Clinical trial NCT04534283
Conditions: Cancer Cancer Metastatic BRAF V600E MEK1 Gene Mutation MEK2 Gene Mutation ERK Mutation RAF1 Gene Mutation
Keywords: Point Mutation Metastatic Cancer Advanced Cancer
Sponsor: Anita Turk
Start date: 2020-10-05; Completion date: 2023-08-07
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of CTO-IUSCC-0730 study is to assess the clinical efficacy of LY3214996 in combination with abemaciclib at the recommended phase 2 dose of LY3214996 200 mg orally daily and abemaciclib 150 mg orally twice daily. Patients will be treated until evidence of disease progression, non-compliance with study protocol, unacceptable major toxicity, at subject's own request for withdrawal, or if the study closes for any reason.

Detailed description:

Arms: arm 1: Subjects will receive Abemaciclib 150 mg orally twice daily with LY3214996 200 mg orally daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study.
Interventions: intervention 1: Abemaciclib intervention 2: LY3214996
Intervention descriptions: intervention 1: Subjects will receive Abemaciclib 150 mg orally twice daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study. intervention 2: Subjects will recieve LY3214996 200 mg orally daily until disease progression, unacceptable toxicity, or patient preference to withdraw from study.

Protocol documents:
Prot_SAP_000.pdf: 
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CTO-IUSCC-0730 
A Phase 2 basket trial of an ERK1/2 inhibitor (LY3214996) in 
combination with abemaciclib for patients whose tumors 
harbor pathogenic alterations in BRAF, RAF1, MEK1/2, 
ERK1/2, and NF1 
 
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 LY3214996, 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. 
 
Principal Investigator: 
Anita Turk, MD 
Division of Hematology/Oncology 
Indiana Cancer Pavilion 
535 Barnhill Dr., Suite RT130C 
Indianapolis, IN 46202 
Phone: 317-948-7576 
aaturk@iu.edu 
 
 
 
 
 
Collaborating Investigator: Bryan Schneider, MD 
Division of Hematology/Oncology 
Indiana University Simon Cancer Center 
1030 W. Michigan St., Suite 3307 
Indianapolis, IN 46202 


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Phone: 317-948-9510  
bpschnei@iu.edu 
 
 
Biostatistician:    
Yong Zang, PhD  
Department of Biostatistics and Health Data Sciences 
Indiana University School of Medicine 
410 West 10th Street, Suite 3000 
Indianapolis, IN 46202 
Phone: 317-278-2108 
zangy@iu.edu 
 
IND # 
151580 
 
Protocol Version: 
6/28/2022 
 
 
 
 
 
 


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E x pecte d I R B S u b missi o n Date  
 
 
 
I nstr ucti o ns t o t he i n vesti gat or: Please SI G N a n d D A T E t his 
si g nat ure pa ge. P RI N T y o ur na me a n d title, t he na me a n d l ocati o n of 
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U ni versit y Si m o n Ca ncer Ce nter a n d kee p a rec or d f or y o ur files.  


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Table of Contents 
Section 
Page 
 
Synopsis ...................................................................................................................................9 
 
Schedule of Activities ............................................................................................................11 
 
Introduction ...........................................................................................................................13 
 Study Rationale .....................................................................................................................13 
 Rationale for Investigation of LY3214996, an ERK1/2 Inhibitor ..................................13 
 Rationale for Combination Therapy ...............................................................................13 
 Background ...........................................................................................................................16 
 General Introduction to LY3214996 ...............................................................................16 
 
Objectives and Endpoints ......................................................................................................21 
 
Study Design .........................................................................................................................22 
 Overall Design .......................................................................................................................22 
 Study Period and Subject Status Definitions ..................................................................22 
 Subject Status Definitions ...............................................................................................22 
 Study Period Definitions .................................................................................................22 
 Number of Patients ................................................................................................................23 
 End of Study Definition ........................................................................................................23 
 Scientific Rationale for Study Design ...................................................................................23 
 
Study Population ...................................................................................................................23 
 Inclusion Criteria ...................................................................................................................23 
 Exclusion Criteria ..................................................................................................................25 
 Lifestyle Restrictions .............................................................................................................26 
 Screen Failures ......................................................................................................................26 
 
Patient Registration ...............................................................................................................26 
 
Treatment ...............................................................................................................................27 
 Treatments Administered ......................................................................................................27 
 Treatment Plan ................................................................................................................27 
 Packaging and Labelling .................................................................................................27 
 Selection and Timing of Doses .......................................................................................27 
 Blinding .................................................................................................................................28 
 Dosage Modification .............................................................................................................28 
 Treatment Compliance ..........................................................................................................28 
 Evaluable Patients ...........................................................................................................28 
 Preparation/Handling/Storage/Accountability ......................................................................29 
 Concomitant Therapy ............................................................................................................29 
 Supportive Care ..............................................................................................................30 


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 Treatment after the End of the Study ....................................................................................33 
 
Discontinuation Criteria ........................................................................................................33 
 Discontinuation from Study Treatment .................................................................................33 
 Discontinuation of Inadvertently Enrolled Patients ..............................................................34 
 Discontinuation from the Study ............................................................................................34 
 Follow Up ..............................................................................................................................35 
 Lost to Follow-Up .................................................................................................................35 
 
Study Assessments and Procedures .......................................................................................35 
 Efficacy Assessments ..........................................................................................................35 
 Safety ...................................................................................................................................36 
 Other Safety Measures ..................................................................................................36 
 Safety Monitoring .........................................................................................................36 
 Pharmacokinetics ................................................................................................................36 
 Processing .....................................................................................................................37 
 Genomics .............................................................................................................................37 
 Whole Blood and Tumor Samples for Genomic Biomarker 
Research ...................................................................................................................37 
 Biomarkers ..........................................................................................................................38 
 Samples for Non-pharmacogenomic Biomarker Research ...........................................39 
 Tissue Samples for Research ........................................................................................39 
 Health Economics ...............................................................................................................41 
 
Data Forms and Submission Schedule ..................................................................................41 
 
Reporting Adverse Events .....................................................................................................41 
 Adverse Events ....................................................................................................................42 
 Serious Adverse Events .......................................................................................................42 
 Adverse Event and Serious Adverse Event Reporting ........................................................42 
 Reporting to the IRB .....................................................................................................43 
 Reporting to the FDA....................................................................................................43 
 Reporting to Lilly ..........................................................................................................44 
 Suspected Unexpected Serious Adverse Reactions ............................................................44 
 Complaint Handling ............................................................................................................45 
 Treatment of Overdose ........................................................................................................45 
 
Data and Safety Monitoring ..................................................................................................45 
 Data and Safety Monitoring Committee .............................................................................45 
 IND Annual Reports ............................................................................................................46 
 Study Auditing and Monitoring ..........................................................................................46 
 Data Management/ Oncore Reporting Requirements .........................................................46 
 Study Accrual Oversight .....................................................................................................46 


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 Oncore Safety Reporting .....................................................................................................46 
 Protocol Deviation Reporting ..............................................................................................46 
 
Statistical Considerations ......................................................................................................46 
 Sample Size Determination .................................................................................................46 
 Populations for Analyses .....................................................................................................47 
 Statistical Analyses .............................................................................................................47 
 Safety Analyses .............................................................................................................47 
 Efficacy Analyses .........................................................................................................48 
 
Patient Consent and Peer Judgement .....................................................................................49 
 
References .............................................................................................................................50 
 


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List of Tables 
Table 
Page 
Table 2.1 Schedule of Activities ....................................................................................................11 
Table 3.1 Summary of Phase I DLTs .............................................................................................20 
Table 3.2 Summary of Related TEAEs in >10% of the patients (total) ........................................21 
Table 4.1 Objectives ....................................................................................................................21 
Table 8.1 Management Recommendations for Skin Reactions .....................................................31 
 


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List of Appendices 
Appendix 
Page 
Appendix 1 
Abbreviations and Definitions ...................................................................55 
Appendix 2 
Study Governance, Regulatory, and Ethical Considerations .....................58 
Appendix 3 
Creatinine Clearance Formula ...................................................................60 
Appendix 4 
Dose Modification of LY3214996 & Abemaciclib ...................................61 
Appendix 5 
Sensitive CYP3A Substrates and Narrow Therapeutic Range Drugs ........66 
Appendix 6 
Patient Dosing Instructions and Diary .......................................................67 
 
 
 
 


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 Synopsis 
 
TITLE 
A Phase 2 basket trial of an ERK1/2 inhibitor (LY3214996) in combination with 
abemaciclib for patients whose tumors harbor pathogenic alterations in BRAF, 
RAF1, MEK1/2, ERK1/2, and NF1. 
PHASE  
2 
OBJECTIVES 
Primary Objective: 
• 
To evaluate the proportion of patients with objective response to an ERK1/2 
inhibitor (LY3214996) in combination with abemaciclib for patients whose 
tumors harbor pathogenic alterations in BRAF, RAF1, MEK1/2, ERK1/2, 
and NF1 
Secondary Objective:  
• 
To evaluate the safety and tolerability of LY3214996 + abemaciclib as 
defined by CTCAE v5 criteria.  
• 
To evaluate the median progression-free survival (PFS). 
• 
To evaluate the duration of response (DOR). 
Correlative Objectives:  
• 
To identify potential predictive biomarkers beyond the genomic alteration by 
which treatment is assigned and/or resistance mechanisms. 
• 
To evaluate pharmacokinetic parameters of LY3214996 and abemaciclib. 
STUDY DESIGN 
Single arm, non-randomized, open-label 
TOTAL NUMBER OF 
SUBJECTS  
35  
KEY INCLUSION 
CRITERIA  
1. Patients must have histologically confirmed, metastatic/advanced cancer 
with tumors that harbor the following alterations as defined below using a 
CLIA-certified next-generation sequencing: 
a. Point mutations in BRAF, RAF1, MEK1/2, or ERK1/2 that have 
been previously characterized to be gain-of-function mutations. 
These mutations have to be specified as gain-of-function as listed in 
the OncoKB and/or JAX-CKB databases.  
i. Patients with NSCLC that harbor BRAF V600E treated with 
prior RAF and/or MEK inhibition therapy will be excluded 
ii. Patients with tumor types other than NSCLC that harbor 
BRAF V600E mutations who have been treated and 
progressed on prior BRAF and/or MEK inhibition will be 
included 
iii. Patients with NSCLC that harbor BRAF V600E will only be 
enrolled if they are not a candidate for FDA approved 
therapy 
b. Amplification of RAF1 defined as > 6 copies of the respective gene. 
c. Gene fusions in which BRAF, RAF1, MEK1/2 or ERK1/2 is a fusion 
partner; in which the fusion is determined to be in-frame; and the 
kinase domain of BRAF, RAF1, MEK1/2, or ERK1/2 is retained. 
d. Point mutations, frameshift insertions/deletions, splice site 
mutations, or stop gain mutations that results in loss-of-function of 
NF1. 


