postdiscontinuation follow-up visit 
(v801) is completed and continues until the patient’s death, lost to follow-up, or overall study 
completion. The variable period depends on whether disease progression has occurred and if
tumor assessments are due. Once disease progression has occurred, visits should occur every 
90 days.
Relative Day
30
Procedure
Category
Procedure
Comments
Physical 
examination 
Physical Exam
X
Neurologic Assessment using NANO 
scale
X
Weight
X
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature.
Karnofsky Performance Status
X
Tumor 
assessment
Brain Gd-MRI (according to RANO-BM)
X
X
Not required if progressive disease is documented while on treatment or if there are clear 
signs of clinical progression. Reassessment should occur approximately every 6 weeks for 
the first 6 months following initiation of abemaciclib and thereafter approximately every 
12 weeks until disease progression.
Radiologic imaging according to RECIST
1.1
X
X
Not required if progressive disease is documented while on treatment or if there are clear 
signs of clinical progression. Reassessment should occur approximately every 6 weeks for 
the first 6 months following initiation of abemaciclib and thereafter approximately every 
12 weeks until disease progression or until the final analysis of OS.  If a patient’s most recent 
response prior to discontinuation was a PR or CR, an additional radiological assessment 
should be performed during the 30-day follow-up period to confirm the response, at least 
28 days after the previous radiological assessment.  Response should be confirmed before the 
initiation of additional anticancer therapy.  However, initiation of new therapy should not be 
delayed solely to confirm response.


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Study Period
Postdiscontinua
tion Follow-Up
Long-Term 
Follow-Up 
Visit 
801
802-X
Posttreatment Discontinuation Follow-Up should begin the day after the last dose of 
abemaciclib or, if abemaciclib has been omitted for an extended period, the date it is decided 
that the patient will not restart abemaciclib.
Duration
30 +/-  5 days
Variable
Long-term follow-up begins the day after the short-term postdiscontinuation follow-up visit 
(v801) is completed and continues until the patient’s death, lost to follow-up, or overall study 
completion. The variable period depends on whether disease progression has occurred and if
tumor assessments are due. Once disease progression has occurred, visits should occur every 
90 days.
Relative Day
30
Procedure
Category
Procedure
Comments
Tumor 
Assessment
Clinical tumor assessment
X
X
Melanoma patients only
Gd-MRI of spine
X
X
Part F patients only
Health outcomes
MDASI-BT
X
Collect MDASI-BT prior to physical exam, administration of the Trail Making Tests, and
extensive interaction with site staff.
Trail Making Tests A and B
X
Tests A and B will be completed prior to physical exam and administered by trained site 
staff.
Survival information
X
X
Although preferable to collect during a clinic visit, survival information may be collected by 
contacting the patient or family directly (for example, via telephone) if no procedures are 
required. This should be collected approximately every 90 days if no other procedures are 
performed.
Adverse events collection/CTCAE grading
X
X
After Visit 801, only study protocol or drug-related events are reported. If a patient has an 
ongoing AE or SAE possibly related to abemaciclib (for instance, abnormal electrolytes), the 
patient should be followed until the event is resolved, the event is no longer considered to be 
drug-related, the event becomes stable or returns to baseline, a new treatment is initiated for 
the patient, or the patient dies or is lost to follow-up.  Any subsequent follow-up(s) for AEs 
will be no more than 30 days ± 5 days in duration.
Concomitant medication notation
X
Lab/
diagnostic tests
Central hematology
X
Central chemistry
X


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Study Period
Postdiscontinua
tion Follow-Up
Long-Term 
Follow-Up 
Visit 
801
802-X
Posttreatment Discontinuation Follow-Up should begin the day after the last dose of 
abemaciclib or, if abemaciclib has been omitted for an extended period, the date it is decided 
that the patient will not restart abemaciclib.
Duration
30 +/-  5 days
Variable
Long-term follow-up begins the day after the short-term postdiscontinuation follow-up visit 
(v801) is completed and continues until the patient’s death, lost to follow-up, or overall study 
completion. The variable period depends on whether disease progression has occurred and if
tumor assessments are due. Once disease progression has occurred, visits should occur every 
90 days.
Relative Day
30
Procedure
Category
Procedure
Comments
Biomarker plasma sample
X
Draw sample only for patients discontinuing due to PD.
Local ECG
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram Gd-MRI = gadolinium-enhanced 
magnetic resonance imaging; MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; NANO = Neurologic Assessment in Neuro-Oncology; 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; v = visit.


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Study Schedule for the continued access period only, Protocol I3Y-MC-JPBO
Perform procedure as indicated.
Study Period
Patients on Abemaciclib
Continued Access Period 
Follow-Up
Cycle
X
Follow-Upa
Visit
501-5XX
901
Approximate 
Visit Duration 
(days)
21
30
Relative day
within a cycle
1
Procedure 
Category
Procedure
Protocol 
Reference
Comments
Adverse events collection/CTCAE grading
Section 10.3
X
X
Data on SAEs that occur before the end of trial will be 
stored in the collection database and the Lilly Safety 
System.
Investigational 
product
Abemaciclib
Section 9.1
X
Patients on abemaciclib who are receiving clinical 
benefit will continue to receive abemaciclib during the 
continued access period.  Abemaciclib is to be 
administered orally every 12 hours on Days 1 through 
21 of each cycle.  
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; OS = overall survival; SAEs = serious adverse events.
a
The continued access period begins after study completion (that is, after final OS analysis) and ends at the end of trial (that is, the last patient visit).


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Attachment 2.Protocol JPBO 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 and bands)
Total protein
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase (ALT)
Platelets
Aspartate aminotransferase (AST)
Total bilirubin and direct bilirubin
Serum pregnancy test (women of childbearing 
potential 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.


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Attachment 3.Protocol JPBO Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Antinuclear antibodya
AST
GGT
CPK
Antismooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells. 
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.Protocol JPBO Karnofsky Performance Status
The Karnofsky Performance Scale Index allows patients to be classified as to their functional 
impairment.  This can be used to compare effectiveness of different therapies and to assess the 
prognosis in individual patients.  The lower the Karnofsky score, the worse the survival for most 
serious illnesses. 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA
Able to carry on normal activity and to work; no 
special care needed.
100 Normal no complaints; no evidence of 
disease.
90 Able to carry on normal activity; minor 
signs or symptoms of disease.
80 Normal activity with effort; some signs 
or symptoms of disease. 
Unable to work; able to live at home and care for 
most personal needs; varying amount of assistance 
needed.
70 Cares for self; unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his personal 
needs.
50 Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
40 Disabled; requires special care and 
assistance.
30 Severely disabled; hospital admission is 
indicated although death not imminent.
20
Very sick; hospital admission 
necessary; active supportive treatment 
necessary.
10 Moribund; fatal processes progressing 
rapidly.
0
Dead
Sources:  Crooks et al. 1991; de Haan et al. 1993; Oxford 1993; Hollen et al. 1994; O’Toole et al. 1991; Schag et al. 
1984.


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Attachment 5.Protocol JPBO RANO-BM and RANO-LM 
Criteria
Section I:  Response Assessment in Neuro-Oncology Brain Metastases Criteria
Intracranial response and progression will be evaluated in Study I3Y-MC-JPBO using the international 
criteria proposed by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)
working group (Lin et al. 2015).
Measurability of Tumor at Baseline
Tumor lesions will be categorized at baseline as measurable or nonmeasurable.  Measurable disease is 
defined by the presence of at least 1 measurable central nervous system (CNS) lesion.
Measurable
A contrast enhancing lesion at least 10 mm in the longest diameter (LD) that is visible on two or more 
axial slices that are preferably ≤5 mm apart with 0-mm skip (and ideally ≤1.5 mm apart with 0-mm skip).  
Additionally, the diameter perpendicular to the longest diameter in the plane of measurement should be at 
least 5 mm.  If the MRI is performed with thicker slices, the lesion must be at least two times the slice 
thickness.  Measurement of tumor around a cyst or surgical cavity represents a challenge, and in general, 
such lesions should be considered non-measureable unless there is a nodular component measuring ≥10 
mm in LD and ≥5 mm in the perpendicular plane.
Nonmeasurable
All other lesions, including small lesions (LD <10 mm) as well as truly nonmeasurable lesions.  Lesions 
considered truly nonmeasurable include those with borders that cannot be reproducibly measured, dural 
metastases, bony skull metastases, cystic-only lesions, and leptomeningeal disease.
Specifications by Methods of Measurement
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.  It is important to use imaging techniques that are 
consistent across all imaging time points to ensure interval appearance or disappearance of lesions or 
change in size is not affected by scan parameters such as slice thickness.  Gd-MRI is the most sensitive 
and reproducible method to measure CNS lesions selected for response assessment.  Suggested MRI 
specifications are included in Appendix A.
Baseline Documentation of Target and Non-Target Lesions
All measurements should be recorded in the eCRF in metric notation.  Baseline evaluations should be 
performed as close as possible to treatment initiation, but no more than 4 weeks prior to treatment.  
Previously treated lesions should be documented with how each lesion was previously treated (e.g., 
stereotactic radiosurgery [SRS], whole brain radiotherapy [WBRT], surgical resection). 
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of five CNS 
lesions total should be identified as target lesions and will be recorded and measured at baseline.


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Target lesions should be selected on the basis of size (those with longest diameter) and lend themselves to 
reproducible repeated measurements.  For patients with recurrent disease and multiple lesions, the 
enlarging lesions should be prioritized as target lesions for evaluation of response.  Lesions with prior 
local treatment (i.e., SRS or surgical resection) can be considered measurable if there has been 
demonstrated progression since the time of local treatment.  However, careful consideration should be 
given to previously SRS-treated lesions given the possibility of radiation necrosis.  If lesions not 
previously treated with local therapies are present, these are the preferred target lesions.  A sum of the 
diameters for all target lesions will be calculated and reported as the baseline sum of longest diameters 
(sum LD).
Non-Target Lesions
All other CNS lesions should be identified as non-target lesions and should be recorded as ‘present’, 
‘absent’, or ‘unequivocal progression’.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all CNS target lesions sustained for at least 4 weeks; no new 
lesions; no corticosteroids; stable or improved clinically.
Partial Response (PR):  At least a 30% decrease in the sum LD of CNS target lesions, taking as reference 
the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid 
dose; stable or improved clinically.
Progressive Disease (PD):  At least a 20% increase in the sum LD of CNS target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, at least one lesion must increase by an absolute value of ≥5 mm 
to be considered progression.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as a reference the smallest sum LD while on study.
Evaluation of Non-Target Lesions
Complete Response (CR):  Requires disappearance of all enhancing CNS non-target lesions and no new 
CNS lesions.
Non-CR/Non-PD:  Persistence of one or more non-target CNS lesions.
Progressive Disease (PD):  Any of the following:  unequivocal progression of existing enhancing non-
target CNS lesions, new lesion(s), or unequivocal progression of existing tumor-related non-enhancing 
(T2/FLAIR) CNS lesions.
Special Considerations for Assessment of CNS Lesions
Target lesions that become too small to measure:  While on study, all CNS target lesions should have 
their actual measurement recorded, even when very small (e.g., 2 mm).  If the lesion disappears, the value 
should be recorded as 0 mm.  However, if the lesion is sufficiently small (but still present) that the 
radiologist does not feel comfortable assigning an exact measure, a default value of 5 mm should be 
recorded on the eCRF.


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Lesions that coalesce on treatment:  As lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximum LD of each individual lesion.  If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximum LD for the ‘coalesced’ lesion.
Definition of new lesions:  The finding of a new CNS lesion should be unequivocal and not due to 
technique or slice variation.  A new lesion is one that was not present on prior scans and visible in axial, 
coronal, and sagittal reconstructions of ≤1.5 mm projections.  If a new lesion is equivocal, for example 
because of its small size (i.e., ≤5 mm), continued therapy may be considered, and follow up evaluation 
will clarify if it represents truly new disease.  If repeat scans confirm there is definitely a new lesion, then 
progression should be declared using the date of the initial scan showing the new lesion.
Definition of unequivocal progression of non-target lesions:  When the patient also has measurable 
disease, to achieve ‘unequivocal progression’ on the basis of non-target disease alone, there must be an 
overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  
When the patient has only non-measurable disease, there must be an overall level of substantial worsening 
to merit discontinuation of therapy.
Guidance in the case of uncertain attribution of radiographic findings and/or equivocal cases:  In the 
case of patients followed after SRS, there may be radiographic evidence of enlargement of target and non-
target lesions which may not necessarily represent tumor progression.  If there is evidence of radiographic 
progression but there is clinical evidence supporting the possibility that the radiological changes are due 
to treatment effect (and not to progression of cancer), additional evidence is required to distinguish true 
progression versus treatment effect, as standard MRI alone is not sufficient.  Patients may be continued on 
protocol therapy pending a repeat scan at the next scheduled evaluation or sooner, although the use of an 
advanced imaging modality such as perfusion MR imaging, magnetic resonance spectroscopy, or 18 FLT 
or 18FDG PET (in the case of SRS) is strongly encouraged.  If subsequent testing demonstrates that 
progression has occurred, the date of progression should be recorded as the date of the scan at which this 
issue was first raised.
Special Considerations Regarding Corticosteroid Use and Clinical Deterioration
An increase in corticosteroid dose alone, in the absence of clinical deterioration related to tumor, will not 
be used as a sole determinant of progression.  Patients with stable imaging studies whose corticosteroid 
dose was increased for reasons other than clinical deterioration related to tumor do not qualify for stable 
disease or progression.  They should be observed closely.  If their corticosteroid dose can be reduced back 
to baseline, they will be considered as having stable disease; if further clinical deterioration related to 
tumor becomes apparent, they will be considered to have PD.
The definition of clinical deterioration is left to the discretion of the treating physician, but it is 
recommended that a decline in the Karnofsky Performance Status (KPS) from 100 or 90 to 70 or less, a 
decline in KPS of at least 20 points from 80 or less, or a decline in KPS from any baseline to 50 or less, 
for at least 7 days, be considered neurologic deterioration unless attributable to comorbid events, 
treatment-related toxicity, or changes in corticosteroid dose.
Summary of Response


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Table1.  Summary of RANO-BM Response Criteria
Criterion
CR
PR
SD
PD
Target lesions
None
≥30% decrease in sum LD 
relative to baseline
<30% decrease relative to 
baseline but <20% 
increase in sum LD 
relative to nadir
≥20% increase in sum LD 
relative to nadir. In 
addition to relative 
increase of 20%, ≥1 
lesion must increase by 
absolute value of ≥5 mm.
*
Nontarget lesions
None
Stable or improved
Stable or improved
Unequivocal PD*
New lesion(s)**
None
None
None
Present*
Corticosteroids
None
Stable or decreased
Stable or decreased
NA+
Clinical status
Stable or improved
Stable or improved
Stable or improved
Worse*
Requirement for 
response
All
All
All
Any+
Abbreviations:  CR = Complete Response; LD = Longest Diameter; PD = Progressive Disease; PR = Partial Response; RANO-BM = Response 
Assessment in Neuro-Oncology for Brain Metastases; SD = Stable Disease.
*Progression occurs when this criterion is met.
**New lesion = new lesion not present on prior scans and visible in at least 2 projections.  If a new lesion is equivocal, for example because of its 
small size, continued therapy may be considered, and follow up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the initial scan showing the new lesion.
+Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical deterioration.
Table 2.  Bi-Compartmental PFS
CNS (by RANO-
BM)
Non-CNS (by RECIST v1.1)
Bi-Compartmental PFS
Note
CR, PR, or SD
PD
Log as PFS event
Log as non-CNS PD
PD
CR, PR, or SD
Log as PFS event
Log as CNS PD
PD
PD
Log as PFS event
Log as both CNS and non-
CNS PD
Abbreviations:  CNS = Central Nervous System; CR = Complete Response; PD = Progressive Disease; PFS = Progression-Free Survival; PR = 
Partial Response; RANO-BM = Response Assessment in Neuro-Oncology for Brain Metastases; RECIST = Response Evaluation Criteria in 
Solid Tumors; SD = Stable Disease.


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Appendix A: Recommendations for Minimum Requirements for Brain Imaging
MR Scanners: 1.5T and 3T MR scanners only

Localizer/Scout

3D T1w pre-contrast (MPRAGE, 3D IR SFPGR T1w)
•
minimum TE
•
TI, TR and flip angle according to manufacturer specific / field strength specific 
recommendations for optimum image quality
•
SENSE / SMASH / GRAPPA / ASSET allowed
•
Slice/3D slab orientation: sagittal or transverse
•
FOV: 256 mm x 256 mm
•
Matrix: 256x256
•
Slice thickness: ≤ 1.5 mm
•
Full brain coverage

DWI
•
single shot EPI sequence
•
minimum TE
•
TR > 3000 ms
•
Spectral fat suppression
•
b: 0 and 1000 s/mm2 (3 directions)
•
SENSE / SMASH / GRAPPA / ASSET: optional for 1.5 T, obligatory for 3 T.
•
Slice orientation: transverse
•
Slice thickness: 5mm
•
Slice gap: 0
•
Number of slices: Full brain coverage
•
FOV: 240 mm x 240 mm
•
Matrix: 128 x 128 or higher
•
Postprocessing: Calculation of ADC maps (diffusion trace maps)

2D FLAIR, transverse
•
Turbo Spin Echo (TSE) / Fast Spin Echo (FSE) sequence
•
TE: 90-140ms
•
TR: 6000-10000 ms
•
TI: 2000-2500 ms (use TI according to optimized protocol for specific inversion pulses 
and field strength)
•
SENSE / SMASH / GRAPPA / ASSET allowed
•
Slice orientation: transverse
•
Slice thickness: 5mm
•
Slice gap: 0
•
Number of slices: same as sequence 2
•
FOV: 240 mm x 240 mm
•
Matrix: 256 x 256 or higher
•
Slice positioning as in sequence 2

3D FLAIR (OPTIONAL)
•
3D Turbo Spin Echo (TSE) / Fast Spin Echo (FSE) sequence
•
TE: 90-140ms
•
TR: 6000-10000 ms
•
TI: 2000-2500 ms (use TI according to optimized protocol for specific inversion pulses 
and field strength)
•
SENSE / SMASH / GRAPPA / ASSET / ARC allowed


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•
Slice orientation: sagittal or transverse
•
Slice thickness: ≤1.5 mm
•
Number of slices: Full brain coverage
•
FOV: 250 mm x 250 mm
•
Matrix: 224 x 224 or higher
•
Slice positioning as in sequence 1

Contrast agent injection
•
0.1 mmol/kg BW of a Gd-based contrast agent

T2w-TSE
•
Turbo Spin Echo (TSE) / Fast Spin Echo (FSE) sequence
•
TE: 80-120ms
•
TR: ≥ 2500 ms
•
SENSE / SMASH / GRAPPA / ASSET allowed
•
Slice orientation: transverse
•
Slice thickness: 5mm
•
Slice gap: 0
•
Number of slices: same as sequence 2
•
FOV: 240 mm x 240 mm
•
Matrix: 256 x 256 or higher
•
Slice positioning as in sequence 2

3D T1w post-contrast (MPRAGE, 3D IR FSPGR T1w)
•
Sequence parameters and slice positioning as in sequence 1
Further sequences can be added to the protocol according to the preferences of the respective center. The 
order and timing of prescribed sequences after contrast administration should also be respected.


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Section II:  Response Assessment in Neuro-Oncology Leptomeningeal Metastases Criteria
Leptomeningeal metastases (LM) response and progression will be evaluated in Study I3Y-MC-JPBO 
using the draft criteria proposed by the Response Assessment in Neuro-Oncology Leptomeningeal 
Metastases (RANO-LM) working group (Chamberlain et al.; unpublished manuscript).
Assessing Response in Leptomeningeal Metastases
Three basic elements are proposed for assessing response in LM:  a standardized neurological 
examination, CSF cytology, and radiographic evaluation.
Neurological Assessment
The RANO-LM working group in conjunction with the RANO Neurological Assessment working group 
has created an instrument for assessing the neurological exam in patients with LM in order to standardize 
response definitions.  This assessment is the Neurologic Assessment in Neuro-Oncology (NANO) scale 
which has been adapted for use in patients with LM.   Progressive disease based on neurological 
assessment is defined by a change of 2 or more levels in a given domain, or alternatively by a change to 
level 3 (or level 2 in domains defined by only 3 levels) in any one domain.  Transient neurological 
symptoms or deficits often are treatment-related and do not represent progression of LM.
CSF Cytology
CSF cytology is usually a qualitative analysis whereby results are reported ass negative, atypical, 
suspicious, or positive.  The RANO-LM working group endorses the binary outcome measure where 
results are considered either positive (includes suspicious) or negative (includes atypia).  Response based 
on CSF cytology is considered when CSF converts from positive to negative and in which a confirmatory 
determination is made from all sites (lumbar or ventricular) previously shown to be positive.  Cytological 
response would be declared in instances where the CSF is cleared of identifiable tumor cells from all sites 
of identified disease and maintains that status for 4 weeks.
Neuroimaging Assessment
The most challenging element of response assessment in LM is the neuroimaging evaluation.  MRI 
abnormalities of LM include enhancement of the leptomeninges of the brain or spinal cord identified as 
enhancement of the cranial nerves and spinal nerve roots, brain surface, cerebellar foliae and within 
cerebral sulci.  Pathological enhancement may be nodular, linear or curvilinear as well as focal or diffuse.  
Because radiographic features typical of LM are generally small in volume and complex in geometry, 
current MRI technology does not permit quantitative assessment. 
The working group recommends contrast MRI of brain and entire spine at baseline and at pre-specified 
times thereafter.  Suggested imaging requirements for MRI are given in Appendix B.  The 
recommendation is to assess 6 regions for pathological contrast enhancement on MRI consistent with LM, 
with findings for each region documented at baseline as present (abnormality present), absent (no 
abnormality; normal), or non-evaluable (NE).  In follow-up, features in these regions (or new regions of 
involvement) should be assessed as completely resolved (+3), definitely improved (+2), possibly 
improved (+1), unchanged (0), possibly worse (-1), definitely worse (-2), or new site of disease (-3) as per 
Table 3.


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Table 3. Radiographic assessment in leptomeningeal metastases
MRI findings
Present (1) or absent (0) or 
non-evaluable (NE)
Dimensions of measurable 
nodules defined as
>5 x 10mm (orthogonal 
diameters)
Change from previous MRI
(-3 to +3)
BRAIN
Nodules (subarachnoid or ventricular)
*Leptomeningeal enhancement
Cranial nerve enhancement
Hydrocephalus^
Parenchymal (brain metastases)^
SPINE
Nodules (subarachnoid)
Leptomeningeal enhancement
Nerve root enhancement
Parenchymal(intramedullary metastases)^
Epidural metastasis ^
TOTAL SCORE
Legend:
*Leptomeningeal enhancement may include pia, cerebellar folia, ventricular ependyma or cerebral sulci.
^Both hydrocephalus and parenchymal metastases, either brain or spine, are noted as present or absent but not used for LM response 
determination.
Column 2: scored as 1 (present) or 0- (absent) or non-evaluable (NE). A maximum of 5 radiographic target lesions are selected from baseline 
imaging to score on follow-up.
Column 3: scores each measurable lesion (at least 10x5mm) excluding parenchymal as 1 (present with maximum orthogonal diameters) or 0 
(absent).
Column 4: change from baseline or prior image scored as same (0), probable improvement (+1), definite improvement (+2), no evidence of 
disease (+3) or probable worsening (-1), definite worsening (-2), new site(s) of disease (-3). Measurable nodules defined as >5x10mm are scored 
as same (0), resolved (no evidence of disease, complete response), definitely better (+2; partial response) [decrease by >50% in the summed 
product of orthogonal diameters], definite worsening (-2; progressive disease) [increase by >25% in the summed product of orthogonal 
diameters]. A composite score (total score) is calculated and compared to the baseline total score. A 25% worsening in the current score relative 
to baseline defines radiographic progressive disease. A 50% improvement in the current score defines a radiographic partial response. Resolution 
of all baseline radiographic abnormalities defines a complete response. All other situations define stable disease.
Response Assessment in Leptomeningeal Metastases
The RANO-LM working group proposes a composite response assessment wherein evaluation of the 
neurologic examination is performed using the adapted NANO scale, CSF cytology is evaluated, and a 
composite score of MRI of the neuraxis is applied.  Table 4 provides a summary of the response 
determination.


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Table 4.  Response determination in leptomeningeal metastases
Assessment
Response
Progressive or refractory disease
Stable disease
Neurological 
examination 
defined 
progression
CSF defined 
disease 
progression
Radiologic 
defined 
disease 
progression
Symptoms^
Neurological 
exam
Stable or 
improved
Worse
Stable
Stable
Stable
Stable
CSF Cytology
Negative
Negative
Positive
Negative
Negative
Negative or 
positive (solid 
tumors only)
CNS imaging
Definite 
Improvement or 
stable
Stable
Stable
Definite 
worsening
Stable
Stable or 
equivocally 
worsening
Symptom 
assessment
Stable or 
improved
Worse or stable
Worse or 
stable
Worse or 
stable
Worse
Stable
Legend:
CSF cytology negative
Defined as either true negative or atypical
CSF cytology positive
Defined as true positive or suspicious
Stable
Defined as stable or indeterminate
Symptoms^
Stable; no change (-1 to +1  in symptom inventory
Worse; -2 to -3 in symptom inventory
Improved; +2 to +3 in symptom inventory
Appendix B: Recommended MRI Parameters in Leptomeningeal Disease
MRI prerequisites
1.5T and 3T MR scanners only
Use of same MRI at baseline and follow-up
MRI to be performed prior to lumbar puncture
Recommended MRI sequences
Brain
Volumetric 3D T1 (MPRAGE or SPGR) post-contrast image with isotropic 1mm 
voxels to permit reformatting in 3 planes (axial, coronal and sagittal)
Reformatted slice thickness 3mm to obtain good SNR & manageable number of 
slices for full brain coverage
IV Contrast dose = 0.1mmol/kg of gadolinium-based agent
Spine
Volumetric 3D T1 (MPRAGE or SPGR) post-contrast image in sagittal plane with 
isotropic 1mm voxels to permit reformatting in 3 planes (axial, coronal and 
sagittal) with a 2-3mm reformatted slice thickness


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Attachment 6.Protocol JPBO RECIST 1.1
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 


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I3Y-MC-JPBO(d) Clinical Protocol
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. 


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I3Y-MC-JPBO(d) Clinical Protocol
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Attachment 7.Protocol JPBO Electrocardiogram and 
Pharmacokinetic Sampling Schedule –
Parts A, B, D, E, and F
I3Y-MC-JPBO Electrocardiogram and Pharmacokinetic Sampling Schedule
Cycle (C) and Day 
(D)
ECG
PK Sample 
Number
Dosing of 
Abemaciclib
Sampling Time for ECG and 
PK from Blooda
Baseline
(Day -14 to Day -1)
X
Day of visit
C1D1
X
1
X
2-4 hrs after abemaciclib dosed in 
the clinic
C2D1
X
2
Xb
Upon arrival at site at least 4 hrs 
after taking abemaciclib dose at 
home
C2D1
3
3 ± 0.5 hr after PK sample 
number 2 (that is, at least 7 ± 0.5 
hrs after taking abemaciclib dose 
at home)
C3D1
4d
Xc
Predose (0 hr)
C3D1
5
3 ± 0.5 hrs after abemaciclib dose
C4D1
X
2 – 4 hrs after abemaciclib dose
30-day follow-up
X
Day of visit
Abbreviations:  C = cycle; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; hr = hour(s); 
PD = progressive disease; PK = pharmacokinetic. 
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
On Cycle 2 Day 1 only, patient should take abemaciclib dose at home at least 4 hours before arrival at site.  The 
time of abemaciclib dose intake must be recorded that day.
c
On Cycle 3 Day 1 only, after collection of PK sample number 4, patients should take abemaciclib immediately 
following the sample collection, prior to conducting other procedures. 
d
For patients participating in Part F, a time-matched sample of CSF should be collected for drug concentration 
analysis as well as CSF cytology.


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Attachment 8.Protocol JPBO Electrocardiogram and 
Pharmacokinetic Sampling Schedule – Part C
I3Y-MC-JPBO Electrocardiogram and Pharmacokinetic Sampling Schedule - Part C 
Cycle (C) and Day 
(D)
ECG
PK Sample 
Number
Dosing of 
Abemaciclib
Sampling Time for ECG and 
PK from Blooda
Baseline
(Day -14 to Day -1)
X
Day of visit
C1D1
X
1
X
2-4 hrs after abemaciclib dosed in 
the clinic
C1 day of surgeryb
2
X
6-12 hrs after taking abemaciclib
dose at home
C1 day of surgery
3
Approximately 6 hours after 
resection of brain tumor tissue
C3D1
X
4
Xc
Upon arrival at site at least 4 hrs 
after taking abemaciclib dose at 
home
C3D1
5
3 ± 0.5 hr after PK sample 
number 4 (that is, at least 7 ± 0.5 
hrs after taking abemaciclib dose 
at home)
C4D1
6
Xd
Predose (0 hr)
C4D1
X
7
3 ± 0.5 hrs after abemaciclib dose
30-day follow-up
X
Day of visit
Abbreviations:  C = cycle; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; hr = hour(s); 
PK = pharmacokinetic. 
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
Blood, CSF, and brain tumor tissue samples for determination of drug concentration will be collected at the time 
of surgery, after 5 to 14 days of abemaciclib dosing (during Cycle 1).
c
On Cycle 3 Day 1 only, patient should take abemaciclib dose at home at least 4 hours before arrival at site.  The 
time of abemaciclib dose intake must be recorded that day.
d
On Cycle 4 Day 1 only, after the predose PK sample, patients should take abemaciclib immediately following the 
sample collection, prior to conducting other procedures.


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Attachment 9.Protocol JPBO Sampling Summary
This table provides estimates of the maximum number of samples (venipunctures and biopsies),
volumes for all sampling, and tests (study qualification, health monitoring, drug concentration, 
tailoring biomarkers, and exploratory) required for each patient during the study.  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, if the patient discontinues from the study early). 
Protocol I3Y-MC-JPBO Sampling Summarya
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number 
Samples
Maximum 
Total Amount
Study qualificationb
Blood
4 mL
3
12 mL
Health monitoring/safety 
monitoring (may be more 
than 1 tube)b
Blood
5 mL/Cycle 
2
50 mL
Archived formalin-fixed, 
paraffin-embedded tumor 
tissue
Tissue
5 micron
21 slides
105 micron
Drug concentration of 
abemaciclib for all patients in 
trial
Blood
2 mL
5
10 mL
Drug concentration of 
abemaciclib for all patients in 
Part C
Tissue
50 mg
1
50 mg
Drug concentration of 
abemaciclib for all patients in 
Part C
CSF
2 mL
1
2 mL
Drug concentration of 
abemaciclib for all patients in 
Part Fc
CSF
2 mL
2
4 mL
Pharmacogenetic blood 
sample
Blood
9 mL
1
9 mL
Plasma for exploratory 
biomarker
Blood
6 mL
3
18 mL
Hepatic monitoringd
Blood
3 - 30 mL
-
a
Covers Cycles 1 through 9 and 1 postdiscontinuation follow up visit.
b
Additional samples may be drawn if needed for safety purposes.
c
Additional CSF to be collected for local cytology results.
d
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 10.
Protocol JPBO Inducers and 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 all these medications (except EIAED as noted below), if clinically indicated.  
However, these medications should be avoided or substituted, if possible.
Inducers of CYP3A
Carbamazepinea
Dexamethasoneb
Phenobarbital/phenobarbitonea
Phenytoina
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide


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CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine
Abbreviations:  CYP = cytochrome P450; EIAED = enzyme-inducing antiepileptic drugs; HIV = human
immunodeficiency virus.
a
Patients may not receive concurrent treatment with EIAEDs.  Patients requiring treatment with antiepileptic 
drugs should be prescribed non-EIAED (eg, levetiracetam, lacosamide, lamotrigine, etc).
b
All patients may receive supportive therapy with dexamethasone.


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Attachment 11.
Protocol JPBO Amendment(d) Summary
A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive 
Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma
Overview
Study I3Y-MC-JPBO, a Phase 2 Study of Abemaciclib in Patients with Brain Metastases 
Secondary to Hormone Receptor Positive Breast Cancer, Non-Small Cell Lung Cancer or
Melanoma has been amended.  The new protocol is indicated by Amendment (d) and will be 
used to conduct the study in place of any preceding version.
The overall changes and rationale for the changes made to this protocol are as follows:

Included TBL and VTE in abbreviations (Section 4).

Section 5.4 incorporated rationale for Amendment (d) to update safety monitoring 
information for hepatic conditions, renal function, and VTEs.

Section 9.4.1.1, Table JPBO.2 modified along with Sections 9.4.1.1.3, 9.4.1.1.4, and 
9.4.1.1.4.1, and incorporated Section 9.4.1.1.4.2 for alignment with safety updates.

Updated requirements for AE/SAE reporting in the CRF (Section 10.3.1).

Sections 10.3.4.1, 10.3.4.2, and 10.3.4.3 incorporated safety monitoring language for hepatic 
conditions, renal function, 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 5.4. Rationale for Amendment (d)
Study JPBK protocol was amended to update the dosing guidance for cases of non-hematologic 
toxicity, diarrhea, and ALT increase.  This amendment will harmonize the dosing guidance 
across all clinical trials of abemaciclib in the metastatic setting.  The amendment updated the 
safety language regarding hepatic monitoring, assessment of renal function, and venous 
thromboembolic events (VTEs) for ongoing patients. Minor typographical and formatting edits 
were made throughout the document for clarity and consistency.


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Section 9.4.1.1. Dose Adjustments and Delays
Table JPBO.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study
I3Y-MC-JPBO
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
…
…
…
…
Hematologic toxicity:  If 
pPatient requires 
administration of blood cell 
growth factors
Sections 9.4.1.1.3 and 9.6.4.
Regardless of severity
(Use of gGrowth factors use 
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 
led to the use of growth 
factor.
Nonhematologic Toxicitya
(except diarrhea and ALT 
increased)
Section 9.4.1.1.4
Persistent or recurrentb Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY MUST be 
suspended until toxicity 
resolves to either baseline 
or Grade 1.
Dose MAY MUST be 
reduced by 1 dose level -
investigator's discretion.
…
…
…
…
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Requires hospitalization or Grade 3 
or 4Grade 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.MUST be 
reduced by 1 dose level.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
Persistent or recurrentb Grade 2 that 
does not resolve with maximal 
supportive measures within 
24 hours to at least Grade 1or any 
Grade of diarrhea that requires 
hospitalization
Dose SHOULD MUST be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY MUST be 
reduced by 1 dose level -
investigator's discretion.
Diarrhea
Sections 9.4.1.1.4 and 9.6.5
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial 
Grade 2 diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 9.4.1.1.4.1 and 9.6.5
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-JPBO
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
ALT Increased 
(Sections 9.4.1.1.4.2 and 
10.3.4.1.)
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 9.4.1.1.4.2 and 
10.3.4.1.)
Grade 4 (>20.0×ULN)
Abemaciclib 
MUST
be 
discontinued.
Abemaciclib MUST be 
discontinued.
ALT Increased with increased 
total bilirubin, in the absence 
of cholestasis
(Sections 9.4.1.1.4.2 and 
10.3.4.1.)
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
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; SHOULD = not mandatory but highly recommended; 
MUST = mandatory.
a
Additional guidance for renal and hepatic monitoring is in Sections 10.3.3.1 and 10.3.3.2.
b Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:
•
shows stable hematological counts (Grade ≤2) during that timeframe
•
has absence of any signs or risk of infection 
•
is benefiting from study treatment
c
Note: the patient who presents with no liver metastases at baseline.
d Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
10.3.4.1 for additional guidance for hepatic monitoring
Section 9.4.1.1.3. Hematologic Toxicity
…
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
…


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Section 9.4.1.1.4. Nonhematologic Toxicity
…
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
, refer to Section 9.4.1.1.4.1 or ALT increased, refer to Section 10.3.4.1) that does not resolve 
with maximal supportive measures within 7 days to either baseline or Grade 1, then dosing of 
abemaciclib may must be suspended (until the toxicity resolves to either baseline or Grade 1), 
and the dose of abemaciclib may must be reduced by 1 dose level as outlined in Table JPBO.3 at 
the discretion of the investigator.  
…
Section 9.4.1.1.4.1. Diarrhea
…
If a patient experiences Grade 2 diarrhea that does not resolve with maximal supportive measures 
(refer to Section 9.6.5) 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 if a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve 
with maximal supportive measures (refer to Section 9.6.5) within 24 hours to at least Grade 1, 
then dosing should must be suspended (until the toxicity resolves to at least Grade 1), and the 
dose of abemaciclib may must be reduced by 1 dose level as outlined in Table JPBO.3 at the 
discretion of the investigator.  If the same dose level was resumed and diarrhea recurred despite 
maximal supportive measures, the dose must be reduced by 1 dose level as outlined in Table 
JPBO.3.  
Section 9.4.1.1.4.2. Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBO.3. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, abemaciclib must be 
suspended until the toxicity has resolved to at least Grade 1 and the dose must be reduced by 
1 dose level. Discontinue abemaciclib for Grade 3 increased ALT (˃5.0 x ULN) with total 
bilirubin (TBL) >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, the patient 
must be discontinued from abemaciclib.  Refer to Section 10.3.4.1 for additional hepatic 
monitoring guidance.


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Section 10.3.1. Adverse Events
…
In addition, the investigator will record all relevant AE/SAE information in the CRFall AEs 
occurring after the patient receives the first dose of abemaciclib must be reported to Lilly or its 
designee via eCRF. 
…
Section 10.3.4.1. 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 with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
Section 10.3.4.2. Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPBO.3).


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Section 10.3.4.3. Venous Thromboembolic Events (VTEs)
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (e.g., deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice. In studies with single-
agent abemaciclib use in the mBC population or other tumor types, including NSCLC, no 
increased rates of VTEs were observed as compared to the incidence of VTEs for these particular 
patient populations who were treated with other anticancer agents.  
Attachment 10. Protocol JPBO Inducers and Strong Inhibitors of CYP3A4 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 all these medications (except EIAED as noted below), if clinically indicated.  
However, these medications should be avoided or substituted, if possible.
Inducers of CYP3A4
Carbamazepinea
Dexamethasoneb
Phenobarbital/phenobarbitonea
Phenytoina
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole


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Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
…
…

Prot_000.pdf: 
Protocol I3Y-MC-JPBO 
 
A Phase 2 Study of Abemaciclib in Patients with Brain Metastasis Secondary to Hormone 
Receptor Positive Breast Cancer, Non-Small Cell Lung Cancer, or Melanoma 
 
NCT02308020 
 
Approval Date: 11-Nov-2014 
 
 
 


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1.
Protocol I3Y-MC-JPBO
A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive 
Breast Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments are subject to United States Freedom of Information Act Exemption 4.
Abemaciclib (LY2835219)
This study is a global, multicenter, open-label, Phase 2 trial of abemaciclib in patients with 
brain metastases secondary to hormone receptor positive breast cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-Nov-2014 GMT


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2.
Synopsis
Study Rationale
Brain metastases occur in a significant number of cancer patients, with the incidence being 
highest in lung and breast cancers.  In the United States (US), the incidence of brain metastases 
is approximately 5% in breast cancer patients, across genders and breast cancer subtypes.  
Although targeted anticancer agents have shown promising results in treating extracranial 
disease, delivery of these agents to the central nervous system (CNS) has presented challenges.
Abemaciclib (LY2835219) is an oral, selective, and potent small molecule inhibitor of 
cyclin-dependent kinase (CDK) 4 and 6 (CDK4/6) with acceptable physical characteristics, 
pharmacokinetic (PK) properties, and safety profile in nonclinical species.  Cell-based studies in 
breast cancer models, which evaluated in vitro growth inhibition across a diverse panel of 
46 breast cell lines representing the known molecular subgroups of breast cancer, indicated that 
abemaciclib inhibits CDK4/6 and induces G1 arrest, specifically in retinoblastoma (Rb) cell lines
with functional Rb.  These studies also showed that sensitivity to CDK4/6 inhibition was greater 
in estrogen receptor positive (ER+) lines with luminal histology. Abemaciclib has demonstrated 
acceptable clinical safety and evidence of single-agent activity in a tumor-specific cohort of 
women with hormone receptor positive (HR+) metastatic breast cancer in the ongoing Phase 1 
Study I3Y-MC-JPBA (JPBA), including patients with human epidermal growth factor receptor 2 
(HER2) positive (HER2+) and HER2 negative (HER2-) disease, as well as in a single patient 
with CNS target disease.  
In radiolabeled studies in rats, [14C]LY2835219-derived radioactivity was measurable in CNS
tissues (cerebellum, cerebrum, medulla, and spinal cord) protected by the blood-brain barrier 
(BBB) through 24 hours after a single dose.  Abemaciclib has also been shown to inhibit 
glioblastoma intracranial xenografts, resulting in a statistically significant and dose-dependent 
improvement in survival.  These preclinical results demonstrating that abemaciclib crosses the 
BBB, as well as the clinical findings from Study JPBA, support further investigation of
abemaciclib in patients with brain metastases secondary to HR+ breast cancer.  
Study I3Y-MC-JPBO (JPBO) is a multicenter, open-label, Phase 2 trial of abemaciclib in 
patients with brain metastases secondary to HR+ breast cancer.  This study will evaluate the 
safety and efficacy of abemaciclib in patients with HR+ metastatic breast cancer and new or not 
previously irradiated brain lesions as well as previously irradiated progressive brain lesions.  