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2. Measurable, metastatic disease amenable to biopsy. If biopsy is deemed 
unsafe at time of procedure, patients will remain eligible for study.  
3. ECOG performance status 0 or 1.  
4. Laboratory evidence of adequate organ function and hematologic function. 
5. Patients with untreated brain metastases are excluded. However, patients with 
metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks 
from therapy completion (incl. radiation and/or surgery), is clinically stable at 
the time of study entry and is receiving a stable or decreasing dose of 
corticosteroid therapy. Brain MRI or head CT is required at screening for 
patients with known brain metastases. 
6. Patients who have received prior treatment with an ERK kinase 
inhibitor are excluded 
TREATMENT PLAN 
Abemaciclib 150 mg orally twice daily with LY3214996 200 mg orally daily 
until disease progression, unacceptable toxicity, or patient preference to 
withdraw from study. 
STATISTICAL 
CONSIDERATIONS 
The primary end point is overall response rate (ORR), where overall response is 
defined as the complete or partial response per RECIST v1.1 criteria. We will 
use the one stage design for the phase II trial. We will specify the null hypothesis 
that the true ORR is 5% versus the alternative hypothesis that that the true ORR 
is 19% using a one-sided test with the designing parameters type-I error=0.05 
and type II error=0.2 (power=80%). 
 
A total sample size of 28 evaluable patients will be accrued. Of note, an 
evaluable patient is defined as a patient who receives at least one dose of trial 
drug. Assuming a 20% drop-out rate, it is anticipated that the total accrual would 
be 35 patients.  
 
An additional early stopping rule for futility will be used to monitor the 
following subgroups of patients with pathogenic alterations in 1) BRAFV600E 2) 
BRAF nonV600E, RAF1 3) MEK1/2, ERK1/2 and 4) NF1 based on the 
Bayesian posterior probability.  
ESTIMATED 
ENROLLMENT 
PERIOD  
12 months 
ESTIMATED STUDY 
DURATION  
18 months  


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 Schedule of Activities 
Table 2.1 presents the schedule of activities for patients receiving LY3214996 in combination with abemaciclib. 
Table 2.1 Schedule of Activities 
Study Evaluation  
Cycle = 28 days 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
and beyond 
Safety 
follow up 
visit 
-21 ± 7 
days  
Day 1 
Day 15 
± 3 days 
Day 1 
± 3 
days 
Day 15 
± 3 
days 
Day 1 
± 7 days 
30 days 
(±7) 
post last 
dose 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical HistoryA 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Vital signs and ECOG 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
Adverse Event EvaluationB 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
ASSESSMENTS 
 
 
 
 
 
 
 
Complete Blood Cell Count 
with differential (CBC)J 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic 
Profile (CMP)C 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum or urine) 
(WOCBP)D 
X 
X 
 
X 
 
X 
X 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
CT of chestE 
X 
 
 
 
 
X 
 
CT or MRI of abdomen and 
pelvisE 
X 
 
 
 
 
X 
 
TREATMENT EXPOSURE 
 
 
 
 
 
 
 


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Study Evaluation  
Cycle = 28 days 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
and beyond 
Safety 
follow up 
visit 
-21 ± 7 
days  
Day 1 
Day 15 
± 3 days 
Day 1 
± 3 
days 
Day 15 
± 3 
days 
Day 1 
± 7 days 
30 days 
(±7) 
post last 
dose 
LY3214996 and abemaciclibF 
 
X 
X 
X 
X 
X 
 
SPECIMEN COLLECTION  
 
 
 
 
 
 
 
Tissue biopsies at screening 
and at progressionG 
X 
 
 
 
 
 
X 
Blood sample for plasma 
ctDNA 
 
X 
 
X 
 
X 
X 
Blood for germline mutations 
X 
 
 
 
 
 
 
Pharmacokinetics (PK)H 
 
 
X 
X 
 
 
 
A: Medical history to include prior treatments, radiation and surgical history. Diagnosis and staging to include 
pathology report and Tumor Node Metastasis (TNM) staging 8th edition. 
B: CTCAE Version [5.0] Adverse Events will be colleted from the time informed consent is signed through 30 days 
after the last dose of study treatment. 
C: To include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total bilirubin, and total protein. 
D: All females of childbearing potential must have a negative blood or urine pregnancy test within 14 days prior to 
enrollment and prior to treatment on day 1 
E: CT or MRI scans of chest and abdomen will be done at baseline to assess the response per RECIST v1.1 criteria.  
CTs or MRIs of the abdomen with IV contrast are encouraged but will be done at the investigator’s discretion. Disease 
assessments should be completed every odd cycle (i.e. cycle 3, cycle 5, etc.).  
F: Antiemetic prophylaxis will be required in cycle 1 in an effort to improve patient safety and reduce the incidence of 
nausea and vomiting. Refer to Section 8.6.1.3 for details. 
G: Biopsy at screening is mandatory if deemed safe by the treating physician and should be completed following 
determination of eligibility, ≤14 (+/- 7) days before start of treatment. Patients unable to undergo the screening biopsy 
may donate archived tissue if available. See Section 10.5.2 for details. Biopsy at time of progression is not mandatory. 
H: Plasma samples for pharmacokinetics will be collected on cycle 1 day 15 and cycle 2 day 1 prior to dosing of 
abemaciclib and LY3214996. Please refer to Section 10.3. 
I: Vital signs to be performed per standard of care and should include heart rate, blood pressure, respiratory and 
oxygen saturation 
J: To include WBC, ANC, platelets, and Hgb 
 
 
 


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 Introduction 
 Study Rationale 
 Rationale for Investigation of LY3214996, an ERK1/2 Inhibitor 
The mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation 
and survival. Abnormalities of the MAPK pathway including alterations in BRAF, RAS, 
Neurofibromin-1 (NF1), and MEK are common in many cancers including melanoma, colorectal 
cancer (CRC), non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), 
ovarian cancer, and many others.  Extracellular signal regulated kinase (ERK) is a downstream 
member of this pathway and plays a central role in transmitting extracellular signals from activated 
receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR), FGFR, 
PDGFR, VEGFR, and others.  When activated, ERK1/2 phosphorylates RSK1, and regulates 
several additional downstream cytoplasmic and nuclear targets involved in cell cycle, cell 
proliferation, cell growth, and cell survival. 
 
The feasibility of pharmacologic inhibition of the MAPK pathway in cancer has been shown 
through the success of BRAF and MEK inhibitors in the treatment of various cancer subtypes 
especially patients who harbor BRAF mutations.  Two BRAF kinase inhibitors, vemurafenib and 
dabrafenib, are approved in the United States (US), Australia and several European countries for 
the treatment of melanoma patients with BRAFV600E mutation.  Two MEK kinase inhibitors – 
trametinib alone, and in combination with a BRAF inhibitor, dabrafenib, and cobimetinib, in 
combination with a BRAF inhibitor, vemurafenib – are approved by the Food and Drug 
Administration (FDA) for the treatment of unresectable or metastatic melanoma patients with 
BRAFV600E/K mutations that have not received previous treatment with a BRAF inhibitor.  
However, while BRAF and MEK inhibitors have proven effective in these patient populations, 
most patients eventually develop drug resistance, which leads to disease relapse (Samatar et al. 
2014).  Most resistance mechanisms to RAF and MEK inhibitors result in reactivation of ERK1/2; 
therefore, blockade of ERK1/2 directly is postulated to overcome many of the current limitations 
of RAF and MEK inhibitors.  In addition, RAF and MEK inhibitors remain ineffective in RAS-
mutant cancers.  Neurofibromin-1, a tumor suppressor gene, is a negative regulator of RAS.  Loss 
of function of NF1 has been linked to the development of tumors in mice (Jacks et al. 1994).  
Neurofibromin-1 deletions and mutations are common in cancers and may recapitulate RAS 
mutations and represent an attractive target in the MAPK pathway (Jacks et al. 1994; Yap et al. 
2014).  LY3214996 is a potent inhibitor of ERK1/2 kinases that can potentially obviate resistance 
mechanisms in cancers that harbor BRAF, RAS, NF1, MEK, and other MAPK alterations.  A 
general introduction of LY3214996 is provided in Section 3.2.1. Detailed information about 
LY3214996 is provided in the Investigator’s Brochure (IB).   
 Rationale for Combination Therapy 
Activating mutations in BRAF and KRAS, key signaling components of the MAPK pathway, are 
among the most common oncogenic mutations in human cancers, occurring in ~7% and ~20% of 
all cancers.  The frequency in common cancer histologies such as NSCLC, PDAC, CRC and 
melanoma (Oikonomou et al. 2014.).  Genome and transcriptome wide analysis in various 
cancers demonstrated a diversity of altered pathway targets and feedback mechanisms that 


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contribute to disease pathogenesis and resistance.  In MAPK driven cancers, this may explain the 
lack of success in RAS mutant tumors, limited efficacy of cancer agents in many BRAF mutant 
tumors and toxicities experienced by patients due to paradoxical signaling when these agents are 
given as a single agent.  The feasibility and usefulness of combining agents that affect targets 
within the MAPK pathway has been clearly demonstrated by the success of combining BRAF 
and MEK inhibitors (vemurafenib and cobimetinib or dabrafenib with trametinib) in BRAFV600E/K 
mutant melanoma patients, improving not just response rates and duration of response but in 
reducing the rates of certain therapy related toxicities.  This underscores the importance of 
combination therapy in MAPK driven tumors.   
 Rationale for Exploring Combination Therapy with Abemaciclib in Tumors 
with Gain-of-Function Alterations in BRAF, RAF1, MEK1/2, and ERK1/2 
 