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Clinical Protocol Synopsis:  Study I3Y-MC-JPBO
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  A Phase 2 Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone 
Receptor Positive Breast Cancer
Number of Planned Patients: 120
Entered: 150
Enrolled/Randomized: 120
Completed: 120
Phase of Development:  2
Length of Study:  approximately 36 months
Planned first patient visit:  February 2015
Planned last patient visit, excluding the continued access period: February 2018
Planned interim analysis:  The interim analysis of objective intracranial response rate (OIRR) for each study part 
(Part A or Part B) will occur 6 months after the 23rd patient has been enrolled into each respective part.  
Objectives:  The primary objective of this study is to evaluate abemaciclib with respect to OIRR (complete 
response [CR] + partial response [PR]) based on tumor assessments and brain metastases response criteria: 

in women with brain metastases secondary to HR+, HER2+ breast cancer.  

in women with brain metastases secondary to HR+, HER2- breast cancer.
The secondary objectives of the study are to evaluate abemaciclib with respect to:

Intracranial disease per brain metastases response criteria
o
Best overall intracranial response (BOIR)
o
Duration of intracranial response (DOIR) (CR + PR)
o
Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
o
Intracranial clinical benefit rate (ICBR) (CR + PR + SD ≥6 months) 

Overall
o
Overall survival (OS)
o
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
and brain metastases response criteria
o
Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and brain metastases response 
criteria
o
Progression-free survival (PFS) per RECIST v1.1 and brain metastases response criteria

Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT)

Safety and tolerability 

PK of abemaciclib and its metabolites
The exploratory objectives of the study are:

To explore change in neurocognitive function as assessed by the Trail Making Tests A and B

To explore change in neurologic signs as assessed by the Neurologic Assessment in Neuro-Oncology 
(NANO) scale

To explore the concentration of abemaciclib and its metabolites in plasma, cerebrospinal fluid (CSF), and 
brain tumor tissue collected at the time of surgical resection for patients participating in Part C, as well as 
patients in Parts A and B with progressive disease (PD) and planned surgical resection.  

To explore biomarkers related to the mechanism of action of abemaciclib, the cell cycle, and/or the 
pathogenesis of breast cancer. 
Study Design:  Study JPBO is a multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain 
metastases secondary to HR+ breast cancer.  The study will consist of 3 parts; 2 of these parts will each accrue as 
few as 23 patients or as many as 56 patients with metastatic breast cancer and at least 1 new or not previously 
irradiated brain lesion or at least 1 progressive previously irradiated brain lesion.  These 2 parts will include 
patients with HR+, HER2+ breast cancer (Part A) and HR+, HER2- breast cancer (Part B).  For patients in Part A 


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and Part B with PD, if surgical resection of brain lesions is clinically indicated following disease progression, these 
patients may consent to provide brain tumor tissue and continue on abemaciclib for up to 14 additional days until 
the time of scheduled surgery.  The third part (Part C) will include approximately 8 breast cancer patients with 
either HR+, HER2+ or HR+, HER2- disease who have 1 to 3 intracranial lesions and for whom surgical resection 
is clinically indicated in order to assess concentrations of abemaciclib and its metabolites in plasma, CSF, and 
brain tumor tissue.  These patients may resume abemaciclib dosing at least 15 days but no greater than 21 days 
postoperatively and continue until 1 of the criteria for discontinuation is met.  
Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients are eligible for inclusion in the study if 
they meet all of the following criteria: 1) have histologically confirmed HR+ metastatic breast cancer; 2) have 
confirmed HER2 overexpression (HER2+) status (Part A), disease which does not demonstrate HER2 
overexpression (HER2-) (Part B), or either HER2+ or HER2- status with brain lesion(s) for which surgical 
resection is clinically indicated and agree to provide posttreatment (5 to 14 days after initiating abemaciclib) brain
tumor tissue (Part C [surgical]); 3) have either ≥1 new or not previously irradiated measurable metastatic brain 
lesion ≥10 mm in the longest diameter (LD) or a progressive previously irradiated metastatic brain lesion (Parts A 
and B) or 1 to 3 metastatic brain lesion(s) for which surgical resection is clinically indicated (Part C [surgical]); 4)
have completed local therapy (surgical resection, whole brain radiotherapy [WBRT], or stereotactic radiosurgery
[SRS]) ≥14 days prior to initiating abemaciclib and recovered from all acute effects; 5) if receiving concomitant 
corticosteroids, must be on a stable or decreasing dose for at least 7 days prior to the baseline gadolinium-enhanced 
magnetic resonance imaging (Gd-MRI); 6) have a Karnofsky performance status of ≥70; 7) have a life expectancy 
≥12 weeks; 8) if currently receiving endocrine therapy, may continue receiving the same endocrine therapy 
provided that extracranial disease is stable for at least 3 months and intracranial disease progression has occurred 
while on this endocrine therapy (if these conditions are not met, patients must discontinue endocrine therapy prior 
to initiation of abemaciclib); 9) have discontinued all previous therapies for cancer for at least 14 days prior to 
receiving abemaciclib and recovered from the acute effects of therapy (Note:  patients currently receiving 
trastuzumab and receiving clinical benefit may continue to receive trastuzumab throughout the study, but 
concurrent treatment with trastuzumab emtansine [T-DM1] is not allowed); 10) for patients receiving concurrent 
trastuzumab, must have left ventricular ejection fraction within investigative site’s normal range; 11) have 
adequate organ function; 12) are female and 18 years of age; 13) if a female of childbearing potential, must have 
a negative serum pregnancy test within 7 days of the first dose of abemaciclib and agree to use a medically 
approved nonhormonal contraceptive method during the treatment period and for 3 months following the last dose 
of abemaciclib; 14) are reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures; and 15) are able to swallow capsules.
Patients will be excluded from the study if they meet any of the following criteria: 16) require immediate local 
therapy, including but not limited to WBRT, SRS, or surgical resection, for treatment of brain metastases; 
17) require concurrent anticancer treatment at any time during the study treatment period (except endocrine 
therapy, trastuzumab [HER2+ patients], or surgical resection [Part C patients only]); 18) are taking concurrent 
enzyme-inducing antiepileptic drugs (EIAED); 19) have evidence of significant (ie, symptomatic) intracranial 
hemorrhage; 20) have evidence of leptomeningeal metastases on brain Gd-MRI or by previously documented CSF 
cytology; 21) have experienced >2 seizures within 4 weeks prior to study entry; 22) have visceral crisis; 23) have 
previously received treatment with any CDK4/6 inhibitor; 24) have known contraindication to Gd-MRI; 25) are 
currently receiving lapatinib; 26) are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the study drug used in this study), or concurrently enrolled in any 
other type of medical research judged not to be scientifically or medically compatible with this study; 27) have 
received treatment with a drug that has not received regulatory approval for any indication within 14 days of the 
initial dose of abemaciclib; 28) have a personal history within the last 12 months of any ventricular arrhythmia 
(including but not limited to ventricular tachycardia and ventricular fibrillation) or sudden cardiac arrest; 29) have 
serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this
study; 30) have a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea; 31) have a history 


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of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in complete 
remission with no therapy for a minimum of 3 years; 32) are lactating; 33) have an active systemic fungal and/or 
known viral infection; 34) have an acute bacterial infection requiring intravenous antibiotics; 35) have received 
recent or concurrent yellow fever vaccination.  
Test Product, Dosage, and Mode of Administration:  Abemaciclib 200 mg will be supplied as capsules 
administered orally every 12 (± 2) hours on Days 1 through 21 of a 21-day cycle, for a total of 42 doses per cycle.
Planned Duration of Treatment:  
Treatment period:  until disease progression or other discontinuation criteria are fulfilled.
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death or overall study completion.
Criteria for Evaluation:  
Efficacy:  

OIRR (CR + PR), as defined by brain metastases response criteria

BOIR

DOIR (CR + PR) 

IDCR (CR + PR + stable disease [SD]) 

ICBR (CR + PR + SD ≥6 months) 

OS

ORR per RECIST v1.1 and brain metastases response criteria

DCR per RECIST v1.1 and brain metastases response criteria

PFS per RECIST v1.1 and brain metastases response criteria
Safety:  

Adverse events (AEs) and serious adverse events (SAEs) using Medical Dictionary for Regulatory 
Activities (MedDRA) and National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE) v4.0
Health Outcomes:  

MDASI-BT to measure patient symptoms
Pharmacokinetics:  

Population PK parameters of abemaciclib and its metabolites
Exploratory:

Trail Making Tests A and B, to measure neurocognitive function

NANO scale to measure neurologic response or progression

Relative concentrations of abemaciclib and its metabolites in plasma, CSF, and tumor tissue

Exploratory correlative analysis of biomarkers related to the mechanism of action of abemaciclib, the cell 
cycle, and/or the pathogenesis of breast cancer.  
Statistical Methods:  
Statistical:  
The primary objective of this clinical trial is to estimate the antitumor activity, measured by OIRR of abemaciclib 
in patients with brain metastases secondary to HR+ breast cancer.  
Two separate Simon 2-stage designs will be employed for this study; one will be used for Part A (patients with 
HR+, HER2+ disease) and another for Part B (patients with HR+, HER2- disease).  Each design assumes a 1-sided 
type I error of 0.05 and 80% power.  
For Part A, up to 56 qualified patients will be enrolled with the possibility of stopping the study early for either 
lack of efficacy or unacceptable toxicity.  Twenty-three qualified patients will be enrolled in the first stage.  If 
fewer than 2 of the first 23 patients respond to abemaciclib, accrual will be stopped, and the conclusion will be 
drawn that abemaciclib is not worthy of further study in the Part-A population.  If at least 2 of the first 23 patients 
respond to therapy, accrual will continue until 33 additional qualified patients have been enrolled.  A total of 
6 responders out of 56 patients in Part A would need to be observed to warrant further investigation of abemaciclib 


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in this patient population.  
The procedure described above tests the null hypothesis (H0) that the true OIRR of abemaciclib in Part A is ≤5% 
versus the alternative hypothesis (Ha) that the true OIRR is ≥15%.  The probability of early termination of the 
treatment arm under H0 is 0.68.  
Part B will have the identical design as Part A.  
Efficacy:
Efficacy analyses will be conducted on the full analysis set (FAS).  This set includes all data from all enrolled 
patients receiving at least 1 dose of abemaciclib.  OIRR will be reported along with 95% confidence intervals (CIs)
using the normal approximation.  Point estimates and 95% CIs (using the normal approximation to the binomial) 
will be calculated for BOIR, IDCR, ICBR, ORR, and DCR for Part A and Part B.  Time-to-event efficacy 
endpoints (OS, PFS, and DOIR) will be summarized for Part A and Part B using Kaplan-Meier techniques if there 
is sufficient data.  If performed, Kaplan-Meier curves will be generated, and quartiles and point probabilities will 
be calculated.  Interval estimates will be calculated using 95% CIs.
Safety:
Safety analyses will be conducted on the FAS.  
Health Outcomes:
Patients with at least 1 baseline and 1 postbaseline assessment will be included in the analyses.  
MDASI-BT data will be summarized for each study part (Parts A and B) and/or response category (CR/PR, SD, 
PD); change from baseline and time to worsening will be explored.  This summary will include mean, standard 
deviation, median, minimum, maximum, and change from baseline.  The MDASI-BT will be reported as core 
symptoms, brain tumor symptoms, symptom interference, and symptom groupings (affect, cognition, focal 
neurologic deficit, treatment-related symptoms, generalized/disease status symptoms, and gastrointestinal 
symptoms). 
Pharmacokinetics:  
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib and have had 
samples collected.  Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and interindividual PK variability will be computed using nonlinear mixed effect 
modeling (NONMEM).  Covariate effects (such as age, weight, sex, creatinine clearance, and plasma protein 
levels) on the PK parameters of abemaciclib in plasma will also be investigated.  
Pharmacodynamics:
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients from the above 
populations from whom a valid assay result (according to laboratory guideline) has been obtained.  
Pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) collected in this study may 
also be analyzed by means of NONMEM and connected to the population PK model in a PK/pharmacodynamic
model.
Exploratory:

Trail Making Tests A and B:  Summary statistics will be provided for Study Part A and Part B and/or 
response category (CR/PR, SD, PD); change from baseline and time to worsening will be explored.

NANO Scale:  Clinical response and progression will be explored and summarized for the NANO scale 
using descriptive statistics.

Drug Concentrations in Plasma, Cerebrospinal Fluid, and Resected Tumor Tissue:  The relative 
concentrations of abemaciclib and its metabolites in plasma, CSF, and tumor tissue collected at the time of 
surgical resection for patients participating in Part C will be explored.  Additionally, patients in Part A and 
Part B with PD and surgical resection clinically indicated may consent to provide samples for this 


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exploratory analysis.  

Biomarkers:  Summary statistics for biomarkers with continuous measures will include means, medians,
corresponding standard errors, quartiles, and ranges. Biomarkers with discrete measures will be 
summarized in frequency tables. Correlative analyses may be performed to investigate associations 
between biomarkers and clinical endpoints.


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3.
Table of Contents
A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive Breast 
Cancer
Section
Page
1.
Protocol I3Y-MC-JPBO  A Phase 2 Study of Abemaciclib in Patients 
with Brain Metastases Secondary to Hormone Receptor Positive 
Breast Cancer......................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................20
6.
Objectives.........................................................................................................................22
6.1.
Primary Objective ........................................................................................................22
6.2.
Secondary Objectives...................................................................................................22
6.3.
Exploratory Objectives.................................................................................................22
7.
Study Population...............................................................................................................23
7.1.
Inclusion Criteria..........................................................................................................23
7.2.
Exclusion Criteria ........................................................................................................25
7.3.
Discontinuation............................................................................................................26
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................26
7.3.2.
Discontinuation of Investigational Product...........................................................26
7.3.3.
Discontinuation from the Study............................................................................27
7.3.4.
Patients who are Lost to Follow-Up .....................................................................27
7.3.5.
Discontinuation of Study Sites .............................................................................27
7.3.6.
Discontinuation of the Study................................................................................27
8.
Investigational Plan...........................................................................................................28
8.1.
Summary of Study Design............................................................................................28
8.1.1.
Study Completion and End of Trial......................................................................30
8.1.2.
Continued Access Period......................................................................................31
8.2.
Discussion of Design and Control ................................................................................32
9.
Treatment..........................................................................................................................33
9.1.
Treatments Administered .............................................................................................33
9.2.
Materials and Supplies .................................................................................................33
9.3.
Method of Assignment to Treatment ............................................................................33


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9.4.
Selection and Timing of Doses.....................................................................................34
9.4.1.
Special Treatment Considerations ........................................................................34
9.4.1.1.
Dose Adjustments and Delays ........................................................................34
9.4.1.1.1.
Dose Adjustments.....................................................................................34
9.4.1.1.2.
Dose Suspension (within a Cycle) and Cycle Delay ..................................34
9.4.1.1.3.
Hematologic Toxicity ...............................................................................35
9.4.1.1.4.
Nonhematologic Toxicity..........................................................................35
9.4.1.1.4.1.
Diarrhea..............................................................................................35
9.5.
Blinding .......................................................................................................................36
9.6.
Concomitant Therapy...................................................................................................36
9.6.1.
Endocrine and HER2-Directed Therapies.............................................................36
9.6.2.
Surgery ................................................................................................................37
9.6.3.
Supportive Care ...................................................................................................37
9.6.4.
Growth Factor......................................................................................................37
9.6.5.
Supportive Management for Diarrhea...................................................................37
9.7.
Treatment Compliance .................................................................................................38
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................39
10.1. Efficacy Measures........................................................................................................39
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................39
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................39
10.1.3.
Primary Efficacy Measure....................................................................................40
10.1.4.
Secondary Efficacy Measures...............................................................................41
10.1.5.
Exploratory Measures ..........................................................................................42
10.2. Health Outcome/Quality of Life Measures ...................................................................42
10.2.1.
Patient-Reported Outcomes..................................................................................42
10.2.1.1.
MD Anderson Symptom Inventory – Brain Tumor 
Module...........................................................................................................42
10.3. Safety Evaluations........................................................................................................43
10.3.1.
Adverse Events ....................................................................................................44
10.3.1.1.
Serious Adverse Events ..................................................................................45
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................46
10.3.2.
Other Safety Measures .........................................................................................47
10.3.2.1.
Electrocardiograms.........................................................................................47
10.3.2.2.
Echocardiograms or Multi-Gated Acquisition Scans.......................................47
10.3.3.
Safety Monitoring ................................................................................................47


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10.3.4.
Complaint Handling.............................................................................................48
10.4. Sample Collection and Testing.....................................................................................48
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................48
10.4.2.
Samples for Biomarkers .......................................................................................48
10.4.2.1.
Blood Samples for Pharmacogenetic Evaluations............................................49
10.4.2.2.
Plasma Samples for Exploratory Biomarker Evaluations.................................49
10.4.2.3.
Archived Tumor Tissue ..................................................................................49
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................50
10.4.3.1.
Drug Concentrations for All Part C Patients and Part A 
and Part B Patients with Progressive Disease and 
Planned Surgical Resection.............................................................................51
10.5. Appropriateness of Measurements................................................................................51
11.
Data Quality Assurance.....................................................................................................52
11.1. Data Capture System....................................................................................................52
12.
Sample Size and Statistical Methods .................................................................................53
12.1. Determination of Sample Size ......................................................................................53
12.2. Statistical and Analytical Plans.....................................................................................53
12.2.1.
General Considerations ........................................................................................53
12.2.2.
Patient Disposition...............................................................................................54
12.2.3.
Patient Characteristics..........................................................................................54
12.2.4.
Concomitant Therapy...........................................................................................54
12.2.4.1.
Postdiscontinuation Therapy...........................................................................54
12.2.5.
Treatment Compliance .........................................................................................54
12.2.6.
Primary Outcome and Methodology.....................................................................55
12.2.7.
Secondary Outcome and Methodology.................................................................55
12.2.8.
Pharmacokinetic and/or Pharmacodynamic Analyses ...........................................55
12.2.9.
Exploratory Analyses...........................................................................................56
12.2.9.1.
Trail Making Tests A and B............................................................................56
12.2.9.2.
Neurologic Assessment in Neuro-Oncology Scale ..........................................56
12.2.9.3.
Drug Concentrations in Samples from Surgical Patients..................................56
12.2.9.4.
Biomarker Analyses .......................................................................................56
12.2.10. Health Outcome/Quality of Life Analyses............................................................56
12.2.11. Safety Analyses....................................................................................................57
12.2.12. Interim Analyses..................................................................................................57
12.2.13. Subgroup Analyses ..............................................................................................58
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................59
13.1. Informed Consent.........................................................................................................59


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13.2. Ethical Review.............................................................................................................59
13.3. Regulatory Considerations ...........................................................................................59
13.3.1.
Investigator Information.......................................................................................60
13.3.2.
Protocol Signatures ..............................................................................................60
13.3.3.
Final Report Signature .........................................................................................60
14.
References ........................................................................................................................61


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List of Tables
Table
Page
Table JPBO.1.
Treatment Regimens/Dosing Schedule ...................................................33
Table JPBO.2.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBO ..................34
Table JPBO.3.
Secondary Efficacy Endpoints................................................................41
Table JPBO.4.
Exploratory Endpoints............................................................................42
Table JPBO.5.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........44


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List of Figures
Figure
Page
Figure JPBO.1.
Illustration of study design......................................................................29
Figure JPBO.2.
Study period and continued access period diagram. ................................31


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBO Study Schedule...............................................................64
Attachment 2.
Protocol JPBO Clinical Laboratory Tests................................................73
Attachment 3.
Protocol JPBO Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................74
Attachment 4.
Protocol JPBO Karnofsky Performance Status........................................75
Attachment 5.
Protocol JPBO Brain Metastases Response Criteria ................................76
Attachment 6.
Protocol JPBO RECIST Criteria 1.1 .......................................................77
Attachment 7.
Protocol JPBO Electrocardiogram and Pharmacokinetic Sampling 
Schedule – Parts A and B .......................................................................84
Attachment 8.
Protocol JPBO Electrocardiogram and Pharmacokinetic Sampling 
Schedule – Part C ...................................................................................85
Attachment 9.
Protocol JPBO Sampling Summary ........................................................86
Attachment 10.
Protocol JPBO Inducers and Strong Inhibitors of CYP3A4.....................87


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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BBB
blood-brain barrier
BOIR
best overall intracranial response
CDK4/6
cyclin-dependent kinases 4 and 6
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
collection database
A computer database where clinical trial data are entered and validated.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit and no undue risks may continue to 
receive study therapy until 1 of the criteria for discontinuation is met. 
CNS
central nervous system


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CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.
CR
complete response
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DCSI
Development Core Safety Information
DOIR
duration of intracranial response
EIAED
enzyme-inducing antiepileptic drugs
ECG
electrocardiogram
EDTA
ethylenediaminetetraacetic acid
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ER
estrogen receptor
ER+
estrogen receptor positive
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
FAS
full analysis set
FISH
fluorescence in-situ hybridization


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GCP
good clinical practice
Gd-MRI
gadolinium-enhanced magnetic resonance imaging
H0
null hypothesis
Ha
alternative hypothesis
H&E
hematoxylin and eosin
HER2
human epidermal growth factor receptor 2
HER2+/-
human epidermal growth factor receptor 2 positive or negative
HR+
hormone receptor positive
IB
Investigator’s Brochure
ICBR
intracranial clinical benefit rate
ICF
informed consent form
ICH
International Conference on Harmonisation
IDCR
intracranial disease control rate
IHC
immunohistochemistry
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or 
3.
used to gain further information about the authorized form.
In this study, the Investigational Product is abemaciclib.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ISH
in-situ hybridization
IWRS
interactive web-response system


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LC/MS/MS
liquid chromatography-tandem mass spectrometry
LD
longest diameter
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LLT
Lower Level Term
MDASI-BT
MD Anderson Symptom Inventory – Brain Tumor
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition
NANO
Neurologic Assessment in Neuro-Oncology
NCI
National Cancer Institute
NONMEM
nonlinear mixed effect modeling
OIRR
objective intracranial response rate
ORR
objective response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetic
PR
partial response
PT
Preferred Term
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis
Rb
retinoblastoma


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RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
rescreen
to screen a patient who was previously declared a screen failure for the same study
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 study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet 1 or more criteria required for participation in a trial
SD
stable disease
SOC
System Organ Class
SRS
stereotactic radiosurgery
Study completion
This study will be considered complete after the final evaluation of overall survival is 
performed.  
SUSARs
suspected unexpected serious adverse reactions 
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limits of normal
US
United States
WBRT
whole brain radiotherapy


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A Phase 2 Study of Abemaciclib in Patients with Brain 
Metastases Secondary to Hormone Receptor Positive Breast 
Cancer
5.
Introduction
Brain metastases occur in a significant number of cancer patients, with the incidence being 
highest in lung and breast cancers.  In the United States (US), the incidence of brain metastases 
is approximately 5% in breast cancer patients, across genders and breast cancer subtypes 
(Davis et al. 2012).  However, in patients with human epidermal growth factor receptor 2
(HER2) positive (HER2+) metastatic breast cancer, approximately 30% to 55% of patients will 
develop brain metastases (Lin et al. 2013).  Current standard-of-care treatment options include 
whole brain radiotherapy (WBRT), surgical resection, and stereotactic radiosurgery (SRS).  
Though surgery and radiotherapy are effective in palliating neurological symptoms, these 
therapies are associated with neurocognitive deficits (Lin et al. 2013), and the prognosis for 
patients remains poor. The median overall survival (OS) of patients with brain metastases 
secondary to breast cancer is 13.8 months (Sperduto et al. 2012).  However, with recent 
improvements in systemic disease control in patients with estrogen receptor (ER) positive (ER+), 
HER2+ disease the median OS is approximately 2 years (Lin et al. 2013).  Although targeted 
anticancer agents have shown promising results in treating extracranial disease, delivery of these 
agents to the central nervous system (CNS) has presented challenges (Adamo et al. 2011). The 
blood-brain barrier (BBB) arises from both a structural barrier and drug efflux transporters that 
may prevent most anticancer drugs from efficiently reaching brain tumors or metastases, though 
the BBB may be partially compromised at the metastatic site, enabling the delivery of some 
drugs to the tumor site (Deeken and Loscher 2007).
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002).  Cyclin-dependent 
kinases 4 and 6 (hereafter referred to as CDK4/6) participate in a complex with the D type 
cyclins to initiate progression through the G1 restriction point.  The CDK4/6 – cyclin D1 
complex regulates the G1 restriction point through phosphorylation and inactivation of the 
retinoblastoma (Rb) tumor suppressor protein, thereby promoting S phase entry.  Alterations in 
this pathway occur frequently in human cancers and involve 1) loss of functional CDK inhibitors 
through deletion or epigenetic silencing, 2) activating mutations and/or overexpression of 
CDK4/6 or the D type cyclins, and 3) loss of functional Rb through mutation or deletion.  Except 
for tumors with functional loss of Rb, which functions downstream of the CDK4/6 – cyclin D1 
complex, most cancers are potentially sensitive to pharmacologic inhibition of CDK4/6.  From a 
therapeutic standpoint, the goal of inhibiting CDK4/6 with a small molecule is to prevent cell 
cycle progression through the G1 restriction point, thus arresting tumor growth.  
Abemaciclib (LY2835219) represents a selective and potent small molecule inhibitor of CDK4/6 
with acceptable physical characteristics, pharmacokinetic (PK) properties, and safety profile in 
nonclinical species.  Cell-based studies in breast cancer models have demonstrated that 


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abemaciclib inhibits CDK4/6 to induce G1 arrest specifically in cell lines with functional Rb
versus lines which lack functional Rb.  These studies, which evaluated in vitro growth inhibition 
across a diverse panel of 46 breast cell lines representing the known molecular subgroups of 
breast cancer, indicated that sensitivity to CDK4/6 inhibition was greater in ER+ lines with 
luminal histology. Abemaciclib shows antitumor activity in additional nonclinical models of 
multiple human cancers including, but not limited to, colorectal cancer, glioblastoma multiforme, 
acute myeloid leukemia, non-small cell lung cancer, and mantle cell lymphoma. In radiolabeled 
studies in rats, [14C]LY2835219-derived radioactivity was measurable in CNS tissues 
(cerebellum, cerebrum, medulla, and spinal cord) protected by the BBB through 24 hours 
postdose after a single dose.  Abemaciclib has also been shown to inhibit glioblastoma 
intracranial xenografts, resulting in a statistically significant and dose-dependent improvement in 
survival (Sanchez-Martinez et al. 2011).  
In the ongoing Phase 1 Study I3Y-MC-JPBA (JPBA) abemaciclib has demonstrated acceptable 
safety across 5 tumor-specific cohorts at the maximum tolerated dose of 200 mg every 12 hours. 
The most common treatment-emergent adverse events (TEAEs) possibly related to study drug 
included diarrhea, nausea, fatigue, vomiting, and neutropenia.  Abemaciclib has also
demonstrated evidence of clinical activity in women with hormone receptor positive (HR+)
metastatic breast cancer, including patients with HER2+ and HER2 negative (HER2-) disease, as 
well as in a single patient with CNS target disease.  These clinical results, as well as the 
preclinical findings demonstrating that abemaciclib crosses the BBB, support further 
investigation of abemaciclib in patients with brain metastases secondary to HR+ breast cancer.  
The Phase 2 Study I3Y-MC-JPBO (JPBO) will evaluate the safety and efficacy of abemaciclib in 
patients with HR+ metastatic breast cancer and new or not previously irradiated brain lesions as 
well as previously irradiated progressive brain lesions.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of abemaciclib may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to abemaciclib may be found in Section 7 
(Development Core Safety Information [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate periodically during the course of the study may be found in 
Section 6 (Effects in Humans) of the IB.  


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6.
Objectives
6.1.
Primary Objective
To evaluate abemaciclib with respect to objective intracranial response rate (OIRR; complete 
response [CR] + partial response [PR]) based on tumor assessments and brain metastases 
response criteria (see Attachment 5):  

in women with brain metastases secondary to HR+, HER2+ breast cancer.

in women with brain metastases secondary to HR+, HER2- breast cancer.
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:
To evaluate abemaciclib with respect to:

Intracranial disease per brain metastases response criteria
o
Best overall intracranial response (BOIR)
o
Duration of intracranial response (DOIR) (CR + PR)
o
Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
o
Intracranial clinical benefit rate (ICBR) (CR + PR + SD ≥6 months)

Overall
o
OS
o
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1 and brain metastases response criteria
o
Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and brain 
metastases response criteria
o
Progression-free survival (PFS) per RECIST v1.1 and brain metastases response 
criteria

Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor 
(MDASI-BT)

Safety and tolerability 

PK of abemaciclib and its metabolites
6.3.
Exploratory Objectives 

To explore change in neurocognitive function as assessed by Trail Making Tests A and B

To explore change in neurologic signs as assessed by the Neurologic Assessment in 
Neuro-Oncology (NANO) scale

To explore the concentration of abemaciclib and its metabolites in plasma, cerebrospinal 
fluid (CSF), and brain tumor tissue collected at the time of surgical resection for patients 
participating in Part C, as well as patients in Parts A and B with progressive disease (PD) 
and planned surgical resection.  

To explore biomarkers related to the mechanism of action of abemaciclib, the cell cycle, 
and/or the pathogenesis of breast cancer. 


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7.
Study Population
Rescreening of individuals who do not meet the criteria for participation in this study is not 
permitted.  
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have histologically confirmed HR+ metastatic breast cancer. To fulfill the 
requirement for HR+ disease, a breast cancer must express, at least 1 of the 
hormone receptors (ER or progesterone receptor [PgR]).  For ER and PgR 
assays to be considered positive, ≥1% of tumor cell nuclei must be 
immunoreactive by immunohistochemistry (IHC) (Hammond et al. 2010).  
[2]
For Part A:  have confirmed HER2 overexpression (HER2+) status.  To fulfill 
the requirement for HER2+ disease, tumor tissue must demonstrate 3+ by IHC 
or gene amplification by in-situ hybridization (ISH) (Wolff et al. 2013).
For Part B:  have disease which does not demonstrate HER2 overexpression 
(HER2-) by either IHC or ISH.  
For Part C (surgical):  have either HER2+ or HER2- status with brain lesion(s) 
for which surgical resection is clinically indicated and agree to provide 
posttreatment (5 to 14 days after initiating abemaciclib) brain tumor tissue.  
[3]
For Parts A and B:  have ≥1 new or not previously irradiated measurable 
metastatic brain lesion ≥10 mm in the longest diameter (LD) or a progressive 
previously irradiated metastatic brain lesion on radiographic imaging by 
gadolinium-enhanced magnetic resonance imaging (Gd-MRI).  
Note:  for patients with prior WBRT or SRS, previously irradiated lesion(s) 
must demonstrate unequivocal progression on baseline Gd-MRI in the opinion 
of the investigator.  Otherwise new or not previously irradiated lesions must 
be present.  
For Part C (surgical):  have 1 to 3 metastatic brain lesion(s) for which surgical 
resection is clinically indicated.
[4]
have completed local therapy (surgical resection, WBRT, or SRS) ≥14 days 
prior to initiating abemaciclib and recovered from all acute effects. Patients 
are not required to have received prior local therapy for study participation.
[5]
if receiving concomitant corticosteroids, must be on a stable or decreasing 
dose for at least 7 days prior to the baseline Gd-MRI.  


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[6]
have a Karnofsky performance status of ≥70 (see Attachment 4).  
[7]
have a life expectancy ≥12 weeks.
[8]
if currently receiving endocrine therapy, a patient may continue to receive the 
same endocrine therapy provided that extracranial disease is stable for at least 
3 months and intracranial disease progression has occurred while on this 
endocrine therapy.  If these conditions are not met, patients must discontinue 
endocrine therapy prior to initiation of abemaciclib.
[9]
have discontinued all previous therapies for cancer (including cytotoxic 
chemotherapy, targeted therapy [including, but not limited to, everolimus], 
radiotherapy, immunotherapy, and investigational therapy) for at least 14 days 
prior to receiving abemaciclib and recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) except for residual alopecia or 
peripheral neuropathy.
Note:  patients currently receiving trastuzumab and receiving clinical benefit
may continue to receive trastuzumab throughout the study.  Concurrent 
treatment with trastuzumab emtansine (T-DM1) is not allowed.
[10] for patients receiving concurrent trastuzumab, must have left ventricular 
ejection fraction within investigative site’s normal range.
[11] 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 aminotransferase (AST) 3.0 times 
ULN (or ALT and AST ≤5 times ULN if liver metastases are present).  

Renal:  Serum creatinine 1.5 times ULN.
[12] are female and 18 years of age.  
[13] if a female of childbearing potential, must have a negative serum pregnancy 
test within 7 days of the first dose of abemaciclib and agree to use a medically 
approved nonhormonal contraceptive method during the treatment period and 
for 3 months following the last dose of abemaciclib. Contraceptive methods 
may include an intrauterine device [IUD] or barrier method. If condoms are 
used as a barrier method, a spermicidal agent should be added as a double 
barrier protection.  
[14] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[15] are able to swallow capsules.  


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7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[16] require immediate local therapy, including but not limited to WBRT, SRS, or 
surgical resection, for treatment of brain metastases.  
[17] require concurrent anticancer treatment at any time during the study treatment 
period.  
Note:  exceptions are endocrine therapy, trastuzumab (HER2+ patients), or 
surgical resection (Part C patients only).  
[18] are taking concurrent enzyme-inducing antiepileptic drugs (EIAED).
[19] have evidence of significant (ie, symptomatic) intracranial hemorrhage.  
[20] have evidence of leptomeningeal metastases on brain Gd-MRI or by 
previously documented CSF cytology.  
Note:  discrete dural metastases are permitted.  
[21] have experienced >2 seizures within 4 weeks prior to study entry.  
[22] have visceral crisis. Visceral crisis is not the mere presence of visceral 
metastases but implies severe organ dysfunction as assessed by symptoms and 
signs, laboratory studies, and rapid progression of the disease.  
[23] have previously received treatment with any CDK4/6 inhibitor.  
[24] have known contraindication to Gd-MRI.  
[25] are currently receiving lapatinib.
[26] are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the study drug used in this 
study), or concurrently enrolled in any other type of medical research judged 
not to be scientifically or medically compatible with this study.
[27] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 days of the initial dose of abemaciclib.  
[28] have a personal history within the last 12 months of any ventricular 
arrhythmia (including but not limited to ventricular tachycardia and 
ventricular fibrillation) or sudden cardiac arrest.  
[29] 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).  
[30] have a preexisting chronic condition resulting in baseline Grade 2 or higher 
diarrhea.  


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[31] have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years.  
[32] are lactating.  
[33] have an active systemic fungal and/or known viral infection (for example, 
human immunodeficiency virus antibodies, hepatitis B surface antigen, or 
hepatitis C antibodies).  Screening is not required for enrollment.  
[34] have an acute bacterial infection requiring intravenous antibiotics.
[35] have received recent (within 28 days of initial dose of abemaciclib) or
concurrent yellow fever vaccination.  
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
Patients who are discontinued from abemaciclib early will have follow-up procedures performed 
as shown in the Study Schedule (Attachment 1).  
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.  
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without abemaciclib.  Inadvertently enrolled patients 
may be maintained in the study and on abemaciclib 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 abemaciclib if the Lilly CRP does not agree with the investigator’s 
determination it is medically appropriate for the patient to continue. The investigator must 
obtain documented approval from the Lilly CRP to allow the inadvertently enrolled patient to 
continue in the study with or without abemaciclib.  
7.3.2. Discontinuation of Investigational Product
Patients will be discontinued from abemaciclib in the following circumstances:  

the patient has intracranial disease progression according to brain metastases response 
criteria or extracranial disease progression according to RECIST v1.1.  For patients in 
Part A or Part B, if surgical resection of brain lesions is clinically indicated following 
progression, these patients may consent to provide brain tumor tissue and continue on 
drug for up to 14 additional days until the time of scheduled surgery.


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
the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication (except those 
noted as allowable in the inclusion/exclusion criteria); discontinuation of abemaciclib
occurs prior to introduction of the new agent.  

the investigator decides that the patient should be discontinued from abemaciclib.

the patient or the patient’s designee (for example, legal guardian) requests that the patient 
be withdrawn from abemaciclib.  

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.  
7.3.3. Discontinuation from the Study 
Patients will be discontinued from the study in the following circumstances:

the patient or the patient’s designee (for example, legal guardian) requests that the patient 
be withdrawn from the study.  

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice (GCP).  
7.3.4. Patients who are Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
3 diligent attempts (by telephone and/or email) to contact patients who fail to return for a 
scheduled visit or who the site is otherwise unable to follow.  
7.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.  
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.  


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8.
Investigational Plan
8.1.
Summary of Study Design
Study JPBO is a multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain 
metastases secondary to HR+ breast cancer.
The study will consist of a total of 3 parts; 2 of these parts will each accrue as few as 23 patients 
or as many as 56 patients with metastatic breast cancer and at least 1 new or not previously 
irradiated brain lesion or at least 1 progressive previously irradiated brain lesion. These 2 parts 
will include patients with HR+, HER2+ breast cancer (Part A) and HR+, HER2- breast cancer
(Part B). For patients in Part A and Part B with PD, if surgical resection of brain lesions is 
clinically indicated following disease progression, these patients may consent to provide brain 
tumor tissue and continue on abemaciclib for up to 14 additional days until the time of scheduled 
surgery.
The third part (Part C) will include approximately 8 breast cancer patients with either HR+, 
HER2+ or HR+, HER2- disease who have 1 to 3 intracranial lesions and for whom surgical 
resection is clinically indicated in order to assess concentrations of abemaciclib and its 
metabolites in plasma, CSF, and brain tumor tissue.  These patients may resume abemaciclib 
dosing at least 15 days but no greater than 21 days postoperatively and continue until 1 of the 
criteria for discontinuation is met (refer to Section 7.3).  In exceptional cases, in consultation 
with the Lilly CRP, a patient may resume dosing more than 21 days postoperatively.  These 
exceptional cases will not be considered protocol violations.
Figure JPBO.1 illustrates the study design.


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*For patients in Part A and Part B with PD, if surgical resection of brain lesions is 
clinically indicated following disease progression, these patients may consent to 
provide brain tumor tissue and continue on abemaciclib for up to 14 additional days 
until the time of scheduled surgery.  
Abbreviations: HER2+ = HER2 positive; HR+ = hormone receptor positive; 
PD = progressive disease; PO = oral; pts = patients; Q12H = every 12 hours.
Figure JPBO.1.
Illustration of study design.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form (ICF) is signed and ends at the first 
study treatment (or at discontinuation, if no treatment is given).  

Study Period:  begins at the first study treatment and ends at study completion. The 
study period does not include the continued access period.  
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue 
abemaciclib.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from abemaciclib.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue abemaciclib.
Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue abemaciclib and lasts 
approximately 30 days.  


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Long-term follow-up begins the day after short-term follow-up is 
completed and continues until the patient’s death or overall study 
completion.

Continued Access Period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on abemaciclib who continue to experience 
clinical benefit and no undue risks may continue to receive abemaciclib until 1 of the 
criteria for discontinuation is met.  The continued access period includes continued 
access follow-up.
o
Continued Access Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue abemaciclib in the 
continued access period and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
The primary analysis of OIRR for each study Part (Part A or Part B) will occur 6 months after up 
to 56 patients have been enrolled into each respective part. This is to ensure that adequate 
durability of response data is available at the time of analysis. Investigators will continue to 
follow the study schedule for all patients until notified by Lilly that study completion has 
occurred.  
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up (Figure JPBO.2).


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LY2835219
Abbreviations:  OIRR = objective intracranial response rate; OS = overall survival.
Figure JPBO.2.
Study period and continued access period diagram.
8.1.2. Continued Access Period 
The continued access period will apply to this study only if at least 1 patient is still on 
abemaciclib when study completion occurs.
Patients receiving abemaciclib and experiencing ongoing clinical benefit and no undue risks may 
continue to receive abemaciclib in the continued access period until 1 of the criteria for 
discontinuation is met (Section 7.3).  Lilly will notify investigators when the continued access
period begins.  
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.  
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.  
During the continued access period, all AEs, SAEs, and abemaciclib exposure will be reported 
on the eCRF.  SAEs will also be reported to Lilly Global Patient Safety (see Section 10.3.1).  In 
Continued Collection of OS Data
End of 
Trial
Study 
Completion
Patients 
on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
a Lilly will notify sites when this begins and ends.  
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Accesss 
Follow-Up
Primary Analysis 
of OIRR
Final Analysis 
of OS Data
Long-Term 
Follow-Up
Patient on 
Study 
Treatment
Short-Term 
Follow-Up 
Patient 
Discontinues 
Study 
Treatment
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment


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the event that an SAE occurs, Lilly may request additional information (such as local laboratory 
results, concomitant medications, and hospitalizations) in order to evaluate the reported SAE.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly
will not routinely collect the results of these assessments.
8.2.
Discussion of Design and Control
A nonrandomized, uncontrolled design is being used in this study.  Although this design has 
known inferential deficiencies, this design is justified for this study for the following reasons:
1. There is no approved chemotherapeutic option for these patients.
2. The primary endpoint in this study is intracranial tumor response, observation of which is 
putative evidence of antitumor effect of abemaciclib.