Abemaciclib Background/Rationale 
Abemaciclib is an orally bioavailable selective cyclin-dependent kinase (CDK) 4 and 6 inhibitor 
currently FDA approved as monotherapy and in combination with endocrine therapy in 
hormone-receptor positive breast cancer.  It causes cell cycle arrest in Rb-proficient cells and has 
significant in vivo antitumor activity in several human cancer xenograft models (Spring et al. 
2016).  Abemaciclib crosses the blood brain barrier and has been shown to inhibit the growth of 
intracranial tumors both as a single agent and in combination with temozolomide (Raub et al. 
2015).  In a KRASG12Vmouse model, a synthetic lethal interaction between the KRASG12V 
mutation and ablation of CDK4 was observed (Puyol M et al. 2010).  Ablation of CDK4 leads to 
immediate senescence response in the lung tumors of KRASG12V animals.  Increased sensitivity to 
abemaciclib has been observed preclinically both in in vitro and in vivo models of KRAS mutant 
NSCLC. 
Abemaciclib has been or is currently being investigated in clinical trials  
• Phase 1 study of abemaciclib for advanced NSCLC, breast cancer, and other solid tumors 
• Phase 1 study of abemaciclib for Japanese patients with advanced cancer 
• Phase 1b study of abemaciclib in combination with endocrine or targeted therapies for 
patients with advanced breast cancer 
• Phase 1b study of abemaciclib in combination with another anti-cancer drugs for patients 
with NSCLC 
• Phase 2 study of abemaciclib in relapsed or refractory mantle cell lymphoma 
• Phase 2 Study of abemaciclib for patients with previously treated hormone receptor 
positive (HR+), HER2 negative metastatic breast cancer 
• Phase 2 study for patients with brain metastasis secondary to HR+ breast cancer, NSCLC, 
or melanoma 
• Phase 2 neoadjuvant study of abemaciclib for postmenopausal women with HR+, HER2 
negative breast cancer (neoMONARCH) 
• Phase 2 study of abemaciclib versus docetaxel for patients with stage intravenous (IV) 
squamous NSCLC previously treated with platinum-based chemotherapy 
• Phase 3 study of fulvestrant with or without abemaciclib for patients with HR+, HER2 
negative locally advanced or metastatic breast cancer (MONARCH 2) 
• Phase 3 study of nonsteroidal aromatase inhibitors with or without abemaciclib in 
patients with HR+, HER2 negative locally advanced or metastatic breast cancer 
(MONARCH 3) 


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• Phase 3 study of abemaciclib plus best supportive care (BSC) versus erlotinib plus BSC 
for patients with stage IV NSCLC with a detectable KRAS mutation who have 
progressed after platinum-based chemotherapy (JUNIPER) 
 
The safety profile of abemaciclib has been manageable when given as monotherapy or in the 
combinations investigated to date.   
 
The Phase 2 MONARCH 1 study treated patients with endocrine resistant, hormone-receptor 
positive breast cancer with single-agent abemaciclib dosed at 200mg twice a day (N=132). 
Safety data from this study showed the most common treatment-emergent adverse events 
(TEAEs) (≥20%) that occurred in patients included diarrhea (90.2%), fatigue (65.2%), nausea 
(64.4%), decreased appetite (45.5), abdominal pain (38.6%), vomiting (34.8%), neutropenia 
(37.1%), anemia (25.0%), headache (20.5%) and thrombocytopenia (20.5%) (IB; Lilly 2019). 
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) may be found in the abemaciclib IB (IB; Lilly 2019). 
 
Rationale for Exploring Combination Therapy with Abemaciclib 
The importance of combination therapy to target various aspects of cancer pathogenesis has 
become more evident in an attempt to facilitate anti-tumor activity or to overcome acquired 
resistance in cancer.  The RAF/MEK/ERK pathway is commonly mutated in a variety of solid 
tumors. While mutations in BRAF are the most common, particularly codon 600, a variety of 
additional mutations in the pathway have been identified that lead to pathway activation. Many 
of these mutations are uncommon but may lead to sensitivity to ERK inhibition. A recently 
published example of a patient with gallbladder cancer that harbored a rare gain-of-function 
BRAF L485W achieved a complete response with the ERK inhibitor, Ulixertinib (Sullivan et al. 
Cancer Discovery 2018). Unpublished preclinical data from Eli Lilly has demonstrated that gain-
of-function mutations in MEK1/2 rendered cell lines sensitive to ERK inhibition. Open questions 
include ERK inhibitor sensitivity to other classes of mutations including BRAF fusions and 
RAF1 amplification. Further, it is not known whether ERK inhibition may play a role in patients 
with BRAF mutations who have become resistant to BRAF inhibition.  
 
Mitogens that stimulate the RAS-MAPK pathway are known to induce expression of D-type 
cyclins via the activation of downstream transcription factors in the AP1 or ETS family, which in 
turn activate CDK4 and CDK6, promoting cell cycle progression (Sherr 1996; Klein and Assoian 
2008).  Therefore, concomitant inhibition of the MAPK pathway exemplified by ERK inhibitors 
may augment the antitumor activity of CDK4 and 6 inhibitors like abemaciclib. Previous 
published data has also demonstrated that CDK4/6 inhibition is synergistic with inhibition of the 
MEK/ERK pathway (de Leeuw et al. Clin Can Res. 2018, Hart LS et al. Clin Can Res. 2016). To 
this end, Lilly has an ongoing phase I trial combining LY3214996 with Abemaciclib (CDK4/6 
inhibitor) for which an RP2D of the combination is established at LY3214996 200 mg orally 
daily with abemaciclib 150 mg orally twice daily. 
 
The manageable clinical safety profile of abemaciclib and preclinical safety data for LY3214996, 
coupled with the additive effects of the combination pre-clinical data provide the rationale for 
clinically evaluating the combination of LY3214996 and abemaciclib in the clinical setting in 


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tumors with overactivated MAPK pathyway identified via pathogenic alterations in BRAF, 
RAF1, MEK1/2, ERK1/2, and NF1.  
 
Expected overlapping toxicities of the combination include nausea, vomiting, fatigue, diarrhea, 
decreased appetite, blood creatinine increase, and alanine aminotransferase increased. Though 
rash is not considered an overlapping toxicitiy, an increased incidence of maculo-papular rash 
and dermatitis acneiform was observed in the combination during dose escalation of the phase 1 
JUAB study. 
 Background 
 General Introduction to LY3214996 
LY3214996 is an adenosine triphosphate (ATP) competitive inhibitor of ERK2 with a Ki of 
0.064 nM and ERK1 with a Ki of 0.65 nM.  LY3214996 has solubility (FasSIF) of 0.113, high 
free fraction (0.39) and DABS (742-1570 mg) above the projected human efficacious dose 
(50-350 mg, QD).  LY3214996 has acceptable ADME properties and a manageable toxicology 
profile.  LY3214996 has a >40-fold selectivity compared to the nearest most potent kinase when 
tested against 464 kinases in a kinome profile. 
 Mechanism of Action and In Vitro/In Vivo Activity 
LY3214996 is an ATP competitive, selective inhibitor of ERK1 and ERK2 with comparable 
biochemical IC50 values of 5 nM for each.  Ki for ERK1-2P is 650 pM and Ki for ERK2-2P is 
64 pM.  It inhibits cellular phospho-RSK1 (T359/S363) in RAF and RAS mutant cancer cell lines.  
In Cancer Cell Sensitivity Profiling (CCSP) of 535 cell lines, LY3214996 showed higher 
sensitivity in a majority of cell lines with MAPK pathway mutations compared to cells lines that 
do not harbor MAPK pathway mutations.  It inhibits cell proliferation and leads to significant 
tumor growth inhibition/regression in preclinical models of CRC (KRAS G13D mutant HCT116, 
BRAFV600E mutant Colo205, MEK1 Q56P mutant SW48), melanoma (NRAS Q61K mutant SK-
MEL-30, vemurafenib-resistant BRAFV600E mutant A375), NSCLC (KRAS Q61K mutant Calu-
6), PDAC (KRAS G12C mutant MiaPaCa-2, BRAFV600E mutant PDX PAXF2196) and AML 
(KRAS Q61L mutant HL-60). 
 
In addition, combination with various agents showed preclinical activity across a range of tumor 
types:  gemcitabine in PDAC (KRAS G12V mutant Capan-2), abemaciclib in PDAC (KRAS 
G12V mutant Capan-2, KRAS G12D mutant HPAF-II) and NSCLC (KRAS G12C mutant H2122, 
KRAS G12S mutant A549, KRAS G12V mutant H441) and CRC (KRAS G13D mutant HCT116) 
and CHK1 inhibitor in PDAC (KRAS G12V mutant Capan-2). 
 Nonclinical Pharmacokinetics/Pharmacodynamics 
Nonclinical pharmacokinetics (PK) of LY3214996 were characterized in rats and dogs following 
IV and oral doses.  Following oral administration, absorption was rapid in the rat and moderate 
in the dog, with mean oral bioavailability ranging from 25.9% to 72.7%.  Following IV 
administration, clearance was less than hepatic blood flow in both rat and dog.  The volume of 
distribution ranged between 1.32 and 2.03 L/kg.  Half-life (t½) ranged from 0.51 to 1.63 hours.  
Toxicokinetics of LY3214996 were determined in male and female rats and dogs following 
LY3214996 oral administration for up to 28 days.  Exposure of LY3214996 increased with dose 
level, with no evidence of accumulation upon multiple dosing. 