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9.
Treatment
9.1.
Treatments Administered
Abemaciclib 200 mg will be administered orally every 12 (± 2) hours on Days 1 through 21 of a 
21-day cycle.
Table JPBO.1 shows the treatment regimen.
Table JPBO.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose 
Abemaciclib
Treatment/21-day cycle
200 mg Q12H PO on Days 1 – 21 of a 
21-day cycle
Abbreviations:  PO = orally; Q12H = once every 12 (± 2) hours.  
The investigator or his/her designee is responsible for the following:  

explaining the correct use of abemaciclib and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of abemaciclib dispensing and collection, 

and returning all unused abemaciclib to Lilly or its designee at the end of the study.  
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with abemaciclib so that the situation can be assessed.  
9.2.
Materials and Supplies
Abemaciclib will be supplied by Lilly as capsules for oral administration. The capsules 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 in the 
original package and in a location inaccessible to children. Abemaciclib will be labeled 
according to country regulatory requirements.
9.3.
Method of Assignment to Treatment
Upon obtaining informed consent, site personnel should access the interactive web-response 
system (IWRS) which will assign a patient number.  The IWRS will be used to assign 
abemaciclib to patients who meet all criteria for enrollment in 1 of 3 study parts:

Part A: patients with HR+, HER2+ breast cancer

Part B: patients with HR+, HER2- breast cancer


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
Part C:  patients with either HR+, HER2+ or HR+, HER2- breast cancer with 1 to
3 intracranial lesions and for whom surgical resection is clinically indicated.
The period between assignment to abemaciclib in IWRS and the first dose (Cycle 1, Day 1) 
should not exceed 7 days.
9.4.
Selection and Timing of Doses
Abemaciclib will be taken orally every 12 (± 2) hours on Days 1 through 21 of a 21-day cycle, 
for a total of 42 doses per cycle. During all cycles, abemaciclib should be taken at 
approximately the same times each day. If a patient misses or vomits a dose, that dose should be 
omitted.
A cycle is defined as an interval of 21 days plus any subsequent delay prior to start of the next 
cycle. A delay in the start of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances will be permitted up to 7 days and not counted as a protocol deviation. 
In exceptional cases, for planned delays (including but not limited to vacation or holidays), 
additional abemaciclib may be dispensed.  
A patient may continue to receive abemaciclib until she meets 1 or more of the specified reasons 
for discontinuation (as described in Section 7.3).
9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
9.4.1.1.1. Dose Adjustments
Abemaciclib dose adjustments, as outlined in Table JPBO.2, are allowed both within a cycle and 
between cycles.  Abemaciclib must be reduced sequentially by 1 dose level.  
For patients requiring dose reduction(s), any reescalation to a prior dose level is permitted only 
after consultation with the Lilly CRP.  
Table JPBO.2.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBO
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
Abemaciclib must be discontinued if further dose reduction is required beyond 100 mg every 
12 hours.  
9.4.1.1.2. Dose Suspension (within a Cycle) and Cycle Delay
Both abemaciclib dose suspension (within a cycle) and cycle delay are permitted up to 14 days to
allow sufficient time for recovery from a toxicity (defined as an AE possibly related to 
abemaciclib per the investigator’s judgment).  Patients not recovering from toxicity within 


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14 days should be considered for discontinuation of abemaciclib.  In exceptional circumstances, 
a delay >14 days is permitted upon agreement between the investigator and the Lilly CRP, and 
abemaciclib dose adjustment is to be considered.  
In the event of a cycle delay due to logistical reasons (for example, due to patient availability), 
the patient should continue on abemaciclib if the patient has adequate drug supply.  If a patient’s 
treatment is interrupted as a result of not having sufficient drug supply, the cycle may be delayed 
up to 7 days (and not be considered a protocol violation). In exceptional circumstances, a delay 
>7 days is permitted upon agreement between the investigator and the Lilly CRP. 
An interruption in Cycle 1 dosing or a delay in the initiation of Cycle 2 may occur in order to 
allow patients participating in Part C to undergo surgical resection.  For additional information, 
refer to Section 9.6.2.  
9.4.1.1.3. Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity, 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 by 1 dose level as outlined in Table JPBO.2.
Before the start of each cycle, hematologic toxicity must resolve to either baseline or at least 
Grade 2.  
9.4.1.1.4. Nonhematologic Toxicity
If a patient experiences ≥Grade 3 nonhematologic toxicity, 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 by 1 dose level as outlined in Table JPBO.2.  
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 9.4.1.1.4.1) that does not resolve with maximal supportive measures within 
7 days to either baseline or at least 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 by 
1 dose level as outlined in Table JPBO.2 at the discretion of the investigator.  
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or at least Grade 1.
9.4.1.1.4.1.
Diarrhea
A patient experiencing diarrhea requiring hospitalization (irrespective of grade) or severe 
diarrhea (Grade 3 or 4) must have dosing suspended (until the toxicity resolves to either baseline 
or at least Grade 1) and must have the abemaciclib dose reduced by 1 dose level as outlined in
Table JPBO.2.  
If a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve with 
maximal supportive measures (refer to Section 9.6.5) within 3 days to either baseline or at least
Grade 1, then dosing should be suspended (until the toxicity resolves to either baseline or at least 
Grade 1), and the dose of abemaciclib may be reduced by 1 dose level as outlined in


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Table JPBO.2 at the discretion of the investigator.  If the same dose level was resumed and 
Grade 2 diarrhea recurs despite maximal supportive measures, the dose must be reduced by 
1 dose level as outlined in Table JPBO.2.  
9.5.
Blinding
This is an open-label study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRF.  Concomitant medications and 
supportive care therapies must also be documented at the time of discontinuation and at the 
30-day short-term follow-up visit.  
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, radiation, surgery for cancer, or 
experimental medications will be permitted while patients are on abemaciclib.  Use of megestrol 
acetate as an appetite stimulant is not permitted.
In vivo in humans, abemaciclib is extensively metabolized through oxidation.  Additionally, the 
results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study indicate 
that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4. Based on these
findings, grapefruit juice as well as inducers and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 10).  Concurrent treatment with EIAED is not 
permitted while on abemaciclib.  Patients requiring treatment with antiepileptic drugs should be 
prescribed a non-EIAED (eg, levetiracetam, lacosamide, lamotrigine, etc).  Although 
dexamethasone is a CYP3A4 inducer, use during the study is allowed.  The dose of 
corticosteroids, including dexamethasone, will be captured throughout the study, with an 
emphasis on recording changes in dose at the time of intracranial tumor assessments.  
In addition, in vitro studies in primary cultures of human hepatocytes indicate that abemaciclib 
and its significant metabolites LSN2839567 and LSN3106726 down regulate mRNA of 1 or 
more CYPs including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A at 
clinically relevant concentrations.  The mechanism of down regulation and its clinical relevance 
are presently not understood.  Therefore, caution should be exercised when coadministering 
substrate drugs of the above CYPs with narrow therapeutic margin.
9.6.1. Endocrine and HER2-Directed Therapies
Patients receiving endocrine therapy prior to study entry may continue to receive the same 
endocrine therapy throughout the study treatment period per the respective label provided that  
extracranial disease is stable for at least 3 months and intracranial disease progression has 
occurred while on this endocrine therapy.  If these conditions are not met, patients must 
discontinue endocrine therapy prior to initiation of abemaciclib.  Patients may not initiate 
endocrine therapy immediately prior to study entry or at any time during the study.  Additionally, 
patients with HER2+ disease receiving trastuzumab prior to study entry and receiving clinical 


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benefit may continue to receive trastuzumab per the label throughout the study treatment period.  
Changes in these concomitant therapies after study entry are not permitted.  Patients requiring a 
change in concomitant therapy should be assessed for PD and be discontinued from abemaciclib.
9.6.2. Surgery 
A patient in Part C with 1 to 3 brain lesions for whom surgical resection is clinically indicated 
may undergo surgery following 5 to 14 days of treatment with abemaciclib. Abemaciclib should 
be taken 6 to 12 hours prior to surgical resection of brain lesions in order to accommodate 
assessment of drug concentrations in tumor tissue.  These patients may resume abemaciclib 
dosing at least 15 days but no greater than 21 days postoperatively to allow adequate time for 
wound healing.  Patients requiring subsequent WBRT or SRS must be permanently discontinued 
from abemaciclib.  
For patients in Part A and Part B with PD, if surgical resection of brain lesions is clinically 
indicated following disease progression, these patients may consent to provide brain tumor tissue 
and continue on abemaciclib following PD for up to 14 additional days until the time of 
scheduled surgery.  The final dose of abemaciclib should be taken 6 to 12 hours prior to surgical 
resection of brain lesions in order to accommodate assessment of drug concentrations in tumor 
tissue.  Following surgery, these patients must be permanently discontinued from abemaciclib 
treatment.
9.6.3. Supportive Care
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care as judged by their treating physician.  If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported on the eCRFs.  
9.6.4. Growth Factor
Growth factors may be administered in accordance with American Society of Clinical Oncology
(ASCO) guidelines (Smith et al. 2006; Rizzo et al. 2008).  
9.6.5. Supportive Management for Diarrhea
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 (eg,
loperamide) and notify the investigator for further instructions and appropriate 
follow-up.

Site personnel should assess response within 1 to 3 days.

If diarrhea does not resolve with antidiarrheal therapy within 3 days to either baseline or 
Grade 1, then dosing should be adjusted as outlined in Section 9.4.1.1 and Table JPBO.2.  

Patients should also be encouraged to drink fluids (eg, 8 to 10 glasses of clear liquids per 
day).


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9.7.
Treatment Compliance
Patient compliance with abemaciclib dosing will be assessed by capsule counts at each visit, with 
the number of capsules taken relative to the number expected to be taken summarized for each 
cycle. The patient must take ≥75% of the planned doses of abemaciclib in a cycle to be deemed 
compliant. As outlined in Section 9.4.1.1.2, dose suspensions or delays may occur and will not 
result in a patient being considered as noncompliant. A patient may be considered noncompliant 
if she is judged by the investigator to have intentionally or repeatedly taken ≥125% of the 
planned doses of abemaciclib in a cycle.
A patient enrolled in Part C who undergoes resection of brain metastases will not be considered 
noncompliant for doses of abemaciclib withheld in conjunction with surgery and will not incur a 
protocol deviation. For additional information, refer to Section 9.6.2. 


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10. Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations. 
Study procedures related to efficacy, safety, health outcome/quality of life measures, sample 
collection, and testing assessments and their timing are described in the sections below and 
shown in the Study Schedule (Attachment 1).  
10.1. Efficacy Measures 
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 28 days before the first dose of abemaciclib, baseline tumor measurements will be 
performed for each patient.  Intracranial tumor assessments will be performed by Gd-MRI 
according to brain metastases response criteria (Attachment 5). Extracranial tumor assessments 
will be performed according to RECIST v1.1 (Attachment 6).  Computed tomography (CT)
scans, including spiral CT scans, and magnetic resonance imaging (MRI) are the preferred 
methods of measurement of extracranial disease.  
For patients with progressive intracranial disease, Gd-MRI acquired prior to study screening 
must be provided to confirm PD on the baseline intracranial tumor assessment.  Additionally, in 
order to document stable extracranial disease for patients receiving concomitant endocrine 
therapy, CT scan or MRI of extracranial lesions acquired at least 3 months prior to study 
screening must be provided.  
The method of assessment used at baseline must be used consistently for tumor assessment and 
will be repeated between Day 14 and Day 21 of every other cycle beginning with Cycle 2 and 
continuing through Cycle 8; thereafter, tumor assessments will be repeated between Day 14 and 
Day 21 of every fourth cycle (beginning with Cycle 12). 
Intracranial and extracranial responses (CR or PR) must be confirmed no less than 28 days from 
the first evidence of response.
During the continued access period, efficacy assessments (frequency and type of assessments) 
will be completed at the discretion of the investigator.  
10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1). 
For those patients who discontinue abemaciclib without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response 
approximately every 6 weeks for the first 6 months following initiation of abemaciclib and 


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thereafter approximately every 12 weeks by the same method used at baseline and throughout the 
study until the patient has objective disease progression, or until the final analysis of OS.  If a 
patient’s most recent response prior to discontinuation is a PR or CR, an additional radiological 
assessment should be performed during the 30-day follow-up period to confirm the response, at 
least 28 days after the previous radiological assessment.  Response should be confirmed before 
the initiation of additional anticancer therapy.  However, initiation of new therapy should not be 
delayed solely to confirm response.  After the patient has objective disease progression, 
radiologic tests are no longer required, and the patient will be followed up approximately every 
90 days until the patient’s death or overall study completion.  
Lilly will continue to collect survival data on all patients but may reduce data collection for other 
efficacy data.  Lilly will notify investigators when this reduced data collection can begin.  
10.1.3. Primary Efficacy Measure
The primary efficacy measure is OIRR (CR + PR) as defined by brain metastases response 
criteria (see Attachment 5). A partial intracranial response is defined as ≥30% decrease in sum 
of LD of up to 5 target brain lesions sustained for at least 4 weeks in the absence of progression 
of nonmeasurable brain lesions, new brain lesions, increased corticosteroid dose, or clinical 
worsening.  
Best response is determined from the sequence of responses assessed.  
A second assessment must be performed ≥28 days after the first evidence of response.  
Two objective status determinations of CR before progression are required for a best response of 
CR.  Two determinations of PR or better before progression, but not qualifying as a CR, are 
required for a best response of PR.  Best response of SD is defined as disease that does not meet 
the criteria for CR, PR, or PD and has been evaluated at least 1 time, at least 6 weeks after the 
start of abemaciclib. 
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
of objective progression or start of new anticancer therapy.  Any responses observed after 
objective progression or the start of new anticancer therapy are excluded from the determination 
of best response.  
The date of first documented objective disease progression must be recorded on the eCRF even if 
it occurs after the patient has started a new therapy.  
Lilly or its designee will collect and store tumor assessment images, and an independent review 
of imaging scans may be performed by Lilly or its designee. 
The OIRR is estimated as the total number of confirmed CRs and PRs divided by the total 
number of patients enrolled. The primary analysis of OIRR for each study Part (Part A or 
Part B) will occur 6 months after up to 56 patients have been enrolled into each respective part. 
This is to ensure adequate durability of response data is available at the time of analysis.


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10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBO.3) will be collected at the times shown 
in the Study Schedule (Attachment 1).  
Table JPBO.3.
Secondary Efficacy Endpoints
Endpoint
Definition
Best overall intracranial 
response (BOIR)
Derived to encompass all tumor assessments (according to brain metastases 
response criteria) from baseline until the earliest of objective progression
(intracranial or extracranial according to brain metastases response criteria or 
RECIST v1.1, respectively) or start of new anticancer therapy. Any responses 
observed after objective progression (intracranial or extracranial) or the start of 
new anticancer therapy are excluded from the determination of best response.  
Each patient’s BOIR will be categorized as CR, PR, SD, PD, or NE.
Duration of intracranial 
response (DOIR) (CR + PR) 
Defined only for responders (patients with a confirmed CR or PR, as defined in 
Section 10.1.3). It is measured from the date of first evidence of a confirmed 
response (CR or PR as defined by brain metastases response criteria) to the date 
of investigator-determined objective progression (intracranial or extracranial as 
defined by brain metastases response criteria or RECIST v1.1, respectively) or 
death from any cause. Patients who have neither progressed nor died will be 
censored on the day of their last radiographic tumor assessment (if available) or 
on the date of response (CR or PR as defined by brain metastases response
criteria) if no radiographic assessment is available.
Intracranial disease control 
rate (IDCR) 
Defined as the proportion of patients with BOIR of CR, PR, or SD (according to
brain metastases response criteria).
Intracranial clinical benefit 
rate (ICBR)
Defined as the proportion of patients with BOIR of CR, PR, or SD with duration 
of SD for at least 6 months (according to brain metastases response criteria).
Overall survival (OS)
Measured from the date of enrollment to the date of death from any cause. For 
each patient who is not known to have died as of the data-inclusion cutoff date for
a particular analysis, OS will be censored for that analysis at the date of last 
contact prior to the data inclusion cutoff date (contacts considered in the 
determination of last contact date include AE date, tumor assessment date, visit 
date, and last known alive date).  Patients will be followed for OS for 18 months 
following the last patient entering treatment in each study part (Parts A or B).
Objective response rate
(ORR) per RECIST v1.1
and brain metastases 
response criteria
The percentage of patients with a best response of CR or PR as defined by 
RECIST v1.1 and brain metastases response criteria.
Disease control rate (DCR)
Defined as the proportion of patients with best overall response of CR, PR, or SD 
(according to RECIST v1.1 and brain metastases response criteria).
Progression-free survival
(PFS)
Measured from the date of enrollment to the date of investigator-determined
objective progression (intracranial or extracranial as defined by brain metastases 
response criteria or RECIST v1.1, respectively) or death from any cause. Patients 
who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment (if available) or date of enrollment if no 
postinitiation (that is, postbaseline) radiographic assessment is available.
Abbreviations:  AE = adverse event; CR = complete response; NE =not evaluable; PD = progressive disease; 
PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.  


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10.1.5. Exploratory Measures
The following exploratory measures (Table JPBO.4) will be collected at the times shown in the 
Study Schedule (Attachment 1).
Table JPBO.4.
Exploratory Endpoints
Endpoint
Definition
Trail Making Test
To assess neurocognitive function using Trail Making Tests A and B. Each test is 
administered by trained site staff and has a time limit (180 seconds for Test Part A 
and 300 seconds for Test Part B).  The score for each test is determined by either 
the time in seconds to complete the test or the last number or letter reached at the
time limit (Reitan 1992; Wefel et al. 2011).
NANO scale
Clinical assessment of change in neurological signs using the NANO scale, which 
consists of 9 domains (gait, strength, ataxia, sensation, visual fields, facial 
strength, language, level of consciousness, and behavior).
Concentration of 
abemaciclib and its 
metabolites 
To explore the concentration of abemaciclib and its metabolites in plasma, CSF, 
and brain tumor tissue collected at the time of surgical resection for patients 
participating in Part C, as well as patients in Parts A and B with PD and planned 
surgical resection.
Biomarkers
To explore biomarkers related to the mechanism of action of abemaciclib, the cell 
cycle, and/or the pathogenesis of breast cancer.
Abbreviations:  CSF = cerebrospinal fluid; NANO = Neurologic Assessment in Neuro-Oncology; PD = progressive 
disease.
10.2. Health Outcome/Quality of Life Measures
Patient-reported symptoms will be assessed with the self-administered MDASI-BT on paper.  
The MDASI-BT assessment will be completed per the Study Schedule (Attachment 1). 
The MDASI-BT should be completed at the beginning of office visits, before any extensive 
contact and consultation with the clinician/study investigator in regards to the tumor 
assessments. Discussion with the clinician may bias perceptions about symptoms and thus affect 
assessments.  
The MDASI-BT will only be completed by patients for whom there is a valid translation in a 
language in which the patient is fluent.  
10.2.1. Patient-Reported Outcomes
10.2.1.1. MD Anderson Symptom Inventory – Brain Tumor Module
The MDASI-BT is a reliable and valid instrument to assess symptoms in patients with brain
metastases (including those with brain metastases secondary to breast cancer) (Armstrong et al. 
2009; Meyers and Brown 2006).  The MDASI-BT consists of 22 symptom items (13 items of the 
core MDASI plus 9 items specific to brain tumors) plus 6 interference items, all with 11-point 
rating scales.  For the symptom items, 0 equals “not present” and 10 equals “as bad as you can 
imagine.”  For the interference items, 0 equals “did not interfere” and 10 equals “interfered 
completely.”  The MDASI-BT may be scored by reporting the individual items or by calculating 


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the means of all symptom items and of all interference items.  The means of the core and brain 
tumor items may be reported separately. The 22 symptom items may also be grouped by their 
underlying constructs:  (1) affect; (2) cognition; (3) focal neurologic deficit; (4) treatment-related 
symptoms; (5) generalized/disease status symptoms; and (6) gastrointestinal symptoms.  
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of patients during the study.  
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator.  
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JPBO.5 presents a summary of AE and SAE reporting guidelines and also shows which 
database or system is used to store AE and SAE data.  


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Table JPBO.5.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or abemaciclib
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving abemaciclib and no 
longer in follow-up)
All SAEs related to protocol procedures 
or abemaciclib that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.  
Lack of drug effect is not an AE in clinical trials because the purpose of the clinical trial is to 
establish drug effect.  
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, and other study procedures that result in a diagnosis should be reported to Lilly or 
its designee.  
Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported.  If a 
patient is determined to be pregnant following abemaciclib initiation, she must discontinue 
treatment immediately.  Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation.  
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.  
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.  


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In addition, all AEs occurring after the patient receives the first dose of abemaciclib must be 
reported to Lilly or its designee via eCRF.  
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drug via eCRF.  
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study drug, study procedure, or other concomitant treatment or pathologies.  To assess the 
relationship of the AE to study drug or study procedure, the following terminologies are defined:  

Probably related:  a direct cause and effect relationship between the study drug and the 
AE is likely

Possibly related:  a cause and effect relationship between the study drug and the AE has 
not been demonstrated at this time and is not probable but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study drug
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug or study procedure.  
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.  
The National Cancer Institute (NCI)- Common Terminology Criteria for Adverse Events
(CTCAE) v4.0 will serve as the reference document for choosing appropriate terminology for, 
and grading the severity of, all AEs and other symptoms.  For AEs without matching 
terminology within the NCI-CTCAE v4.0 criteria, the investigator will be responsible for 
selecting the appropriate System Organ Class (SOC) and assessing severity grade based on the 
intensity of the event.  
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary.  
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.  
10.3.1.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:  

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason


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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition.  
SAE collection begins after the patient has signed informed consent and has received 
abemaciclib.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving abemaciclib, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.  
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.  
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If study site personnel contact Lilly or 
its designee by telephone regarding an SAE, study site personnel must also immediately provide 
official notification on study-specific SAE forms.  
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.  
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.  
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of abemaciclib or other protocol-required procedure) should not 
be considered SAEs.  
SAEs due to disease progression, including death, should not be reported unless the investigator 
deems them to be possibly related to the study drug.  
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study drug, the investigator should report the SAE 
to the sponsor, and the SAE will be entered in the Lilly Safety System.  
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the DCSI in the IB and that the investigator identifies as related to the study drug or study 
procedure.  US 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 


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require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.  
10.3.2. Other Safety Measures
10.3.2.1. Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule (see
Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. ECGs may be obtained at 
additional times, if clinically indicated.  
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 for immediate patient management, should any clinically relevant findings be identified. 
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.  
10.3.2.2. Echocardiograms or Multi-Gated Acquisition Scans
For only those patients receiving concurrent trastuzumab during the study, an echocardiogram or 
multi-gated acquisition (MUGA) scan is required within 28 days of initiation of abemaciclib
(Attachment 1).  Per the trastuzumab prescribing information (Herceptin [trastuzumab] 
highlights of prescribing information, 2014 and Herceptin [trastuzumab] summary of product 
characteristics, 2014), continued cardiac function monitoring throughout treatment is 
recommended but is not required as a protocol procedure.
10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.  
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist and review:  

trends in safety data

laboratory analytes 

AEs

If a patient experiences elevated ALT or AST >5× ULN and elevated total bilirubin 
>2× ULN, clinical and laboratory monitoring should be initiated by the investigator. For 
patients entering the study with ALT or AST >3× ULN in the presence of liver 
metastases, monitoring should be triggered at ALT >2× baseline.  