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Preliminary studies evaluated the in vitro metabolism of LY3214996 in mouse, rat, dog and 
human liver microsomes and cryopreserved hepatocytes, as well as in rat and dog plasma and 
urine following a single oral dose.  The in vitro results were generally predictive of the 
significant metabolic pathways observed in vivo.  Metabolism of LY3214996 appeared to be 
primarily oxidative in nature, with some minor subsequent glucuronide conjugation observed.  
A direct response relationship adequately described the PK-pRSK inhibition in mouse Colo205 
and rat and mouse HCT116 tumor models.  The predicted IC50 values in human were 73 nM, 
459 nM and 760 nM, respectively, after correction for species differences in protein binding.  
Assuming a desired level of target inhibition of greater than 50% for at least 6-8 hours per day, 
human PK simulations suggest that doses of 50 mg (90% prediction interval 20-105 mg) to 
350 mg (90% prediction interval 140-740 mg) and above are expected to fulfill these conditions.   
 Nonclinical Toxicology 
LY3214996 was evaluated in 1-month daily oral dosing toxicity studies in Sprague-Dawley rats 
and Beagle dogs (with 1 month reversibility in mid-dose animals) at tolerated dose levels as well 
as at dose levels that exceeded the maximum tolerated dose (MTD).  Safety pharmacology 
parameters were evaluated in vitro and as part of the repeat-dose toxicity study in dogs.  Genetic 
toxicity was evaluated in a bacterial mutation (Ames) assay.  Results from these studies have 
identified a starting dose that is anticipated to be safe in patients.  Based on nonclinical study 
findings, potential toxicities include:  Gastrointestinal (GI) inflammation, fecal changes, emesis, 
dehydration, sores on gums, scabs on skin, and clinical pathology changes including increased 
neutrophils and monocytes, decreased lymphocytes, decreases in red cell mass, decreased 
albumin, increased globulin and/or increases in serum phosphorus.  Injury to the long bones 
(femur and tibia) and female reproductive tract (ovary) and effects in the skin were also observed 
in rats only.  With the exception of effects on skin, bone and ovaries, all findings either 
recovered or showed evidence of recovery after a 1 month reversal period. 
 
The toxicity of LY3214996 was assessed after daily administration for 1 month in rats (5, 15 and 
30 mg/kg) and dogs (3, 10 and 20 mg/kg).  In rats, the MTD was 15 mg/kg due to all females in 
the 30-mg/kg/day group being either found dead or euthanized due to clinical signs from Days 
17-20.  One male rat (in the Toxicokinetic subgroup) given 30 mg/kg was euthanized on Day 28 
(the day before scheduled sacrifice).  
 
In dogs, the MTD was 10 mg/kg, due to preterminal euthanasia at 20 mg/kg.  Three dogs given 
20 mg/kg (2 males and 1 female) were euthanized on Day 13 due to compound-related clinical 
observations including hunched posture, thin appearance, emesis, hypoactivity, excessive 
salivation, vomitus, liquid and mucoid feces, entire body cold to the touch, and visible sores on 
the gums.  The remaining animals given 20 mg/kg (1 male and 2 female) were euthanized on 
Day 14 with clinical observations that were similar to those euthanized on Day 13.  One female 
dog given 10 mg/kg was put on a dosing holiday on Days 15 and 16 due to clinical observations 
of emesis, excessive salivation, vomitus, red/nonformed feces and 0.7 kg loss in body weight 
(8.8% decrease) from Days 11 to 15.  The animal’s body condition and appetite rebounded 
quickly and by Day 17 it had regained nearly all of the lost weight (0.6 kg).  The animal resumed 
dosing at 10 mg/kg on Day 17 and remained on study to its scheduled sacrifice.  Other clinically 
monitorable changes occurring in dogs given ≥10 mg/kg and rats given ≥15 mg/kg included 


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increases in increased neutrophils and monocytes, decreased lymphocytes, decreases in red cell 
mass, decreased albumin, increased globulin and/or increases in serum phosphorus. 
The dose limiting toxicity (DLT) in dogs at 20 mg/kg/day was identified microscopically as GI 
toxicity (including acute inflammation, necrosis, erosion/ulcer and crypt dilatation).  There were 
no similar findings in the GI tract in rats.  At 10 mg/kg in dogs, increased incidence of crypt 
dilatation in the duodenum was noted at 10 mg/kg in dogs; however this finding was of a lesser 
severity and incidence than in animals given 20 mg/kg and resolved during the recovery phase.   
In rats, the dose limiting toxicity at 30 mg/kg in female rats was identified microscopically as 
soft tissue mineralization.  Mineralization was observed in female rats given 30 mg/kg, 
correlating with mildly to moderately higher serum phosphorous concentrations noted in animals 
given ≥15 mg/kg.  Mineralization of multiple tissues was considered the primary cause of 
morbidity.  Soft tissue mineralization is considered to be the result of calcium:phosphorus 
imbalance due to inhibition of the FGF23 pathway.  MEK inhibitors have shown this effect 
nonclinically through FGF-23 signal blockade in the kidneys of rats, which leads to 
transcriptional upregulation of 25-hydroxyvitamin D(3) 1-alpha-hydroxylase, the rate-limiting 
enzyme in vitamin D activation.  Blocking FGF-23 signaling also leads to down regulation of 
1,25-dihydroxyvitamin D(3) 24-hydroxylase, the enzyme responsible for starting degradation of 
the active form of vitamin D leading to hyperphosphatemia but this has not appeared to translate 
at clinical doses (Diaz et al. 2012; Carvajal et al. 2014; Larkin et al. 2014; Long et al. 2016).  
Clinical monitoring for increased serum phosphorus will help mitigate the concern for tissue 
mineralization. 
In female rats, microscopic findings of decreased numbers of the corpora lutea and the presence 
of retained follicles were observed in the ovary of females given ≥5 mg/kg, correlating with 
decreased ovary weight parameters in females given 15 mg/kg.  While the effect on ovarian 
weights reversed during the recovery period, microscopic effects in the ovary were still present 
in recovery female rats given 15 mg/kg.  These effects of decreased corpora lutea and retained 
follicles were considered adverse to fertility, but not to the overall health of the female rat.  Non-
clinical findings indicate that LY3214996 may adversely influence human female fertility.  
In rats, microscopic findings were observed in the skin of rats given ≥15 mg/kg (including 
epidermal hyperplasia and inflammation).  Effects observed in the skin did not show evidence of 
recovery after a 1 month reversal period. 
In rats, microscopic findings of physeal hypertrophy and increased primary spongiosa were 
observed in the femur and tibia of males given ≥15 mg/kg and in females given ≥5 mg/kg.  The 
finding of physeal hypertrophy was not present in recovery sacrifice rats whereas increased 
primary spongiosa was still evident after a 1 month reversal period.  These effects on bone are 
only expected to occur in growing bone (for example, in juveniles) and are not relevant for an 
adult population. 
In an in vitro hERG (human ether á-go-go-related gene) assay, the half-maximal inhibitory 
concentration (IC50) was 28.1 µM.  This IC50 is at least 10x greater than the highest projected 
Cmax required for efficacy.  Cardiovascular endpoints were evaluated in the 1-month repeat-dose 
dog toxicology study using a jacketed external telemetry system.  No test article-related effects 
were observed in any of the electrocardiogram (ECG) parameters (heart rate, PR interval, 
QRS duration, QT interval, and corrected QT [QTc] interval); therefore the no-observed-effect 
level (NOEL) for cardiovascular endpoints was 20 mg/kg/dose, the highest dose tested.   


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An Ames test for mutagenicity was negative.  Two additional genetic toxicity assays (in vitro 
micronucleus [MN] and in vivo rat MN) demonstrated increases in micronuclei.  The in vitro 
MN assay established a no-observed-effect-level (NOEL) concentration of 5 µg/mL.  In the 
in vivo rat MN assay, LY3214996 showed weak evidence of inducing micronuclei in the 
polychromatic erythrocytes of the bone marrow of male rats at doses of 50 and 100 mg/kg.  The 
NOEL was 25 mg/kg based on effects at 50 and 100 mg/kg in male rats.  Subsequent mechanistic 
analysis in the in vitro assay, with the use of fluorescence in situ hybridization with pan 
centromeric DNA probes, demonstrated that the causal basis for the MN was consistent with an 
aneugenic mechanism.  Micronuclei induction by aneugens is generally recognized as being a 
threshold effect (Guérard et al. 2015).  Any clinical trial in healthy subjects should be designed 
to maintain exposures that do not exceed the threshold required for micronuclei induction (AUC 
and Cmax exposures in male rats at the MN NOEL of 25 mg/kg were 13417 ng·hr/mL and 
1225 ng/mL, respectively).  In advanced cancer patients, the potential benefit of treatment likely 
outweighs the risk; even in cases where the threshold for MN induction is exceeded. 
LY3214996 was a nonirritant in the Bovine Corneal Opacity and Permeability (BCOP) and non-
toxic with minimal potential irritation (sporadic erythema) at 2000 mg/kg in the acute dermal 
toxicity study in rats. 
 
Combination toxicology studies with LY3214996 and abemaciclib or LY3214996 and 
gemcitabine plus nab-paclitaxel have not been conducted, as these studies are not warranted to 
support combination clinical trials intended to treat patients with advanced cancer (Nonclinical 
Evaluation for Anticancer Pharmaceuticals, ICH S9).  The toxicity profiles of abemaciclib, 
gemcitabine, and nab-paclitaxel have been characterized individually in both clinical and 
nonclinical studies and they have a clinically manageable safety profile.  The clinical assessment 
of safety and tolerability for LY3214996 and abemaciclib do not indicate a significant or 
unreasonable risk from overlapping toxicity (e.g. GI toxicity).   
 
Please refer to the IB for additional details on nonclinical toxicology information. 
 Clinical Pharmacokinetics 
In an ongoing phase I JUAB study of LY3214996, the pharmacokinetics (PK), 
pharmacodynamics (PD), safety, and anti-tumor activity of LY3214996 are being evaluated. This 
initial Phase 1 study of LY3214996 consists of a once daily (QD) dose escalation phase (Part A), 
a twice a day (BID) dose escalation phase (Part A2), a drug-drug interaction (DDI) study to 
evaluate potential CYP3A4 drug-drug interaction of LY3214996 with midazolam (Part B1), and 
a tumor expansion phase of LY3214996 given as a monotherapy in 5 tumor expansion cohorts 
(Parts B2-6).  LY3214996 was also given in combination with other agents including 
abemaciclib, gemcitabine/nab-paclitaxel, and encorafenib/cetuximab (Parts C, D, and E 
respectively).  
 