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
Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests (See Attachment 3).
10.3.4. Complaint Handling
Lilly collects product complaints on study drug used in clinical trials in order to ensure the safety 
of study participants, monitor quality, and to facilitate process and product improvements.  
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.  
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.  
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.  
Attachment 7 provides a schedule of ECG collection and PK sampling during the study for 
patients in Parts A and B.  
Attachment 8 provides a schedule of ECG collection and PK sampling during the study for 
patients in Part C.
Attachment 9 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.  
10.4.1. Samples for Study Qualification and Health Monitoring
Investigators must document their review of each laboratory safety report.  
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Biomarkers 
Required samples for biomarker research to be collected from all patients enrolled in this study 
are the following:


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
whole blood

plasma

archived tumor tissue
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.  Similar analyses may be 
performed with brain tumor tissue and CSF collected from patients undergoing surgical resection
(Section 10.4.3.1).
These samples are described in the following sections.
10.4.2.1. Blood Samples for Pharmacogenetic Evaluations
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Samples may be genotyped and analysis may be performed to evaluate a genetic association with 
response or lack of response to abemaciclib.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to 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 abemaciclib.
Samples will be destroyed according to a process consistent with local regulation.
10.4.2.2. Plasma Samples for Exploratory Biomarker Evaluations
Ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma samples will be collected and 
analysis may be performed on biomarkers that may play a role in the abemaciclib mechanism of 
action (refer to Attachment 1).  The evaluation of these samples may involve analysis of DNA, 
RNA, and proteins (including any of these components derived from exosomes) to investigate 
their association with observed clinical outcomes to abemaciclib.  The samples will be coded 
with the patient number and stored for up to 15 years.  Details for collecting, processing, and 
storing the samples are similar those provided in Section 10.4.2.1.
10.4.2.3. Archived Tumor Tissue
For patients in the study, a small amount of archival, preserved tumor tissue is required to be 
provided by sites upon patient assignment to abemaciclib for biomarker research. However, if 


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this sample is not available for a patient, this should be discussed with the sponsor.  A protocol 
deviation will not be incurred, and the patient is still eligible for the study.
Available formalin-fixed, paraffin-embedded archived primary and/or metastatic tumor tissue 
should be in a whole block, partial block, or 20 unstained slides, cut at 5 microns, and 
1 hematoxylin and eosin (H&E) slide containing tumor specimen will be requested, if available,
to be used for exploratory analysis.  Due diligence should be used to make sure that a 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. 
In tumor tissue samples, the CDK4/6 pathway components (for example, Rb and its targets) and 
markers relevant to breast cancer pathogenesis may be evaluated to assess any potential 
correlation with response to abemaciclib.  These studies will be performed in a laboratory 
designated by the sponsor and may include, but are not limited to, IHC of proteins, fluorescence 
in-situ hybridization (FISH) for copy number alterations, mRNA gene-expression profiling, 
and/or genetic analyses of the tumor DNA.  Such analyses may employ targeted or 
high-throughput sequencing approaches.  For this purpose, the results of this analysis will be 
correlated with clinical efficacy data.  
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics 
PK samples will be collected for Part A and Part B as specified in the Pharmacokinetic Sampling 
Schedule (Attachment 7). A separate Pharmacokinetic Sampling Schedule (Attachment 8) is 
provided for patients participating in Part C.
At the visits and times specified in the Pharmacokinetic Sampling Schedules (Attachment 7 and 
Attachment 8), venous blood samples of approximately 2 mL each will be collected to determine 
the plasma concentrations of abemaciclib and its metabolites.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  It 
is preferred that the blood samples be obtained from a peripheral location.  Blood samples will 
be allowed from central access devices, but precautions must be taken to prevent obtaining a 
dilute sample when the sample is drawn for PK from a central catheter of any type.  If multiple 
samples are obtained centrally, the PK sample should be the last specimen drawn to reduce the 
potential for a diluted or improperly drawn sample.  The actual date and time (24-hour clock 
time) of each sampling will be recorded. A maximum of 5 samples may be drawn at additional 
time points during the study if warranted and agreed upon between both the investigator and 
Lilly.  
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 the
study site.


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These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib and its metabolites will be assayed using a validated liquid 
chromatography-tandem mass spectrometry (LC/MS/MS) method.
Bioanalytical samples collected to measure abemaciclib concentration and metabolism and/or 
protein binding will be retained for a maximum of 1 year following last patient visit for the 
study.  The PK samples will be stored at a facility designated by the sponsor.
10.4.3.1. Drug Concentrations for All Part C Patients and Part A and Part B 
Patients with Progressive Disease and Planned Surgical Resection
Blood and CSF samples will be collected for exploratory measurement of abemaciclib and, if 
deemed necessary, the concentrations of its metabolites. These samples will be collected at the 
time of surgery for patients participating in Part C.  In addition, resected brain tumor samples 
will be collected for exploratory measurement of abemaciclib and, if deemed necessary, the 
concentrations of its metabolites.  Separate samples are not required for the parent and its 
metabolites. Supplies and instructions for the collection and handling of blood, CSF, and tumor 
samples will be provided by the sponsor.  In cases where collection of CSF is not feasible, a 
missing sample will not be considered a protocol deviation.  
Plasma, CSF, and resected tumor samples will be analyzed at a laboratory designated by the 
sponsor.  Concentrations of abemaciclib and, if deemed necessary, its metabolites will be 
explored using an LC/MS/MS method.  
In addition to the collection of blood, CSF, and tumor tissue from patients participating in Part C, 
for patients in Part A and Part B with PD, if surgical resection of brain lesions is clinically 
indicated following disease progression, these patients may consent to provide brain tumor tissue 
and continue on abemaciclib for up to 14 additional days following PD until the time of 
scheduled surgery.  For these patients, plasma and CSF samples would also be collected at the 
time of surgery.
The remaining tumor tissue and CSF samples after drug concentration measurements may be 
used for additional analyses including, but not limited to, nucleic acid and protein profiles to 
better understand the disease process and to develop predictive biomarkers.
10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between effective and ineffective 
agents.
Safety measurements by laboratory monitoring are standard, widely used, and generally 
recognized as reliable, accurate, and able to discriminate between agents with acceptable and 
unacceptable safety profiles.


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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the 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 use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.  
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.  
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
eCRF data will be encoded and stored in a clinical trial database.  Data managed by a central 
vendor, such as laboratory test data, will be stored electronically in the central vendor’s database 
system.  Data will subsequently be transferred from the central vendor to Lilly.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this clinical trial is to estimate the antitumor activity, measured by 
OIRR of abemaciclib in patients with brain metastases secondary to HR+ breast cancer.  
Two separate Simon 2-stage designs (Simon 1989) will be employed for this study; one will be 
used for Part A (patients with HR+, HER2+ disease) and another for Part B (patients with HR+, 
HER2- disease). Each design assumes a 1-sided type-I error of 0.05 and 80% power.
For Part A, up to 56 qualified patients will be enrolled with the possibility of stopping the study 
early for either lack of efficacy or unacceptable toxicity. Twenty-three qualified patients will be 
enrolled in the first stage. If fewer than 2 of the first 23 patients respond to abemaciclib, accrual 
will be stopped, and the conclusion will be drawn that abemaciclib is not worthy of further study 
in the Part-A population. If at least 2 of the first 23 patients respond to therapy, accrual will 
continue until 33 additional qualified patients have been enrolled. A total of 6 responders out of 
56 patients in Part A would need to be observed to warrant further investigation of abemaciclib 
in this patient population.  
The procedure described above tests the null hypothesis (H0) that the true OIRR of abemaciclib 
in Part A is ≤5% versus the alternative hypothesis (Ha) that the true OIRR is 15%.  The 
probability of early termination of the treatment arm under H0 is 0.68.  
Part B will have the identical design as Part A.
Assuming approximately 20% screening failure, the study will enter approximately 150 patients.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.  
Efficacy and safety analyses will be conducted on the full analysis set (FAS).  This set includes 
all data from all enrolled patients receiving at least 1 dose of abemaciclib.  
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.  
All tests will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.  All tests of 
interactions will be conducted at a 2-sided alpha level of 0.1, and all confidence intervals (CIs)
will be given at a 2-sided 95% level, unless otherwise stated.  


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Unless otherwise stated, all analyses will be conducted on each study part separately. Pooled 
analyses including patients from all 3 parts will be conducted when applicable.  
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.  
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided. 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 discontinuation will be given.
A summary of all important protocol deviations will be provided.  
12.2.3. Patient Characteristics
Patient demographics including age, sex, screening height and weight, and screening body mass
index will be reported using descriptive statistics.  
Baseline disease characteristics will be summarized by presenting frequency counts and
percentages for pathological diagnosis (histological or cytological), disease stage, or
performance status.  
Preexisting conditions, historical illnesses, and prior chemotherapy (including both cytotoxic and 
targeted agents) will be summarized.  
Other patient characteristics will be summarized as deemed appropriate.  
12.2.4. Concomitant Therapy
Concomitant medication will be summarized in a frequency table listing the terms recorded on 
the eCRF.  
12.2.4.1. Postdiscontinuation Therapy 
The numbers and percentages of patients reporting postdiscontinuation anticancer therapies will 
be provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.  
12.2.5. Treatment Compliance 
The number of dose omissions, reductions, delays, cycles received, and dose intensity will be 
summarized for all treated patients.  


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Treatment compliance information for abemaciclib will be collected through pill counts at each 
visit.  The estimate of percent compliance will be given by:
Percent Compliance =
Actual cumulative dose taken
Expected cumulative dose to be taken x 100
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed.  The 
expected cumulative dose to be taken will be determined based on the assigned dose and will 
take into account any dose reductions or omissions.  
12.2.6. Primary Outcome and Methodology
The primary endpoint of this study is OIRR assessed using brain metastases response criteria
(see Attachment 5). The OIRR will be reported along with 95% CIs using the normal 
approximation. 
12.2.7. Secondary Outcome and Methodology
The secondary objectives for this study are stated in Section 6.2; secondary efficacy measures
are defined in Section 10.1.4.  
Point estimates and 95% CIs (using the normal approximation to the binomial) will be calculated 
for BOIR, IDCR, ICBR, ORR, and DCR for Part A and Part B.  
Time-to-event efficacy endpoints (OS, PFS, and DOIR) will be summarized for Part A and 
Part B using Kaplan-Meier techniques (Kaplan and Meier 1958) if there is sufficient data. If 
performed, Kaplan-Meier curves will be generated, and quartiles and point probabilities will be 
calculated. Interval estimates will be calculated using 95% CIs (Brookmeyer and Crowley 
1982).  
12.2.8. Pharmacokinetic and/or Pharmacodynamic Analyses
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected (see Pharmacokinetic Sampling Schedules in Attachment 7 and 
Attachment 8).  
Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and interindividual PK variability will be computed using nonlinear 
mixed effect modeling (NONMEM).  The current PK model for abemaciclib, which has been 
developed using plasma concentration data available from the Phase 1 Study JPBA, will be 
updated using the plasma data collected in this study.  Covariate effects (such as age, weight, 
sex, creatinine clearance, and plasma protein levels) on the PK parameters of abemaciclib in 
plasma will also be investigated.
Finally, pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) 
collected in this study may also be analyzed by means of NONMEM and connected to the 
population PK model in a PK/pharmacodynamic model.  


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The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.9. Exploratory Analyses
12.2.9.1. Trail Making Tests A and B
Neurocognitive function will be assessed using Trail Making Tests A and B.  Summary statistics 
will be provided for Study Part A and Part B and/or response category (CR/PR, SD, and PD); 
change from baseline and time to worsening will be explored. 
12.2.9.2. Neurologic Assessment in Neuro-Oncology Scale
Clinical response and progression will be explored and summarized for the NANO scale using 
descriptive statistics.  Neurologic response will be defined as an improvement of ≥2 on any 
single domain in the absence of deterioration in other domains.  Neurologic progression will be 
defined as worsening of ≥2 from baseline on any single domain.  These results may be compared
with objective tumor assessment results.  
12.2.9.3. Drug Concentrations in Samples from Surgical Patients
The relative concentrations of abemaciclib and its metabolites in plasma, CSF, and tumor tissue 
collected at the time of surgical resection for patients participating in Part C will be explored.
Additionally, patients in Part A and Part B with PD and surgical resection clinically indicated 
may consent to provide samples for this exploratory analysis.  
12.2.9.4. Biomarker Analyses
The distributions of biomarkers with continuous measures, such as gene or protein expression, 
will be described.  Summary statistics will include means, medians, corresponding standard 
errors, quartiles, and ranges.  Biomarkers with discrete measures, such as genotype locus, will be 
summarized in frequency tables.  Correlative analyses may be performed to investigate 
associations between biomarkers and clinical endpoints as deemed appropriate.
12.2.10.
Health Outcome/Quality of Life Analyses 
Patients with at least 1 baseline and at least 1 postbaseline assessment will be included in 
the analyses. Compliance with completing the questionnaires will be summarized at the 
group-level at each assessment period (defined as the number of completed 
questionnaires/number expected questionnaires given those that are still on study).
Reason for missing questionnaires will be assessed.
Relationships among MDASI-BT, Trail Making Tests, and other clinical parameters such 
as performance status, OS, and disease assessments may be explored.
Data will be summarized for each study part (Parts A and B) and/or response category 
(CR/PR, SD, PD); change from baseline and time to worsening will be explored. This
summary will include mean, standard deviation, median, minimum, maximum, and 
change from baseline.  The MDASI-BT will be reported as core symptoms, brain tumor 
symptoms, symptom interference, and symptom groupings (affect, cognition, focal


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neurologic deficit, treatment-related symptoms, generalized/disease status symptoms, and 
gastrointestinal symptoms). Time to worsening will be described for these categories.
Further analyses will be specified in the statistical analysis plan.  
12.2.11.
Safety Analyses
All safety summaries and analyses will be based upon the FAS as defined in Section 12.2.1. 
Overall exposure to abemaciclib, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments. 
AEs will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and SOC of the corresponding MedDRA Lower Level Term (LLT), 
unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as AEs that begin prior to the first dose of abemaciclib. A 
TEAE is defined as an event that first occurred or worsened in severity after baseline.
Comparisons of preexisting conditions to on-treatment events at the LLT level will be used in the 
treatment-emergent computation.  
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to abemaciclib and repeated for events regardless of abemaciclib causality.  
The following summaries will be produced by PT within SOC:  preexisting conditions, SAEs, 
TEAEs, drug-related TEAEs, and procedure-related TEAEs.  
The following summaries will be produced by PT within SOC and maximum CTCAE grade:  
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs, 
and drug-related nonlaboratory-based TEAEs.  
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation. 
Hospitalizations and transfusions during the study treatment period or during the 30-day 
short-term follow-up period will be summarized by treatment group.  
12.2.12.
Interim Analyses
The Simon 2-stage design has a built-in interim analysis to analyze OIRR and to meet threshold 
continuation criteria. The interim analysis of OIRR for each study part (Part A or Part B) will 
occur 6 months after the 23rd patient is enrolled into each respective part.  This is to ensure 


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adequate durability of response data is available at the time of analysis. This interim analysis for 
response must be strictly followed to preserve the statistical properties of the Simon 2-stage
design. Due to this requirement, objective data will be obtained to document response and to 
determine if the trial is to continue based on the OIRR. Because of this, no Assessment 
Committee or Data Monitoring Committee will be convened to oversee this trial. 
Additional interim analyses will be planned if deemed necessary.
12.2.13.
Subgroup Analyses
Subgroup analyses will be performed for potential prognostic subgroup variables.


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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or, 
where permitted by local law or regulation, by the patient's legal representative.  This includes 
obtaining the appropriate signatures and dates on the ICF prior to the performance of any 
protocol procedures and prior to the administration of study drug.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative sites.  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites. 
The study site’s ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

ICH GCP Guideline (E6)

applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
Lilly will select an investigator to serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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14. References
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Armstrong TS, Gning I, Mendoza TR, Weinberg JS, Gilbert MR, Tortorice ML, Cleeland CS. 
Clinical utility of the MDASI-BT in patients with brain metastases. J Pain Symptom Manage.
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Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics.
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Crooks V, Waller S, Smith T, Hahn TJ. The use of the Karnofsky Performance Scale in 
determining outcomes and risk in geriatric outpatients. J Gerontol. 1991;46(4):M139-M144.
Davis FG, Dolecek TA, McCarthy BJ, Villano JL. Toward determining the lifetime occurrence 
of metastatic brain tumors estimated from 2007 United States cancer incidence data. Neuro
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Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan 
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de Haan R, Aaronson A, Limburg M, Hewer RL, van Crevel H. Measuring quality of life in 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, 
Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, 
Taube S, Toralakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, 
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Herceptin (trastuzumab) [summary of product characteristics]. Welwyn Garden City, United 
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Hollen PJ, Gralla RJ, Kris MG, Cox C, Belani CP, Grunberg SM, Crawford J, Neidhart JA. 
Measurement of quality of life in patients with lung cancer in multicenter trials of new 
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Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
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Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast 
cancer: old challenge, new frontiers. Clin Cancer Res. 2013;19(23):6404-6418.  
Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of
patients with CNS tumors. J Clin Oncol. 2006;24(8): 1305-1309.  
Ortega S, Malumbres M, Barbacid M. Cyclin-D dependent kinases INK4 inhibitors and cancer.
Biochim Biophys Acta. 2002;1602(1):73-87.
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Oxford textbook of palliative medicine. 1st ed. Oxford University Press;1993:109.
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Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
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Wishart GN, Raub TJ. LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 
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Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672-1677.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials.
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Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update 
of recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006;24(19):3187-3205.
Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, 
Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, 
Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M. Summary Report on the graded 
prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for 
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Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, 
Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
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2013;31(31):3997-4013.


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Attachment 1.Protocol JPBO Study Schedule
Baseline Assessments
Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Informed consent 
X
Informed consent form signed (prior to performance of any 
protocol-specific tests/procedures).
Pregnancy test 
X
Women with childbearing potential must have a negative serum 
pregnancy test within 7 days of the first dose of abemaciclib.
Medical history
X
Including alcohol/tobacco use and other relevant habits 
assessments.
Physical exam, vital 
signs, height, and 
weight
X
Vital signs include temperature, blood pressure, pulse rate, and 
respiration rate.
Neurologic assessment 
using the NANO scale
X
Karnofsky 
Performance Status
X
Concomitant 
medications
X
CTCAE v4.0 grading 
(preexisting 
conditions)
X
To be reported only after study eligibility is confirmed.  
Brain Gd-MRI
X
Required for all patients.  Performed locally (Day -28 to Day -1) at 
baseline.
Radiological tumor 
assessment according 
to RECIST v1.1
X
Imaging studies (CT scan or Gd-MRI) are performed locally 
(Day -28 to Day -1) at baseline.  It is recommended that CT 
imaging of the abdomen and pelvis be performed with IV contrast, 
whenever possible.  For patients with known hypersensitivity to CT 
contrast material, a CT scan of the chest without contrast and 
Gd-MRI of the abdomen/pelvis are encouraged.  Imaging based 
evaluation should be done rather than clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam.
Echocardiogram or 
MUGA
X
Echocardiogram or MUGA is required at baseline only for patients 
receiving concurrent trastuzumab.  Per the trastuzumab prescribing 
information, continued cardiac function monitoring throughout 
treatment is recommended but is not required as a protocol 
procedure.
ECG 
X
ECGs will be performed locally.  


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Central hematology
X
Enrollment and treatment decisions may be based upon results of 
tests performed locally. If local laboratory tests are used for this 
purpose, then a duplicate specimen must be submitted to the central 
laboratory. Discrepancies between the local and central laboratory 
that may have an impact on eligibility or treatment decisions will 
not be considered protocol deviations.
Central chemistry 
X
Enrollment and treatment decisions may be based upon results of 
tests performed locally. If local laboratory tests are used for this 
purpose, then a duplicate specimen must be submitted to the central 
laboratory. Discrepancies between local and central laboratory that 
may have an impact on eligibility or treatment decisions will not be 
considered protocol deviations.
MDASI-BT 
X
To be completed prior to physical exam and preferably prior to 
administration of the Trail Making Tests.
Trail Making Tests A 
and B
X
To be completed prior to physical exam and administered by trained 
site staff.
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; Gd-MRI = gadolinium-enhanced magnetic resonance imaging; IV = intravenous; 
MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; MUGA = multi-gated acquisition scan; 
NANO = Neurologic Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria in Solid Tumors.


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Study Schedule, Protocol I3Y-MC-JPBO
During Treatment Study Schedule
Study Period
Study Treatment Period
Cycle/Visit
1
2
3
4-X
Duration
21 days
21 days
21 days
21 days
A cycle is defined as the planned treatment interval of 21 days plus 
any subsequent delay prior to the start of the next cycle. A delay of 
a cycle due to holidays, weekends, bad weather, or other unforeseen 
circumstances will be permitted up to 7 days and not counted as a 
protocol deviation.  Additionally, a cycle delay up to 14 days to 
allow sufficient time for recovery from a toxicity is permitted.
Relative Day within 
Dosing Cycle
1
1
14-
21
1
1
14-
21
Procedure 
Category
Procedure
Comments
Physical 
examination
Physical exam
X
X
X
X
Neurologic assessment using
NANO scale
X
X
X
X
Weight 
X
X
X
X
Vital signs
X
X
X
X
Includes blood pressure, pulse, respiratory rate, and temperature. 
Karnofsky Performance 
Status
X
X
X
X
Archived tumor tissue
X
Formalin-fixed paraffin-embedded archived tumor tissue must be 
requested after study eligibility is confirmed.  The absence of an 
available specimen of the patient’s tumor does not constitute a 
protocol deviation (see Section 10.4.2.3).
Adverse events collection/CTCAE grading
X
X
X
X
Concomitant medication notation
X
X
X
X
Lab/
diagnostic tests
Central hematology
X
X
X
X
Central hematology labs may be drawn up to 3 days prior to Day 1 
of each cycle. Additional local hematology labs may be drawn for 
treatment adjustment and patient management purposes.  Duplicate 
central labs should be submitted for assessment.
Central chemistry
X
X
X
X
Central chemistry labs may be drawn up to 3 days prior to Day 1 of
each cycle. Additional local chemistry labs may be drawn for 
treatment adjustment and patient management purposes. Duplicate 
central labs should be submitted for assessment.
PK sampling 
X
X
X
See Pharmacokinetic Sampling Schedule (Attachment 7 and 
Attachment 8)


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Study Period
Study Treatment Period
Cycle/Visit
1
2
3
4-X
Duration
21 days
21 days
21 days
21 days
A cycle is defined as the planned treatment interval of 21 days plus 
any subsequent delay prior to the start of the next cycle. A delay of 
a cycle due to holidays, weekends, bad weather, or other unforeseen 
circumstances will be permitted up to 7 days and not counted as a 
protocol deviation.  Additionally, a cycle delay up to 14 days to 
allow sufficient time for recovery from a toxicity is permitted.
Relative Day within 
Dosing Cycle
1
1
14-
21
1
1
14-
21
Procedure 
Category
Procedure
Comments
Pharmacogenetic blood 
sample
X
Draw sample before patient is dosed on C1D1. 
Biomarker plasma sample
X
X
Draw sample before patient is dosed on C1D1 and upon arrival at 
site on C2D1. 
Local ECG
X
X
X
X
ECGs will be performed according to separate schedule (see 
Attachment 7 and Attachment 8).
Tumor 
assessment
Brain Gd-MRI
X
X
Performed locally.  Repeat between D14 and D21 of every other 
cycle beginning with C2 and continuing through C8; thereafter,
tumor assessments will be repeated between D14 and D21 of every 
fourth cycle (beginning with C12).
Radiologic imaging according 
to RECIST v1.1
X
X
Performed locally.  Imaging studies should be repeated between 
D14 and D21 of every other cycle beginning with C2 and 
continuing through C8; thereafter, tumor assessments will be 
repeated between D14 and D21 of every fourth cycle (beginning 
with C12). The same method of imaging used at baseline should be 
used for each subsequent assessment.
Health 
outcomes
MDASI-BT
X
X
X
X
MDASI-BT will be administered on D1 of each cycle prior to
physical exam, administration of the Trail Making Tests, and
extensive interaction with site staff.  On C1D1, MDASI-BT is to be 
administered before the first dose of abemaciclib in the clinic.
Trail Making Tests A and B
X
X 
X
X
Tests A and B will be completed on D1 of each cycle prior to 
physical exam and administered by trained site staff.  On C1D1, 
Tests A and B are to be administered before the first dose of 
abemaciclib in the clinic.
Investigational 
product
Abemaciclib 
Take 200 mg or prescribed dose orally every 12 hours on Days 1 
through 21 of every cycle.
The period between assignment to abemaciclib in IWRS and the 
first dose (C1D1) should not exceed 7 days.


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Abbreviations:  C = cycle; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; IWRS = interactive web-response 
system; MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; Gd-MRI = gadolinium-enhanced magnetic resonance imaging; NANO =
Neurologic Assessment in Neuro-Oncology; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors.


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Post Treatment Discontinuation Study Schedule
Study Period
Postdiscontinua
tion Follow-Up
Long-Term 
Follow-Up 
Visit 
801
802-X
Posttreatment Discontinuation Follow-Up should begin the day after the last dose of 
abemaciclib or, if abemaciclib has been omitted for an extended period, the date it is decided 
that the patient will not restart abemaciclib.
Duration
30 +/-  5 days
Variable
Long-term follow-up begins the day after the short-term postdiscontinuation follow-up visit 
(v801) is completed and continues until the patient’s death, lost to follow-up, or overall study 
completion. The variable period depends on whether disease progression has occurred and if
tumor assessments are due. Once disease progression has occurred, visits should occur every 
90 days.
Relative Day
30
Procedure 
Category
Procedure
Comments
Physical 
examination 
Physical Exam
X
Neurologic Assessment using NANO 
scale
X
Weight
X
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature.
Karnofsky Performance Status
X
Tumor 
assessment
Brain Gd-MRI
X
X
Not required if progressive disease is documented while on treatment or if there are clear 
signs of clinical progression. Reassessment should occur approximately every 6 weeks for 
the first 6 months following initiation of abemaciclib and thereafter approximately every 
12 weeks until disease progression.
Radiologic imaging according to RECIST
1.1
X
X
Not required if progressive disease is documented while on treatment or if there are clear 
signs of clinical progression. Reassessment should occur approximately every 6 weeks for 
the first 6 months following initiation of abemaciclib and thereafter approximately every 
12 weeks until disease progression or until the final analysis of OS.  If a patient’s most recent 
response prior to discontinuation was a PR or CR, an additional radiological assessment 
should be performed during the 30-day follow-up period to confirm the response, at least 
28 days after the previous radiological assessment.  Response should be confirmed before the 
initiation of additional anticancer therapy.  However, initiation of new therapy should not be 
delayed solely to confirm response.


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Study Period
Postdiscontinua
tion Follow-Up
Long-Term 
Follow-Up 
Visit 
801
802-X
Posttreatment Discontinuation Follow-Up should begin the day after the last dose of 
abemaciclib or, if abemaciclib has been omitted for an extended period, the date it is decided 
that the patient will not restart abemaciclib.
Duration
30 +/-  5 days
Variable
Long-term follow-up begins the day after the short-term postdiscontinuation follow-up visit 
(v801) is completed and continues until the patient’s death, lost to follow-up, or overall study 
completion. The variable period depends on whether disease progression has occurred and if
tumor assessments are due. Once disease progression has occurred, visits should occur every 
90 days.
Relative Day
30
Procedure 
Category
Procedure
Comments
Health outcomes
MDASI-BT
X
Collect MDASI-BT prior to physical exam, administration of the Trail Making Tests, and
extensive interaction with site staff.
Trail Making Tests A and B
X
Tests A and B will be completed prior to physical exam and administered by trained site 
staff.
Survival information
X
X
Although preferable to collect during a clinic visit, survival information may be collected by 
contacting the patient or family directly (for example, via telephone) if no procedures are 
required. This should be collected approximately every 90 days if no other procedures are 
performed.
Adverse events collection/CTCAE grading
X
X
After Visit 801, only study protocol or drug-related events are reported. If a patient has an 
ongoing AE or SAE possibly related to abemaciclib (for instance, abnormal electrolytes), the 
patient should be followed until the event is resolved, the event is no longer considered to be 
drug-related, the event becomes stable or returns to baseline, a new treatment is initiated for 
the patient, or the patient dies or is lost to follow-up.  Any subsequent follow-up(s) for AEs 
will be no more than 30 days ± 5 days in duration.
Concomitant medication notation
X
Lab/
diagnostic tests
Central hematology
X
Central chemistry
X
Biomarker plasma sample
X
Draw sample only for patients discontinuing due to PD.
Local ECG
X


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Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram Gd-MRI = gadolinium-enhanced 
magnetic resonance imaging; MDASI-BT = MD Anderson Symptom Inventory – Brain Tumor; NANO = Neurologic Assessment in Neuro-Oncology; 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; v = visit.


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Study Schedule for the continued access period only, Protocol I3Y-MC-JPBO
Perform procedure as indicated.
Study Period
Patients on Abemaciclib
Continued Access Period 
Follow-Up
Cycle
X
Follow-Upa
Visit
501-5XX
901
Approximate 
Visit Duration 
(days)
21
30
Relative day
within a cycle
1
Procedure 
Category
Procedure
Protocol 
Reference
Comments
Adverse events collection/CTCAE grading
Section 10.3
X
X
Data on SAEs that occur before the end of trial will be 
stored in the collection database and the Lilly Safety 
System.
Investigational 
product
Abemaciclib
Section 9.1
X
Patients on abemaciclib who are receiving clinical 
benefit will continue to receive abemaciclib during the 
continued access period.  Abemaciclib is to be 
administered orally every 12 hours on Days 1 through 
21 of each cycle.  
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; OS = overall survival; SAEs = serious adverse events.
a
The continued access period begins after study completion (that is, after final OS analysis) and ends at the end of trial (that is, the last patient visit).


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Attachment 2.Protocol JPBO 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 and bands)
Total protein
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase (ALT)
Platelets
Aspartate aminotransferase (AST)
Total bilirubin and direct bilirubin
Serum pregnancy test (women of childbearing 
potential 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.


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Attachment 3.Protocol JPBO Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Antinuclear antibodya
AST
GGT
CPK
Antismooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells. 
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.Protocol JPBO Karnofsky Performance Status
The Karnofsky Performance Scale Index allows patients to be classified as to their functional 
impairment.  This can be used to compare effectiveness of different therapies and to assess the 
prognosis in individual patients.  The lower the Karnofsky score, the worse the survival for most 
serious illnesses. 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA
Able to carry on normal activity and to work; no 
special care needed.
100 Normal no complaints; no evidence of 
disease.
90 Able to carry on normal activity; minor 
signs or symptoms of disease.
80 Normal activity with effort; some signs 
or symptoms of disease. 
Unable to work; able to live at home and care for 
most personal needs; varying amount of assistance 
needed.
70 Cares for self; unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his personal 
needs.
50 Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
40 Disabled; requires special care and 
assistance.
30 Severely disabled; hospital admission is 
indicated although death not imminent.
20
Very sick; hospital admission 
necessary; active supportive treatment 
necessary.
10 Moribund; fatal processes progressing 
rapidly.
0
Dead
Sources:  Crooks et al. 1991; de Haan et al. 1993; Oxford 1993; Hollen et al. 1994; O’Toole et al. 1991; Schag et al. 
1984.


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Attachment 5.Protocol JPBO Brain Metastases Response
Criteria
Imaging and assessment criteria for intracranial disease can be found in a separate manual.


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Attachment 6.Protocol JPBO RECIST Criteria 1.1
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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Response Criteria
Evaluation of Target Lesions 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
.


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I3Y-MC-JPBO Clinical Protocol
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Attachment 7.Protocol JPBO Electrocardiogram and 
Pharmacokinetic Sampling Schedule – Parts A and B
I3Y-MC-JPBO Electrocardiogram and Pharmacokinetic Sampling Schedule
Cycle (C) and Day 
(D)
ECG
PK Sample 
Number
Dosing of 
Abemaciclib
Sampling Time for ECG and 
PK from Blooda
Baseline
(Day -14 to Day -1)
X
Day of visit
C1D1
X
1
X
2-4 hrs after abemaciclib dosed in 
the clinic
C2D1
X
2
Xb
Upon arrival at site at least 4 hrs 
after taking abemaciclib dose at 
home
C2D1
3
3 ± 0.5 hr after PK sample 
number 3 (that is, at least 7 ± 0.5 
hrs after taking abemaciclib dose 
at home)
C3D1
4
Xc
Predose (0 hr)
C3D1
5
3 ± 0.5 hrs after abemaciclib dose
C4D1
X
2 – 4 hrs after abemaciclib dose
At PD
6d
6-12 hrs after taking final
abemaciclib dose at home prior to 
surgical resection
7
Approximately 6 hours after 
resection of brain tumor tissue
30-day follow-up
X
Day of visit
Abbreviations:  C = cycle; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; hr = hour(s); 
PD = progressive disease; PK = pharmacokinetic. 
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
On Cycle 2 Day 1 only, patient should take abemaciclib dose at home at least 4 hours before arrival at site.  The 
time of abemaciclib dose intake must be recorded that day.
c
On Cycle 3 Day 1 only, after collection of PK sample number 4, patients should take abemaciclib immediately 
following the sample collection, prior to conducting other procedures. 
d
For patients with PD for whom surgical resection is clinically indicated, dosing of abemaciclib may continue for 
up to 14 days after PD to allow for optional collection of plasma, CSF, and brain tumor tissue samples for 
determination of drug concentration at the time of surgery.  Samples should be collected at approximately the 
same time of day.


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Attachment 8.Protocol JPBO Electrocardiogram and 
Pharmacokinetic Sampling Schedule – Part C
I3Y-MC-JPBO Electrocardiogram and Pharmacokinetic Sampling Schedule - Part C 
Cycle (C) and Day 
(D)
ECG
PK Sample 
Number
Dosing of 
Abemaciclib
Sampling Time for ECG and 
PK from Blooda
Baseline
(Day -14 to Day -1)
X
Day of visit
C1D1
X
1
X
2-4 hrs after abemaciclib dosed in 
the clinic
C1 day of surgeryb
2
X
6-12 hrs after taking abemaciclib
dose at home
C1 day of surgery
3
Approximately 6 hours after 
resection of brain tumor tissue
C3D1
X
4
Xc
Upon arrival at site at least 4 hrs 
after taking abemaciclib dose at 
home
C3D1
5
3 ± 0.5 hr after PK sample 
number 3 (that is, at least 7 ± 0.5 
hrs after taking abemaciclib dose 
at home)
C4D1
6
Xd
Predose (0 hr)
C4D1
X
7
3 ± 0.5 hrs after abemaciclib dose
30-day follow-up
X
Day of visit
Abbreviations:  C = cycle; CSF = cerebrospinal fluid; D = day; ECG = electrocardiogram; hr = hour(s); 
PK = pharmacokinetic. 
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
Plasma, CSF, and brain tumor tissue samples for determination of drug concentration will be collected at the time 
of surgery, after 5 to 14 days of abemaciclib dosing (during Cycle 1).
c
On Cycle 3 Day 1 only, patient should take abemaciclib dose at home at least 4 hours before arrival at site.  The 
time of abemaciclib dose intake must be recorded that day.
d
On Cycle 4 Day 1 only, after the predose PK sample, patients should take abemaciclib immediately following the 
sample collection, prior to conducting other procedures.


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Attachment 9.Protocol JPBO Sampling Summary
This table provides estimates of the maximum number of samples (venipunctures and biopsies),
volumes for all sampling, and tests (study qualification, health monitoring, drug concentration, 
tailoring biomarkers, and exploratory) required for each patient during the study.  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, if the patient discontinues from the study early). 
Protocol I3Y-MC-JPBO Sampling Summarya
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number 
Samples
Maximum 
Total Amount
Study qualificationb
Blood
4 mL
3
12 mL
Health monitoring/safety 
monitoring (may be more 
than 1 tube)b
Blood
5 mL/Cycle 
2
50 mL
Archived formalin-fixed, 
paraffin-embedded tumor 
tissue
Tissue
5 micron
21 slides
105 micron
Drug concentration of 
abemaciclib for all patients in 
trial
Blood
2 mL
5
10 mL
Drug concentration of 
abemaciclib for all patients in 
Part C and patients in Parts A 
and B undergoing surgical 
resection
Tissue
50 mg
1
50 mg
Drug concentration of 
abemaciclib for all patients in 
Part C and patients in Parts A 
and B undergoing surgical 
resection
CSF
2 mL
1
2 mL
Tailoring biomarkers
Blood
9 mL
1
9 mL
Plasma for exploratory 
biomarker
Blood
6 mL
3
18 mL
Hepatic monitoringc
Blood
3 - 30 mL
-
a
Covers Cycles 1 through 9 and 1 postdiscontinuation follow up visit.
b
Additional samples may be drawn if needed for safety purposes.
c
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 10.
Protocol JPBO Inducers and Strong 
Inhibitors of CYP3A4 
The information in this attachment is provided for guidance to investigators and does not 
preclude the use of all these medications, if clinically indicated.  However, these medications 
should be avoided or substituted, if possible.
Inducers of CYP3A4
Carbamazepinea
Dexamethasoneb
Phenobarbital/phenobarbitonea
Phenytoina
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
Abbreviations:  CYP = cytochrome P450; EIAED = enzyme-inducing antiepileptic drugs; HIV = human
immunodeficiency virus.
a
Patients may not receive concurrent treatment with EIAEDs.  Patients requiring treatment with antiepileptic 
drugs should be prescribed non-EIAED (eg, levetiracetam, lacosamide, lamotrigine, etc).
b All patients may receive supportive therapy with dexamethasone.

SAP_001.pdf: 
Statistical Analysis Plan  
I3Y-MC-JPBO: A Phase 2 Study of Abemaciclib in Patients with Brain Metastases Secondary to 
Hormone Receptor Positive Breast Cancer, Non-small Cell Lung Cancer, or Melanoma 
 
NCT02308020 
 
Approval Date: 9-Aug-2018 
 
 


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1.
Statistical Analysis Plan 
I3Y-MC-JPBO:  A Phase 2 Study of Abemaciclib in 
Patients with Brain Metastases Secondary to Hormone 
Receptor Positive Breast Cancer, Non-small Cell Lung 
Cancer, or Melanoma
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Abemaciclib (LY2835219)
This study is a global, multicenter, open-label, Phase 2 trial of abemaciclib in patients with 
brain metastases secondary to hormone receptor positive breast cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Statistical Analysis Plan V1 electronically signed and approved by Lilly:  12 Feb 2015
Statistical Analysis Plan V2 electronically signed and approved by Lilly
on date provided below.
Approval Date: 09-Aug-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan  I3Y-MC-JPBO:  A Phase 2 Study of 
Abemaciclib in Patients with Brain Metastases Secondary to 
Hormone Receptor Positive Breast Cancer, Non-small Cell Lung 
Cancer, or Melanoma..........................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Consideration..................................................................................................10
6.1.1.
Populations ..........................................................................................................10
6.1.2.
Definitions and Conventions ................................................................................11
6.2.
Handling of Dropouts or Missing Data.........................................................................12
6.3.
Patient Disposition .......................................................................................................12
6.4.
Patient Characteristics ..................................................................................................12
6.4.1.
Baseline Demographics and Patient Characteristics..............................................12
6.4.2.
Historical Illnesses ...............................................................................................12
6.4.3.
Prior Therapies.....................................................................................................12
6.4.4.
Post Study Treatment Discontinuation Therapies .................................................13
6.5.
Treatment Compliance .................................................................................................13
6.6.
Concomitant Therapy...................................................................................................13
6.7.
Efficacy Analyses ........................................................................................................13
6.7.1.
Primary Outcome and Methodology.....................................................................13
6.7.2.
Secondary Outcome and Methodology.................................................................14
6.7.3.
Exploratory Outcome...........................................................................................15
6.8.
Health Outcomes/Quality-of-Life Analyses..................................................................15
6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................16
6.10. Tailoring Biomarker Analyses......................................................................................16
6.11. Safety Analyses............................................................................................................16
6.11.1.
Extent of Exposure...............................................................................................16


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6.11.2.
Adverse Events ....................................................................................................16
6.11.3.
Deaths..................................................................................................................17
6.11.4.
Clinical Laboratory Evaluation.............................................................................17
6.11.5.
Vital Signs and Other Physical Findings...............................................................17
6.11.6.
Electrocardiograms ..............................................................................................17
6.11.7.
Hospitalizations and Transfusions ........................................................................17
6.12. Subgroup Analysis .......................................................................................................17
6.13. Interim Analysis...........................................................................................................18
6.14. Protocol violation.........................................................................................................18
6.15. Annual Report Analysis ...............................................................................................18
6.16. Clinical Trial Registry Analyses...................................................................................18
7.
Unblinding Plan................................................................................................................20
8.
References ........................................................................................................................21


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


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3. Revision History 
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit.   
SAP Version 2 was approved on 09-August-2018.  The rationale for SAP version 2 was to 
incorporate changes to the protocol in amendments JPBO(b) and JPBO(c).  Based on amendment 
JPBO(b), Part D, Part E and Part F were added and incorporated into the study objectives.  Based 
on amendment JPBO (c), Simon two-stage analyses are based on evaluable patients.  More 
details were added to Section 6.1.1 Populations.  More details for derivations of BOIR and BOR 
were added to Section 6.7.2 Secondary outcome and Methodology. 