After oral administration, maximum plasma concentrations of LY3214996 were reached 
approximately 1 to 2 hours post dose. The mean t1/2 was approximately 3 to 5 hours, suggesting 
little to no accumulation upon multiple QD and BID dosing. Exposures increased with dose from 
25 to 800 mg, and AUCτ at steady state on Day 15 was similar to AUC0-∞ on Day 1, suggesting 
that the PK of LY3214996 did not change with time at these doses. Early exposures (AUC0-6) in 
the sparse sampling patients in Parts B2 to B6, C and D did not appear to differ from the 


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intensive sampling patients in Parts A, A2, and B1. Therefore, the PK of LY3214996 did not 
appear to be affected by the presence of abemaciclib, gemcitabine, or paclitaxel.  
 
The variability in exposures, assessed by percentage coefficient of variation, ranged from 3% to 
126% for both Cmax and AUC and did not display any apparent trend with dose. These 
variabilities are most likely associated with a typical Phase 1 patient population that is heavily 
pre-treated with varying metabolic functions and small numbers of patients per dose level. 
 Clinical Safety 
In Part A daily dosing of LY3214996 of the phase 1 study, the maximum tolerated single agent 
dose was deemed to be 400 mg. Within part A (N = 54), the most common adverse event leading 
to dose limiting toxicity (DLT) as blood creatinine increase, acute kidney injury, and 
dehydration. Treatment related adverse events occurring > 10% included nausea (53.7%), 
vomiting (35.2%), maculo-papular rash (27.8%), diarrhea (27.8%), dermatitis acneiform 
(22.2%), fatigue (18.5%), pruritis (16.7%), blurred vision (14.8%), and rash (11.1%).  
In Part C combinging LY3214996 and abemaciclib, one DLT was experienced at the 200 mg 
LY3214996 dose. A summary of DLTs is provided in Table 3.1.   
Table 3.1 Summary of Phase I DLTs 
 
 
Of the 108 patients in all parts, 105 (97.2%) experienced at least 1 treatment-emergent adverse 
event (TEAE); 62 patients (57.4%) had Grade 3 or higher TEAE. Of the total TEAEs, the most 
commonly reported TEAEs included nausea, vomiting, fatigue, diarrhea, anemia, rash maculo-
papular, decreased appetite, and dermatitis acneiform. Table 3.2 summarizes TEAEs that 
occurred in > 10% of patients.  


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Table 3.2.  Summary of Related TEAEs in >10% of the patients (total) 
 
 Single-Agent Clinical Activity 
Part A (N = 54) included patients with CRC (44.4%), NSCLC (5.6%), breast cancer (1.9%), 
ovarian (3.7%), PDAC (14.8%), and other (29.6%). Of these, 23 had KRAS mutations, 10 NRAS 
mutations, and 18 with BRAF mutations. At time data presentation, 41 patients have evaluable 
disease. No partial responses were seen. 13 patients had stable disease and 28 with progressive 
disease. Notably, some patients with BRAF or NRAS mutations treated at higher doses of 
LY3214996 (400 mg and 600 mg daily) stayed on treatment longer with stable disease for >4 
months. Further efficacy studies are ongoing as part of the phase 1 JUAB study. 
 Objectives and Endpoints 
Table 4.1 shows the objectives of the study. 
Table 4.1 Objectives 
Objectives 
Primary 
• 
To evaluate the proportion of patients with objective response to an ERK1/2 inhibitor 
(LY3214996) in combination with abemaciclib for patients whose tumors harbor pathogenic 
alterations in BRAF, RAF1, MEK1/2, ERK1/2, and NF1 


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Secondary 
• 
To evaluate the safety and tolerability of LY3214996 + abemaciclib as defined by CTCAE v5 
criteria. 
• 
To evaluate the median progression-free survival (PFS). 
• 
To evaluate the duration of overall response. 
Correlative 
• 
To identify potential predictive biomarkers beyond the genomic alteration by which treatment is 
assigned and/or resistance mechanisms. 
• 
To evaluate pharmacokinetic parameters of LY3214996 and abemaciclib. 
 
NOTE:  For a more complete description of terms and abbreviations, see Appendix 1. 
Abbreviations:  ORR = overall response rate; PFS = progression-free survival 
 Study Design 
 Overall Design 
The purpose of CTO-IUSCC-0730 is to assess the clinical efficacy of LY3214996 in 
combination with abemaciclib at the recommended phase 2 dose of LY3214996 200 mg orally 
daily and abemaciclib 150 mg orally twice daily.  Patients will be treated until evidence of disease 
progression, non-compliance with study protocol, unacceptable major toxicity, at subject’s own 
request for withdrawal, or if the study closes for any reason.  
 Study Period and Subject Status Definitions 
 Subject Status Definitions 
• Baseline/Screening:  Begins when the informed consent form (ICF) is signed, and ends 
at the first study treatment (defined as receiving any study drug); if no study treatment is 
given, baseline/screening ends with the decision not to enroll.  Lasts up to 28 days. 
• Study Treatment Period:  begins with the day of the patient’s first study treatment and 
ends the day the patient and investigator agree that the patient will discontinue study 
treatment (discontinuation of assigned study drug(s); Section 9).  Individual patients who 
enroll in Study CTO-IUSCC-0730 may continue treatment until they have confirmed 
progressive disease, or discontinued study treatment for any other reason (Section 9). 
• 30-Day Safety Follow-Up Visit: Once decision is made to discontinue study treatment, 
this visit occurs approximately 30 days (+/- 7) after last dose of study drug. 
 Study Period Definitions 
• Study Period:  The overall study period for CTO-IUSCC-0730 begins the day of the first 
patient’s first dose of study treatment and ends at overall study completion (as defined in 
a bullet below). 
 
• Study Completion: occurs after the last patient’s last’s visit.  


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• End of Trial: occurs when the clinical trial database is locked and the final analysis and 
evaluation of the study endpoints have been performed.   
 Number of Patients 
It is anticipated that approximately 35 patients will be enrolled.  
For sample size calculations, see Section 14.1. 
 End of Study Definition 
Study Completion and End of Trial are defined in Section 5.1.1. 
 Scientific Rationale for Study Design 
The general rationale for the study design is described in the Study Rationale of the Introduction 
(Section 3.1), and the Statistical Considerations Section 14.   
 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
 Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
 
1. Have a histological or cytological diagnosis of advanced unresectable or metastatic 
cancer (American Joint Committee on Cancer Staging Criteria) (Edge et al. 2009).  
2. The patient must be, in the judgement of the investigator, an appropriate candidate for 
experimental therapy, either after available standard therapies (per available local 
guidelines) have failed to provide clinical benefit for their disease or after the patient 
has refused standard treatments.  
3. Have one of the following alterations as defined below using a CLIA-certified next-
generation sequencing test: 
a. Point mutation in BRAF, RAF1, MEK1/2, or ERK1/2 that have been 
previously characterized to be gain-of-function mutations. These mutations 
have to be specified as gain-of-function as listed in the OncoKB and/or JAX-
CKB databases. 
i. Patients with NSCLC that harbor BRAF V600E treated with prior 
RAF and/or MEK inhibition therapy will be excluded.  
ii. Patients with tumor types other than NSCLC that harbor BRAF V600E 
mutations who have been treated and progressed on prior BRAF 
and/or MEK inhibition will be included. 
iii. Patients with NSCLC that harbor BRAF V600E will only be enrolled 
if they are not a candidate for FDA approved therapy 
a. Amplification of RAF1 defined as >6 copies of the respective gene. 
b. Gene fusion in which BRAF, RAF1, MEK1/2, or ERK1/2, is a fusion partner; 
in which the fusion is determined to be in-frame; and the kinase domain of 
BRAF, RAF1, MEK1/2, or ERK1/2 is retained.  


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c. Point mutations, frameshift insertions/deletions, splice site mutations, or stop 
gain mutations that results in loss-of-function of NF1. 
4. Have measurable disease amenable to biopsy. If biopsy is deemed unsafe at time of 
procedure, patients will remain eligible for study.  
5. Must be able to provide written informed consent and HIPAA authorization for 
release of personal health information. 
6. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology 
(Group (ECOG) scale (Oken et al. 1982) within 21 (+/-7) days prior to registration for 
protocol therapy. 
7. Have discontinued previous systemic treatments > 3 weeks for cancer prior to first 
dose of investigational therapy. Patient must have resolution, except for alopecia, of 
all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy 
to Grade ≤1 by National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0.  
8. Have adequate organ function, as defined below: 
System 
Laboratory Value 
Hematologic 
ANC 
≥1.5 × 109/L 
Platelets 
≥100 × 109/L 
Hemoglobin 
≥9.0 g/dL 
 
Transfusions to increase the patient’s hemoglobin 
level to 9 g/dL are not permitted within 1 week prior 
to the baseline hematology profile 
Hepatic 
Total bilirubin 
≤1.5 × ULN OR 
<2.0 mg/dL in patients with Gilbert’s disease 
ALT and AST 
≤2.5 × ULN OR 
≤5 × ULN if the liver has tumor involvement 
Renal 
Serum creatinine OR 
Calculated creatinine clearance (see 
Appendix 3) 
≤1.5 × ULN OR 
≥50 mL/min 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
ANC = absolute neutrophil count; ULN = upper limit of normal. 
 
9. Are at least 18 years old at the time of screening. 
10. Are male patients who are sterile (including vasectomy confirmed by post vasectomy 
semen analysis), or agree to use an effective method of contraception and not to 
donate sperm, or who practice total abstinence from heterosexual activity, starting 
with the first dose of study treatment, during the study, and for at least 6 months 
following the last dose of study treatment.  