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of study I3Y-MC-JPBO (JPBO) is to evaluate abemaciclib with respect to 
objective intracranial response rate (OIRR; complete response [CR] + partial response [PR]) 
based on tumor assessments and brain metastases response criteria (see protocol attachment 5):

in women with brain metastases secondary to HR+, HER2+ breast cancer.

in women with brain metastases secondary to HR+, HER2- breast cancer.

in patients with brain metastases secondary to NSCLC.  

in patients with brain metastases secondary to melanoma.
4.2.
Secondary Objectives
The secondary objectives of the study are as follows:
To evaluate abemaciclib with respect to:

Intracranial disease per brain metastases response criteria
o
Best overall intracranial response (BOIR)
o
Duration of intracranial response (DOIR) (CR + PR)
o
Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
o
Intracranial clinical benefit rate (ICBR) (CR + PR + SD≥6 months)

Overall
o
OS
o
Objective response rate (ORR) per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and RANO-BM
o
Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and RANO-
BM
o
Progression-free survival (PFS) per RECIST v1.1 and RANO-BM

Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain 
Tumor (MDASI-BT)

Safety and tolerability

PK of abemaciclib and its metabolites
4.3.
Exploratory Objectives

To explore change in neurocognitive function as assessed by Trail Making Tests 
A and B


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
To explore change in neurologic signs as assessed by the Neurologic Assessment 
in Neuro-Oncology (NANO) scale

To explore the concentration of abemaciclib and its metabolites in plasma, 
cerebrospinal fluid (CSF), and brain tumor tissue collected at the time of surgical 
resection for patients participating in Part C, as well as concentrations in time-
matched samples of plasma and CSF for patients participating in Part F.

To explore biomarkers related to the mechanism of action of abemaciclib, the cell 
cycle, and/or the pathogenesis of HR+ breast cancer, NSCLC, and melanoma

To assess the effect of abemaciclib on leptomeningeal metastases (LM) in patients with 
HR+ breast cancer, NSCLC, or melanoma based on proposed RANO-LM response 
criteria

To explore the relationship between abemaciclib exposure and response


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5.
Study Design
5.1.
Summary of Study Design
Study JPBO is a multicenter, open-label, Phase 2 trial of abemaciclib in patients with brain 
metastases secondary to HR+ breast cancer, NSCLC or melanoma.
Figure 5.1 illustrates the study design.
* All patients in Parts A, B, D, E, and F will receive abemaciclib PO Q12H until PD, unacceptable toxicity, or 
withdrawal from the study.  Patients in Part C will receive abemaciclib PO Q12H for 5 to 14 days prior to 
surgical resection; dosing may resume after a wound healing period and continue until PD, unacceptable toxicity 
or withdrawal.
Abbreviations:  HER2+ = HER2 positive; HER2-= HER2 negative; HR+ = hormone receptor positive; mg = 
milligrams; NSCLC = Non-small cell lung cancer; PD = progressive disease; PO = orally; pts = patients; Q12H = 
every 12 hours.
Figure 5.1.
Illustration of study design.
5.2.
Determination of Sample Size
Separate Simon 2-stage designs (Simon 1989) will be employed for Part A, Part B, Part D and 
Part E.  Each design assumes a 1-sided type-I error of 0.05 and 80% power.  
For Part A, 23 qualified patients will be enrolled in the first stage.  If at least 2 of the first 23 
evaluable patients respond to therapy, accrual will continue until 33 additional evaluable patients 
have been enrolled in second stage.  A total of 6 responders out of 56 evaluable patients in Part A 
would need to be observed to warrant further investigation of abemaciclib in this patient 
population.  


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The procedure described above tests the null hypothesis (H0) that the true OIRR of abemaciclib
in Part A is ≤5% versus the alternative hypothesis (Ha) that the true OIRR is ≥15%.  The
probability of early termination of the treatment arm under H0 is 0.68.  
Part B, Part D and Part E will have the identical design as Part A.  
Assuming approximately 20% screening failure, the study will enter approximately 309 patients.


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6.
A Priori Statistical Methods
6.1.
General Consideration
Statistical analysis of this study will be the responsibility of Lilly.
All tests will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.  All
confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise stated.
Unless otherwise stated, all analyses will be conducted on each study part separately.  Pooled
analyses including patients from all parts will be conducted when applicable.
Any change to the data analysis methods described in the protocol will require an amendment
only if it changes a principal feature of the protocol.  
Any other change to the data analysis methods described in the protocol, and the justification for
making the change, will be described in the clinical study report.
6.1.1. Populations
The entered population includes all patients who sign the informed consent document.
The Full Analysis Set (FAS) includes all enrolled patients receiving at least 1 dose of 
abemaciclib.
The OIRR evaluable population includes all enrolled patients receiving at least 1 dose of 
abemaciclib who have at least one measurable brain lesion at time of enrollment (per RANO-
BM) and for whom at least one post-baseline overall response assessment for intracranial disease 
is available.
Safety analyses will be conducted on the Full Analysis Set (FAS). Efficacy analyses will be 
conducted in the FAS population and in the OIRR evaluable population when appropriate, 
including the following.


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Endpoint
Analysis Population
Objective Intracranial Response Rate
FAS
OIRR evaluable population
Best overall intracranial response (BOIR)
FAS
OIRR evaluable population
Duration of intracranial response (DOIR) 
(CR + PR) 
FAS
OIRR evaluable population
Intracranial disease control rate (IDCR) 
FAS
OIRR evaluable population
Intracranial clinical benefit rate (ICBR)
FAS
OIRR evaluable population
Objective response rate (ORR) per RECIST 
v1.1 and RANO-BM
FAS
FAS Patients with extracranial disease
Best overall extracranial response (BOR)
FAS
FAS Patients with extracranial  disease
Disease control rate (DCR)
FAS
FAS Patients with extracranial disease
Overall survival (OS)
FAS
OIRR evaluable population
Bicompartamental Progression-free survival 
(PFS)
FAS
OIRR evaluable population
Intracranial Progression-free survival (PFS)
FAS
OIRR evaluable population
Extracranial Progression-free survival (PFS)
FAS
FAS Patients with extracranial disease
Intracranial tumor data
OIRR evaluable population
Extracranial tumor data
FAS Patients with extracranial disease
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected.  
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients
from the above populations from whom a valid assay result (according to laboratory guideline)
has been obtained.
6.1.2. Definitions and Conventions
Study drug refers to LY2835219 (abemaciclib).
The date of first dose is the date of the first dose of study drug.
The baseline value of an assessment is the last value observed prior to the first dose of study 
drug.
The study day of an event or assessment will be calculated as the difference between the day of 
the event or assessment and the date of first dose plus 1.  For example, if an event occurs on 
08JUN2014 and the date of first dose was 06JUN2014, the study day of the event is 3.


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One month is defined as 365/12 days.
6.2.
Handling of Dropouts or Missing Data
With the exception of dates, missing data will not be imputed.  The method of imputation for any
dates that are imputed is described in the relevant section.
6.3.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, treated in the study, reasons for 
discontinuation from study treatment and reasons for discontinuation from study.  Reason for 
discontinuation from both study treatment and the study will be summarized by pre-determined 
categories.  If the reason for discontinuation is adverse event (AE), the associated AE term will 
be reported.
A summary of all important protocol deviations will be provided.
6.4.
Patient Characteristics
6.4.1. Baseline Demographics and Patient Characteristics
Patient demographics and baseline disease characteristics will be listed for all patients on therapy
and summarized by study part.  
Patient demographics will include sex, race, age, height, weight, and body mass index (BMI).  
Baseline disease characteristics will include basis for diagnosis, initial pathological diagnosis,
Eastern Cooperative Oncology Group (ECOG) performance status, number of target brain 
lesions and location of extracranial lesions
6.4.2. Historical Illnesses
Historical illnesses are clinically relevant events in the past that ended before the screening visit.  
Historical illnesses (using Preferred Term(s) [PTs] from the most current version of the Medical
Dictionary for Regulatory Activities [MedDRA]) will be summarized.
6.4.3. Prior Therapies
Prior radiotherapy, surgery, and systemic therapy will be summarized.  Prior radiotherapy and
surgery will be categorized by reason for regimen.  Prior systemic therapies will be categorized
by reason for regimen ([neo]adjuvant therapy or therapy for locally advanced or metastatic
disease) and specific therapy.  Frequency of each specific therapy will be tabulated within each
reason for therapy.  
Prior local therapy for target brain lesions will be summarized by therapy category (whole-brain 
radiation therapy (WBRT) or stereotactic radiosurgery (SRS) or surgical resection or not done)
Most recent systemic therapy and the duration of that therapy will be summarized within each of
the following subgroups:


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
Patients whose most recent systemic therapy was an adjuvant therapy

Patients whose most recent systemic therapy was for locally advanced or 
metastatic disease.
This summary will include median duration of treatment (date of end of therapy – date of start 
of therapy + 1), median time to progression (date of progression – date of first dose + 1), and
frequency of each specific therapy.  If only the month and year of a treatment date or progression
date is available, the day will be imputed to the 15th.
6.4.4. Post Study Treatment Discontinuation Therapies
Systemic therapies and intracranial therapies received following study treatment discontinuation 
will be summarized overall and by category.
6.5.
Treatment Compliance
Treatment compliance of abemaciclib will be measured by pill counts and summarized by cycle.  
Within each cycle, compliance will be calculated as the ratio of total dose taken to the total 
assigned dose (minus any dose adjustments and doses omitted/withheld for medical reasons).  
The total assigned dose for a patient with no adjustments or omissions is 200 mg per dose × 2 
doses per day × 21 days = 8400 mg.  
6.6.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World
Health Organization (WHO) drug dictionary. All concomitant medications will be summarized
for the FAS population using the preferred name. Corticosteroids usage and dose changes will be 
summarized by study part.
6.7.
Efficacy Analyses
6.7.1. Primary Outcome and Methodology
The primary efficacy measure is OIRR (CR + PR) as defined by RANO-BM.  A partial 
intracranial response is defined as ≥30% decrease in sum of LD of up to 5 target brain lesions 
sustained for at least 4 weeks in the absence of progression of nonmeasurable brain lesions, new 
brain lesions, increased corticosteroid dose, or clinical worsening.  Radiologic PD is defined as 
≥20% increase in sum of LD of up to 5 target brain lesions from the nadir with at least one target 
nrain lesion incresing by 5 mm or more, unequivocal progression of at least on non-target brain 
lesion, or the appearance of an unequivocal new brain lesion. Clinical PD is neurologic 
deterionation or worsening of disease status. 
Best response is determined from the sequence of responses assessed.  If the first assessments are 
radiologic SD and clinical PD on the same day then best response will be determined to be PD.
A second assessment must be performed ≥28 days after the first evidence of response (CR or 
PR).  Two objective status determinations of CR before progression are required for a best 
response of CR.  Two determinations of PR or better before progression, but not qualifying as a 


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CR, are required for a best response of PR.  Best response of SD is defined as disease that does 
not meet the criteria for CR, PR, or PD and has been evaluated at least 1 time, at least 35 days
after the start of abemaciclib. If there is only one SD on or after day 35 and no other assessment
then BOIR is SD. If there is only one SD prior to day 35 and no other assessment then BOIR is 
NE.
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
of objective progression or start of new anticancer therapy.  Any responses observed after 
objective progression or the start of new anticancer therapy are excluded from the determination 
of best response.  
The date of first documented objective disease progression must be recorded on the eCRF even if 
it occurs after the patient has started a new therapy.  
Lilly or its designee will collect and store tumor assessment images (including photographs of 
visible lesions), and an independent review of imaging scans may be performed by Lilly or its 
designee.  
The OIRR is estimated as the total number of confirmed CRs and PRs divided by the total 
number of evaluable patients enrolled.  The primary analysis of OIRR for each study Part (A, B, 
D, or E) will occur approximately 6 months after up to 56 patients have been enrolled into each 
respective part.  This is to ensure adequate durability of response data is available at the time of 
analysis. 
6.7.2. Secondary Outcome and Methodology
The secondary objectives for this study are stated in section 4.2; secondary efficacy measures are 
defined in protocol section 10.1.4.
Point estimates and 95% CIs (using the normal approximation to the binomial) will be calculated
for BOIR, IDCR, ICBR, ORR, and DCR for Part A , Part B, Part D and Part E.
Best overall intracranial response
Best overall intracranial response (BOIR) is derived to encompass all tumor assessments 
(according to RANO-BM) from baseline until the earliest of objective progression (intracranial 
or extracranial according to RANO-BM or RECIST v1.1, respectively) or start of new anticancer 
therapy.  Any responses of RANO-BM observed after objective intracranial progression or the 
start of new anticancer therapy are excluded from the determination of BOIR.  Any responses of 
RANO-BM observed after objective extracranial progression which occur at a later cycle than 
the extracranial progression will be excluded from the determination of BOIR.  However, any 
responses of RANO-BM observed after objective extracranial progression which occur at the 
same cycle as the extracranial progression will be included in the definition of BOIR, even it 
occurs after the extracranial progression.  Each patient’s BOIR will be categorized as CR, PR, 
SD, PD, or NE.


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Best overall extracranial response
Best overall extracranial response (BOR) is derived to encompass all tumor assessments 
(according to RECIST 1.1) from baseline until the earliest of objective progression (intracranial 
or extracranial according to RANO-BM or RECIST 1.1, respectively) or start of new anticancer 
therapy.  Any responses of RECIST 1.1 observed after objective extracranial progression or the 
start of new anticancer therapy are excluded from the determination of BOR.  Any responses of 
RECIST 1.1 observed after objective intracranial progression which occur at a later cycle than 
the intracranial progression will be excluded from the determination of BOR.  However, any 
responses of RECIST 1.1 observed after objective intracranial progression which occur at the 
same cycle as the intracranial progression will be included in the definition of BOR, even it 
occurs after the intracranial progression.  Each patient’s BOR will be categorized as CR, PR, SD, 
PD, or NE.
Time-to-event efficacy endpoints (OS, PFS, and DOIR) will be summarized for Part A, B, D and 
E using Kaplan-Meier techniques (Kaplan and Meier 1958) if there is sufficient data.  If
performed, Kaplan-Meier curves will be generated, and quartiles and point probabilities will be
calculated.  Interval estimates will be calculated using 95% CIs (Brookmeyer and Crowley 1982).
6.7.3. Exploratory Outcome
Investigator-assessed leptomeningeal metastases responses will be summarized for Part F. 
Neurological assessment in Neuro-Pncology (NANO) scale, CSF cytology, neuroimaing 
assessment, and symptoms will be listed.
6.8.
Health Outcomes/Quality-of-Life Analyses
Patient-reported outcomes are measured through paper versions of MD Anderson Symptom
Inventory-Brain Tumor (MDASI-BT)
Patients with at least 1 baseline and at least 1 postbaseline assessment will be included in the 
analyses.  Compliance with completing the questionnaires will be summarized at the group-level 
at each assessment period (defined as the number of completed questionnaires/number expected 
questionnaires given those that are still on study).  Reason for missing questionnaires will be 
assessed.
Data will be summarized for each study part (Parts A, Part B , Part D and Part E) and response 
category (CR/PR, SD, PD); change from baseline and time to worsening will be explored.  This
summary will include mean, standard deviation, median, minimum, maximum, and change from 
baseline.  The MDASI-BT will be reported as core symptoms, brain tumor symptoms, symptom 
interference, and symptom groupings (affect, cognition, focal neurologic deficit, treatment-
related symptoms, generalized/disease status symptoms, and gastrointestinal symptoms).  Time 
to worsening will be described for these categories.
Additional exploratory analysis will be described in a separate health outcome analysis plan.


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6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic (PK) analyses will be performed according to a separate PK analysis plan.
6.10. Tailoring Biomarker Analyses
Analysis of biomarkers will be described in a separate biomarker SAP.
6.11. Safety Analyses
6.11.1. Extent of Exposure
For abemaciclib, extent of exposure will be measured by pill counts and summarized by cycle 
and cumulatively.  The summary will include total dosage taken and dose intensity.  Dose
intensity will be calculated as the ratio of total dose taken to the assigned cumulative dose.  The
assigned cumulative dose for each patient during each cycle is 200 mg per dose × 2 doses per
day × 21 days = 8400 mg.  The assigned cumulative dose while on study is 8400 mg × number of 
cycles started.
Dose adjustments and omissions, along with the reason for adjustment or omission, will be
summarized.
6.11.2. Adverse Events
Verbatim text for the adverse events will be entered by the investigator , as well as the adverse
event (AE) terms and severity grades per CTCAE Version 4.0.
Since all the terms in CTCAE Version 4.0 are themselves LLTs of MedDRA, adverse events will
be handled in the following manner:

The CTCAE Version 4 term reported by the investigator will be mapped to the 
corresponding MedDRA PT and system organ class (SOC), unless the reported 
CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Serious adverse event (SAE) and relationship of AE to the study drug are defined in protocol 
section 10.3.1.1.  The derivation of treatment emergent adverse event (TEAE) is described in 
protocol section 12.2.11.
Overview of adverse event will be summarized for abemaciclib.  The following TEAE/SAE 
listings and summaries will be produced:

Summary of TEAEs by PT (all grade and grade ≥3)

Summary of TEAEs by SOC and PT (all grade and grade ≥3)

Summary of TEAEs by PT and maximum grade (1-5)

List of SAEs


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
Summary of SAEs by SOC and PT (all grade and grade ≥3)
The four summaries will be produced for all TEAEs/SAEs and repeated for TEAEs/SAEs related
to study treatment.
6.11.3. Deaths
All deaths on study not attributed to study disease by the investigator will be listed along with
the reason for death, if known.  For those deaths attributed to an AE, the listing will include the
PT of the AE.  A summary of deaths including reasons for death will be produced.
6.11.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE
Version 4.  These calculated grades will be summarized by cycle and maximum post-baseline
grade over the entire study.
6.11.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, respiration rate, weight and ECOG PS will be
summarized by cycle.
6.11.6. Electrocardiograms
Local electrocardiograms (ECGs) will be summarized by cycle and overall.  The summary by
cycle will classify patients as having normal or abnormal ECG and summarize AEs identified by
ECG within each cycle.  The overall summary will classify patients as having an abnormal ECG
at any point and summarize all AEs identified by ECG.
6.11.7. Hospitalizations and Transfusions
The frequency and percentage of patients with any hospitalizations experienced during the study
treatment period or 30-day post discontinuation follow-up period will be summarized by
treatment arm and best response category.
6.12. Subgroup Analysis
Subgroup analyses of OIRR will be performed for each subgroup variables:

Age (<65 years vs. ≥65 years)

Region (North America vs. Europe vs. Asia vs. Other)

Race (Caucasian vs. Asian vs. Other)

Prior brain metastases therapy (yes vs. no)Concurrent endocrine therapy (yes vs. 
no)
Graded Prognostic Assessment (GPA) score (<3 vs. ≥3)If a level of a factor consists of fewer 
than 10% of enrolled patients, analysis within that level will be omitted.  
Other exploratory subgroup analyses may be performed as deemed appropriate.


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6.13. Interim Analysis
The Simon 2-stage design has a built-in interim analysis to analyze OIRR and to meet threshold
continuation criteria.  The interim analysis of OIRR for each study part (Part A, Part B, Part D 
and Part E) will occur 6 months after the 23rd evaluable patient is enrolled into each respective 
part.  This is to ensure adequate durability of response data is available at the time of analysis.  
This interim analysis for response must be strictly followed to preserve the statistical properties 
of the Simon 2-stage design.  Due to this requirement, objective data will be obtained to
document response and to determine if the trial is to continue based on the OIRR.  Because of 
this, no Assessment Committee or Data Monitoring Committee will be convened to oversee this 
trial.  
Additional interim analyses will be planned if deemed necessary.
6.14. Protocol violation
Protocol violations that can be derived from the data and are related to inclusion/exclusion
criteria or treatment will be summarized.  These violations will include those defined by:

Inclusion/Exclusion Criteria
o
Diagnosis
o
Prior treatments received
o
Age
o
Performance Status

Treatment
o
Dose delays
o
Dose reductions
6.15. Annual Report Analysis
Annual report analyses, including Developmental Safety Update Report (DSUR) and
Investigational Brochure (IB) analyses, are described in the LY2835219 Program Safety
Analysis Plan.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry
(CTR) requirements.  Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs and
‘Other’ AEs will be summarized by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a treatment emergent adverse 
event (TEAE).


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
An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each SAE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in 
fewer than 5% of patients/subjects in every treatment group may not be included 
if a 5% threshold is chosen (5% is the minimum threshold).

Adverse event (AE) reporting is consistent with other document disclosures for 
example, the clinical study report (CSR), manuscripts, and so forth.
In addition, a participant flow will be created that will describe how many enrolled patients
completed the study, and for those who did not, the frequency of each reason for not completing.  
This analysis will be based on study discontinuation, not treatment discontinuation.  A patient
will be identified as having completed the study if the patient dies while on the study or the
patient had discontinued study treatment and is in follow up at the time of the final OS analysis.  
Patients who withdraw consent before the final OS analysis or who are still on treatment at the
time of the final OS analysis will be identified as not completing the study.


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7.
Unblinding Plan
JPBO is an open-label study.


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8.
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