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11. Are female patients of non-childbearing potential (surgically sterile after having a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy or postmenopausal), 
or are female patients of child-bearing potential who are not pregnant, as confirmed 
by a serum pregnancy test within 14 (+/-7) days prior to receiving first dose of study 
treatment and who agree to use 2 methods of birth control (hormonal or intrauterine 
plus a barrier method) or practice total abstinence from heterosexual activity during 
the study for at least 6 months following the last dose of the study treatment.  
12. Are able to swallow capsules or tablets 
13. Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator.  
 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Have a serious concomitant systemic disorder (for example, active infection or 
a gastrointestinal disorder causing clinically significant symptoms such as 
nausea, vomiting or diarrhea, or profound immune suppression) that, in the 
opinion of the investigator, would compromise the patient’s ability to adhere to 
the protocol.  
2. Have or known activated/reactivated hepatitis A, B, or C (screening is not 
required). 
3. Uncontrolled human immunodeficiency virus (HIV) infection are considered 
ineligible. HIV- infected patients on effective anti-retroviral therapy with 
undetectable viral load within 6 months are eligible for this trial. Known HIV 
positive patients who meet the following criteria will be considered eligible: 
a. CD4 count ≥ 350 cells/mm3 
b. Undetectable viral load 
c. Maintained on modern therapeutic regimens utilizing non-CYP 
interactive agents (i.e. excluding ritonavir) 
d. No history of AIDS-defining opportunistic infections 
4. Have symptomatic and untreated central nervous system (CNS) malignancy or 
metastasis (screening is not required). 
a. Patients with treated CNS metastases are eligible for this study if they 
are not currently receiving corticosteroids for their CNS metastasis 
and/or anticonvulsants. Patient must be > 4 weeks from therapy 
completion (including radiation and/or surgery) and clinically stable at 
time of study entry. Brain MRI or head CT is required at screening for 
patients with known brain metastases. 
5. Have current hematologic malignancies, acute or chronic leukemia 
6. Have a second primary malignancy that in the judgment of the principle 
investigator may affect the interpretation of results 
7. Have prior malignancies within the last 3 years prior to study enrollment.  
Patients with carcinoma in situ of any origin and patients with prior 
malignancies who completed curative intent-treatment and whose likelihood of 
recurrence is very low, as judged by the principal investigator, will remain 
eligible for this study.  The principal investigator will approve enrollment of 
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8. Are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study 
9. Have participated, within the last 28 days in a clinical trial involving an 
investigational product.   
10. Have previously completed or withdrawn from this study or any other study 
investigating an ERK1/2 inhibitor. 
11. Had prior therapy with an ERK1/2 inhibitor.  
12. Had prior chemotherapy within 3 weeks of study registration.  
13. Had prior non-CNS radiation within 2 weeks of study registration. Please refer 
to exclusion criteria #4 for patients who have required radiation for CNS 
disease.  
14. If female, is pregnant, breastfeeding, or planning to become pregnant. 
15. Currently using concomitant medications that are strong inhibitors or inducers 
of CYP3A4. 
16. Have serious and/or uncontrolled preexisting medical condition(s) that, in the 
judgment of the investigator, would preclude participation in this study.  
a. This includes cardiogenic syncope, ventricular arrhythmias, history of 
sudden cardiac arrest, or severe dyspnea at rest or requiring oxygen 
therapy. 
b. This includes patients with any evidence of interstitial lung disease 
(ILD) (not just serious and/or uncontrolled ILD) and any history of 
severe ILD. 
 Lifestyle Restrictions 
Patients must meet the study entry criteria.  There are no additional lifestyle restrictions for 
participation in Study CTO-IUSCC-0730. 
 Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened one time.  Each time re-screening is performed, the 
individual must sign a new informed consent form (ICF) and will be assigned a new 
identification number. 
 
Repeating of laboratory tests during the 21-day screening period does not constitute re-screening. 
 Patient Registration 
All patients will be registered with the Indiana University Simon Cancer Center (IUSCC) 
Clinical Trials Office (CTO). Regulatory files will be maintained by the IUSCC CTO. 
Applicable regulatory documents must be completed and on file prior to registration of any 
patients. Potential patients will be identified in the Oncology outpatient clinics or by referrals 
from outside physicians. Patients who appear to be eligible for this trial will undergo the 
Informed Consent Process and be screened for eligibility utilizing the Eligibility Criteria. The 
original signed IRB approved Informed Consent Document and completed Eligibility Checklist 
will be forwarded to the CTO designee for eligibility verification and registration in the 


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OnCore® database. Notification will be sent to the principal investigator, treating physician and 
research nurse when registration is complete to confirm registration and inform them of patient 
ID number. 
 Treatment  
The investigator or his/her designee is responsible for the following: 
• explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patients and study site personnel. 
• verifying that instructions are followed properly  
• maintaining accurate records of study treatment dispensing and collection 
• timely reporting of adverse events and product complaints to Lilly 
• at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and sites have agreed all unused medication is to be destroyed by the 
site, as allowed by local law. 
 Treatments Administered 
 Treatment Plan 
 LY3214996 
LY3214996 will be administered at a dose of 200 mg orally once daily on Days 1 through 28 of 
a 28-day cycle. LY3214996 can be taken with or without food.  Doses should be taken 
approximately the same time each day (± 2 hours) as much as possible.  If a patient misses or 
vomits a dose, that dose should be omitted.  Treatment will be continued until progressive 
disease, unacceptable toxicity or patient desire to discontinue study therapy. 
 Abemaciclib 
Abemaciclib will be administered at a dose of 150 mg orally Q12 hours (± approximately 2 
hours) on Days 1 through 28 of a 28-day 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.  LY3214996 should be taken at the same time as either the a.m. or p.m. dose of 
abemaciclib. 
 Packaging and Labelling 
LY3214996 and abemaciclib will be provided by Lilly in the United States and will be labeled 
according regulatory requirements.  Lilly will perform the labeling and the final packaging of 
these study medications under good manufacturing practice (GMP) conditions.  All 
capsules/tablets should be stored according to their associated product label and taken as 
indicated.  Patients should store these agents in the original package provided and according to 
the product label (where applicable) and be instructed to keep all medications out of reach of 
children. 
 Selection and Timing of Doses 
A cycle is defined as an interval of 28 days.  A delay of a cycle due to holiday, weekend, bad 
weather, or other unforeseen circumstances will be permitted for a maximum of 7 days and not 
counted as a protocol deviation.  The reason for the treatment interruption should be documented 


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on the CRF.  A cycle begins when study treatment is dispensed for the cycle and administered.  
Thus, if an expected cycle start is delayed, the number of days in the current cycle is increased 
beyond 28 days. 
 
A patient may continue to receive study treatment until confirmed progressive disease 
(Section 10.1), unacceptable toxicity, or discontinuation for any other reason (Section 9). 
 Blinding 
This is an open-label study. 
 Dosage Modification 
Please refer to Appendix 4 for dose adjustment guidelines.  
 
Study therapy may be held up to 3 weeks to allow sufficient time for recovery. Patients who do 
not recover from drug-related toxicity to ≤ grade 1 within 3 weeks will be discontinued (except 
alopecia, fatigue, skin rash, elevated creatinine, nausea, vomiting, constipation or diarrhea that 
can be controlled with treatment).  If a dose adjustment is made, the patient must be maintained 
at the reduced dose level for all remaining cycles.  
 
For the purposes of dose modification, the investigator must first assess if the toxicity is 
considered at least possibly due to one of the study drugs, and must then apply the study drug-
specific dose-modification guidelines accordingly.  If the toxicity is not clearly attributable to 
either individual study drug, then the causality should be attributed to both study drugs.   
Dosing interruptions of any study drug are permitted for reasons not related to study treatment 
(for example, minor surgery, unrelated medical events, patient vacation, and/or holidays).  The 
reason for interruption should be documented on the CRF. 
 Treatment Compliance 
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by direct questioning and counting returned tablets/capsules.  Deviations from the 
prescribed dosage regimen should be recorded in the CRF.  A patient dosing diary will be used to 
capture dose information for LY3214996 and abemaciclib.  
   
The patient must take ≥80% of the intended doses in each cycle to be deemed compliant with 
study drug administration.  Similarly, a patient may be considered noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of drug(s).  Potential discontinuation of a patient due to study drug noncompliance will 
be discussed between the treating physician and the principal investigator before the final 
determination is made to discontinue the patient. 
 Evaluable Patients 
Patients who withdraw from the study before receiving study drug will be replaced and will not 
be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for anti-tumor activity.   
 


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Patients evaluable for anti-tumor activity will comprise all patients who receive at least one dose 
of trial drugPatients who have clinical progression prior to first disease evaluation will 
discontinue therapy due to progressive disease and not be replaced. Patients who are not 
evaluable for anti-tumor activity (e.g., study discontinuation due to patient decision before first 
scan) may be replaced upon consultation with the principal investigator to ensure adequate tumor 
response data.  
 Preparation/Handling/Storage/Accountability 
LY3214996 will be supplied as 100-mg capsules for oral consumption. LY3214996 should be 
stored within the temperature range stated on the label.  Investigators should instruct patients to 
store the capsules at home in the original container and to keep out of the reach of children.  
Capsules should not be opened, crushed, or dissolved. 
 
Abemaciclib will be supplied as 50-mg tablets and should be stored within the temperature range 
stated on the label.  Investigators should instruct patients to store the capsules at home in the 
original container and to keep out of the reach of children.  Tablets should not be opened, 
crushed, or dissolved. 
 Concomitant Therapy 
No other chemotherapy, radiotherapy immunotherapy, cancer related hormone therapy, or 
experimental drugs, or herbal supplements intended to treat cancer will be permitted while the 
patients are on this study.  An exception will be made for the following circumstances: 
• Prostate cancer patients continuing GnRH agonist therapy or breast cancer patients 
continuing antiestrogen therapy (for example, an aromatase inhibitor).   
• Patients on stable doses of bisphosphonates or denosumab are allowed to continue.  
These agents should not be initiated within the 2 weeks prior to study enrollment or at 
any point while on the study 
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Replacement hormone therapy initiated before 
study entry will be allowed.  
 
In vitro data suggests potential inhibition of CYP3A4-mediated metabolism by LY3214996, 
therefore use of concomitant therapy with sensitive substrates of CYP3A4, particularly those that 
also have a narrow therapeutic range, should be used with caution for all patients in Study CTO-
IUSCC-0730.  Concomitant therapy with sensitive substrates of CYP3A4 must be avoided 
(Appendix 5). 
 
In vitro, LY3214996 was an inducer of CYP2D6 and CYP3A5 messenger ribonucleic acid.  The 
clinical relevance of the in vitro induction of CYP2D6 and CYP3A5 by LY3214996 is currently 
unknown.  Caution should be used when using concomitant therapy with CYP2D6 and CYP3A5 
substrates as the metabolism of such drugs may be induced.  
 
In vitro data indicates that the major cytochrome P450 involved in the clearance of LY3214996 
is CYP3A (~88%).  Clinical studies have demonstrated that the major route of abemaciclib 
clearance is through CYP3A metabolism. Therefore, patients are not allowed to have any 
concomitant medications that are moderate or strong inhibitors (that is, grapefruit juice, 


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ketoconazole, etc.) or inducers of CYP3A4.  Please refer to Appendix 5 for a list of 
contraindicated medications. Because the lists of these agents are constantly changing, it is 
important to regularly consult a frequently-updated medical reference for a list of drugs to avoid.  
 
Abemaciclib and its major metabolites inhibit the efflux transporters P-glycoprotein and breast 
cancer-resistant protein and the renal transporters organic cation transporter 2, multidrug and 
toxin extrusion protein 1 (MATE 1), and MATE2-K at clinically relevant concentrations.  
Therefore, substrates of these transporters such as metformin and those with a narrow therapeutic 
index such as digoxin and dofetilide should be substituted or avoided if possible. 
 
All premedication, supportive care and concomitant medication must be reported on the 
electronic case report form (eCRF) at each visit. 
 Supportive Care 
Patients should receive full supportive care.  Patients are instructed to maintain adequate oral 
hydration at home, in order to prevent dehydration secondary to vomiting and diarrhea.  During 
visits, patients should be evaluated for signs and symptoms of dehydration and, if necessary, 
intravenous hydration should be implemented at the discretion of the investigator.  American 
Society of Clinical Oncology (ASCO) guidelines (Smith et al. 2015) should be followed for 
patients requiring support with granulocyte-colony stimulating factor (G-CSF).  If G-CSF is 
required, study therapy should be held. Patients should not receive G-CSF prophylactically in the 
first cycle of therapy.   
 
If clinically indicated at any time during the study, packed red blood cell transfusions may be 
used according to ASCO guidelines (Rizzo et al. 2008).  Prophylactic antibiotic treatment should 
be consistent with ASCO guidelines (Flowers et al. 2013). 
 
All concomitant medications should be recorded throughout the patient’s participation in the 
study. 
 Supportive Management Recommendations for Rash 
LY3214996 may cause rash.  To help mitigate the rash, the following recommendations are 
provided.  These recommendations are intended to be a guideline for the investigator and should 
not replace the investigator’s best judgment. 
 
Once a patient starts treatment on the study, patients will be instructed to initiate the use of a 
moisturizer with no scents added.  In addition, patients will be directed to limit sun exposure or 
to apply sunscreen protection before going outdoors (PABA-free, SPF 15 or higher) if 
appropriate.  A prescription for topical antimicrobials and steroidal agents based on institutional 
practice or guidelines will be provided by the investigator(s)/nurse(s) to the patient.  The patient 
will be instructed to immediately fill the prescription for the topical agents and to start it 
immediately at the first onset of a Grade 1 rash.  If the rash escalates further, then the patient will 
be instructed to call the study investigator(s)/nurse(s) and additional interventions per 
institutional practice or guidelines for oral steroids, oral antimicrobials, or dose reductions per 
investigator discretion may be implemented.  Rash management recommendations are listed in 
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Table 8.1 Management Recommendations for Skin Reactions 
Toxicity Grade 
Management Recommendations 
Grade 1 
• 
Administer topical clindamycin 1% or topical hydrocortisone 1% in lotion base twice 
daily to affected areas until resolution of reaction. 
Grade 2 
• 
Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice 
daily to affected areas until resolution of reaction. 
• 
If clinically appropriate in the opinion of the investigator, administer oral minocycline or 
doxycycline 100 mg twice daily (or equivalent), for a minimum of 4 weeks and continue 
using for as long as rash is symptomatic. 
Grade 3 
• 
Temporarily withhold LY3214996 and abemaciclib until symptoms resolve to Grade ≤2 
or pre-treatment baseline. Treatment may be held for up to 21 days 
• 
Continue ongoing rash treatment. 
• 
Following improvement to Grade ≤2, re-administer LY3214996 with a dose reduction of 
1 dose level. Abemaciclib does not require a dose reduction 
• 
If symptoms do not recur for another treatment cycle, the LY3214996 dose may be 
re-escalated to the previous dose level. 
Grade 4 
• 
Immediately and permanently discontinue treatment with LY3214996 and abemaciclib. 
• 
Continue ongoing rash management treatment. 
• 
Provide intravenous hydration or electrolyte replacement if needed. 
• 
Request dermatologist advice if needed. 
 
 Supportive Management for Diarrhea 
Patients should receive instructions on the management of diarrhea.  In the event of diarrhea 
(Appendix 4), supportive measures should be initiated as early as possible.  These include the 
following: 
• At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (for 
example, loperamide) and notify the investigator/site for further instructions and 
appropriate follow-up. 
• Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day). 
• Site personnel should assess response within 24 hours. 


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• If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to either baseline 
or Grade 1, abemaciclib should be suspended until diarrhea is resolved to either baseline 
or at least Grade 1. 
• When abemaciclib resumes, dosing should be adjusted as outlined in Appendix 4. 
In severe cases of diarrhea, the measurement of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered. 
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed. 
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte 
replacement. 
 
Loperamide 
Based on the toxicities observed with abemaciclib loperamide, 2 mg orally, may be administered 
with the first dose of abemaciclib daily.  If the daily dose of loperamide is not taken with the first 
dose of abemaciclib, it should be taken after the first loose stool.  Patients may take an additional 
2-mg-dose (1 capsule/tablet) of loperamide after each loose stool up to a maximum of 16 mg 
(8 capsules/tablets) per day (including doses taken with abemaciclib).  In the event a patient 
experiences Grade 2 diarrhea (4 to 6 loose stools per day above baseline) despite loperamide, a 
dose reduction (−1 level) of abemaciclib can be considered before additional doses of loperamide 
are taken.  If diarrhea recurs within 24 hours despite a dose reduction, additional doses (2 mg 
each) of loperamide may be taken at the investigator’s discretion.  Loperamide may be 
discontinued 28 days after initiation of abemaciclib therapy at the investigator’s discretion.  
Loperamide dose can be omitted if the abemaciclib dose is omitted for a reason other than 
diarrhea.  Loperamide administration, including dose adjustments (increases and/or decreases) 
and changes for indicated use, will be captured on the electronic case report form (eCRF). 
If a patient experiences constipation or other symptoms related to loperamide dosing (for 
example, abdominal cramping), the investigator may reduce/stop the patient’s dosing of 
loperamide.  If a patient does not have a bowel movement for ≥36 hours, loperamide is to be 
suspended until bowel movements resume.  If loperamide administration resumes, the dose may 
be adjusted (e.g., once every other day) at the investigator’s discretion.  Investigators should take 
into account the patient’s history and/or risk of constipation when considering increases in 
loperamide dosing. 
 Supportive Management Recommendations for Nausea and Vomiting 
Approximately 90% of patients have experienced nausea and/or vomiting due to LY3214996, 
which in a limited number of cases has led to more severe adverse events (i.e., dehydration, acute 
kidney injury).  Therefore, patients will be required to receive antiemetic prophylaxis in cycle 1, 
in an effort to improve patient safety and reduce the incidence of these events.  Recommended 
antiemetic treatment should follow current guidelines for high/moderate emetic risk agents, such 
as consensus-based guidelines from the National Comprehensive Cancer Network, but is left to 
investigator’s discretion based on patient characteristics and local medical practices. 
 
Current recommendation for antiemetic treatment consists of a 5-HT3 receptor antagonist and 
should be given prior to starting study drug (continue daily, choose 1): 


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• Ondansetron 8-16 mg (total dose) PO daily 
• Dolasetron 100 mg PO daily, as needed 
 
Breakthrough treatment can be given by adding 1 agent from a different drug class to the current 
regimen (i.e., olanzapine 5-10 mg PO daily, dexamethasone 12 mg PO/IV daily). 
 
In the event that the investigator believes concomitant antiemetic medication is not necessary in 
cycles 2+, the antiemetic regimen may be discontinued. 
 
Caution should be taken when administering medications that are metabolized by CYP3A4 when 
given with LY3214996 due to the potential inhibition of CYP3A4 metabolism by LY3214996 
that could result in increased exposures of the co-medications.  If possible, alternate medications 
that are not reliant on CYP3A4 metabolism for elimination should be utilized whenever possible. 
 Growth Factor Therapy 
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 and LY3214996 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. 
 Treatment after the End of the Study 
Study completion occurs after the last patient’s last visit (Section 5.1.1). End of Trial occurs 
when the clinical trial database is locked and the final analysis and evaluation of the study 
endpoints has been performed (Section 5.1.1).  Investigators will continue to follow Schedule of 
Activities (Section 2) for all patients until study completion has occurred. 
 Discontinuation Criteria 
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Medical research data collected prior to the 
withdrawal consistent with the original authorization may continue to be used.  
 Discontinuation from Study Treatment 
Patients will be discontinued from study treatment in the following circumstances: 
 
• the patient is enrolled in any other clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
• the patient becomes pregnant during the study 
• the patient is significantly noncompliant with study procedures and/or treatment 
• disease progression 


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o If a patient is clinically stable at the first radiologic progressive disease by 
RECIST v1.1 (Eisenhauer et al. 2009), the patient may be considered for 
continuation on the study until progression is confirmed.  For patients to be 
considered for continuation the following criteria must all be met, and after 
consultation with the Principal Investigator:  
 Absence of symptoms and signs indicating clinically significant 
progression of disease 
 No decline in ECOG performance status 
 Absence of symptomatic rapid disease progression requiring urgent 
medical intervention (e.g. symptomatic pleural effusion, spinal cord 
compression). 
o Treatment beyond progression must not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., central nervous system 
metastases).  
o Subjects’ clinical data must be available for CRF source verification. Copies of 
tumor images must be made available for review by the sponsor or its designee 
upon request. 
• unacceptable toxicity 
• the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  Discontinuation 
from study treatment will occur prior to introduction of the new agent. 
• the investigator decides that the patient should be discontinued from study treatment 
• the patient requests to be discontinued from study treatment  
• the patient’s designee (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from study treatment 
 
Patients are considered to have discontinued from study treatment when all study treatments are 
no longer administered.  Based on investigator discretion and/or patient preference, patients may 
continue on study treatment while taking either LY3214996 or abemaciclib alone.   
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2). 
 Discontinuation of Inadvertently Enrolled Patients 
If a patient who did not meet enrollment criteria was inadvertently enrolled, a discussion must 
occur between the Lilly CRP, the principal investigator, and the treating physician to determine 
if the patient may continue in the study.  If both agree it is medically appropriate to continue, the 
investigator must obtain documented approval from the Lilly CRP to allow the inadvertently 
enrolled patient to continue in the study with or without study treatment. 
 Discontinuation from the Study 
Patients will be discontinued from the study in the following circumstances: 
• participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP) 
• The patient becomes pregnant during the study.  See Section 12 regarding regulatory 
reporting requirements on fetal outcome and breast-feeding 
• the investigator decides that the patient should be discontinued from the study 


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• the patient requests to be discontinued from the study 
• the patient’s designee (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from the study 
 
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2 and Section 9.4). 
 Follow Up 
Patients will be followed until the day 30 safety follow up visit (Table 2.1) after removal from 
study or until death, whichever occurs first. Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  
 
Post study-treatment anticancer therapies will be collected and will include type of therapy 
(surgery, radiotherapy, or systemic therapy), drug class and/or name, overall and by line of 
therapy. 
 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.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up. 
 Study Assessments and Procedures 
Study procedures, assessments, and related timing are described in the sections below and shown 
in the Schedule of Activities (Section 2). 
 
   Efficacy Assessments 
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2). 
 
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be ≤5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT.  Intravenous and oral contrast 
is required unless medically contraindicated. 
 
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast).  A PET scan alone or as part of a PET-CT 
may be performed for additional analyses but cannot be used to assess response according to 
RECIST v.1.1 (Eisenhauer et al. 2009). 
 


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The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Each patient’s full extent of disease will be assessed using RECIST v1.1 (Eisenhauer et 
al. 2009). 
 
See Section 14.3.2 for definitions of the efficacy endpoints. 
 Safety 
 Other Safety Measures 
For each patient, vital signs, laboratory tests, or other tests should be collected as shown in the 
Schedule of Activities (Section 2).   
 
 Safety Monitoring 
Aggregate safety data will periodically be reviewed within the study by appropriate methods. 
 
Interstitial lung disease (ILD) or pneumonitis has been identified as an adverse drug reaction for 
abemaciclib.  The majority of events observed in clinical trials were Grade 1 or Grade 2 with 
serious cases and fatal events reported.  Additional information is available in the IB. 
 
Ask your patients to report any new or worsening respiratory symptoms such as cough, dyspnea, 
fever, and investigate and treat as per your local clinical practice (including corticosteroids, as 
appropriate).  If ILD/pneumonitis is suspected, investigations may include imaging such as high 
resolution computed tomography (HRCT), broncheoalveolar lavage, and biopsy, as clinically 
indicated. 
 
Refer to Appendix 4 for guidance on dose adjustments of abemaciclib.  
 
  Pharmacokinetics 
The plasma pharmacokinetics of abemaciclib, metabolites of abemaciclib (M2 and M20), and 
LY3214996 will be evaluated on all patients who have received at least 1 dose of study treatment 
and have had samples collected. On each day with a PK collection time point, abemaciclib and 
LY 3214996 will be dosed in clinic. Plasma samples will be collected prior to dosing of 
abemaciclib and LY3214996 on cycle 1 day 15 and cycle 2 day 1.  
 
PK Sample Time points 
Cycle, Day 
PK Samplea 
Comments 
Cycle 1 Day 15 
3  
Prior to study drug dosing 
Cycle 2 Day 1 
3 
Prior to study drug dosing 
a    PK sampling will include abemaciclib and metabolites of abemaciclib (M2 and M20), and 
LY3214996. 
 


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It is essential that exact dosing times are recorded. Also, it is recommended that the exact time of 
collection of each venous blood sample be based on the clock used to record dosing times.  
Adherence to the time points listed in the sampling schedule as closely as possible is requested.  
Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  
 
 Processing  
Whole blood is drawn into K2EDTA Vacutainer tubes and is gently mixed by inversion (~8-10 
times) and is kept on wet ice. 
 
• The samples must be processed by centrifugation within ~60 minutes after the sample is 
drawn. 
• The samples are spun to plasma at ~1500 to 2000 x g for 15-20 minutes. 
• Plasma is transferred, ensuring no RBC contamination. 
• Plasma samples must be frozen at -20ºC +/- 10ºC (or colder) as soon as possible.  
Samples can be placed on dry-ice for short-term storage; however, must be placed in the 
appropriate freezer within 24 hours of the draw-time. 
 
Pharmacokinetic analyses will be conducted on all patients who have received at least 1 dose of 
study treatment and have had samples collected. Plasma concentrations of study drugs 
(LY3214996, abemaciclib and its metabolites) will be summarized using descriptive 
statistics.  Additional analyses utilizing the population PK approach may also be conducted if 
deemed appropriate.  Relationships between exposure, toxicity, and measures of efficacy and 
safety may be explored. 
 
Detailed sample collection, shipping, and storage instructions are included the Laboratory 
Manual.  
 
  Genomics 
 Whole Blood and Tumor Samples for Genomic Biomarker 
Research 
 
A whole blood sample will be collected for germline genomic analysis as specified in Section 2. 
 
Using DNA from the tumor biopsy at screening and progression (along with the aforementioned 
blood germline control), we plan to perform next-generation whole-exome sequencing. The 
results will serve two purposes: 1) to compare the mutational profile of a tumor biopsy at 
progression compared to the baseline tumor mutational profile to identify potential acquired 
mutations driving resistance and 2) to provide mutational data to help identify potential novel 
biomarkers of response in the form of genomic aberrations either within the 
RAS/REF/MEK/ERK pathways and/or potentially other cancer pathways. Sequencing will be 
performed at Indiana University using the Illumina NovaSeq 6000 at our Center for Genomics 


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and Bioinformatics. Samples will not be used to conduct unspecified disease or population 
genetic research either now or in the future.   
 
All samples will be coded with the patient ID and sample ID.  These samples and any data 
generated can be linked back to the patient only by the study site personnel.  Samples will be 
retained for a maximum of 15 years after the last patient visit for the study, or for a shorter 
period if local regulations and/or ethical review boards (ERBs) impose shorter time limits, at a 
facility selected by Lilly.  This retention period enables use of new technologies, response to 
questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of LY3214996 or after LY3214996 becomes 
commercially available. 
 
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, candidate gene studies, and 
epigenetic analyses.  Regardless of the technology utilized, data generated will be used only for 
the specific research scope described in this section. 
 
Detailed sample collection, shipping, and storage instructions are included the Laboratory 
Manual. 
 Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA (including circulating 
tumor DNA, ctDNA), ribonucleic acid (RNA), proteins, lipids, and other cellular elements.   
 
As part of Indiana University’s ongoing efforts to understand the relationship between cancer, 
genetics, and response to therapy, this study will analyze biomarkers relevant to LY3214996 and 
abemaciclib, immune functioning, and the disease state, and to correlate these markers to clinical 
outcome, and/or for related research methods or validation of diagnostic tools or assays. 
 
Samples for biomarker research will be collected as specified in Section 2.  
 
It is possible that biomarker data for patients in the study has already been generated from 
samples that were collected and analyzed prior to enrolling in this trial.  This may include data 
generated from genetic analyses.  If available, these data may be requested from medical records 
for pre-screening for enrollment eligibility in the molecularly defined cohorts, or used in the 
research described in Sections 10.5.1 and 10.5.2. 
 
Detailed sample collection, shipping, and storage instructions are included the Laboratory 
Manual. 


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 Samples for Non-pharmacogenomic Biomarker Research 
Plasma and whole blood samples for non-pharmacogenomic biomarker research will be collected 
as specified in Section 2. 
 
Samples will be examined for biomarkers related to the disease state, variable response to, and 
the mechanism of action of, LY3214996, abemaciclib, immune functioning, and/or for research-
related methods, or validating diagnostic tools or assays. 
 
All samples will be coded with the patient and sample number.  These samples and any data 
generated can be linked back to the patient only by the study site personnel. 
 
Samples will be retained for a maximum of 15 years after the last patient visit for the study at a 
facility selected by Indiana University.  This retention period enables use of new technologies, 
response to questions from regulatory agencies, and investigation of variable response that may 
not be observed until later in the development of LY3214996 or after LY3214996 become 
commercially available. 
 Tissue Samples for Research 
Tumor tissue will be examined for biomarkers related to the disease state, LY3214996 in 
combination with abemaciclib, and immune functioning.  
 
Collection of the following tumor tissue sample is required for all patients in order to participate 
in this study via newly obtained biopsy specimens, following determination of eligibility, ≤14 
(+/- 7) days before start of treatment. If biopsy of tumor tissue is not deemed safe by the 
investigator, the patient may still enroll on study and archived tumor tissue will be requested if 
available. Archived tissue may be from a primary or metastatic site.  
 
In addition to the required biopsies and biomarker samples discussed in Sections 10.5.1 and 
10.5.2, patients will undergo collection of an additional biopsy specimen and blood sample after 
treatment with LY3214996 has been initiated, including after disease progression.  Such 
additional biopsies should be performed only if clinically feasible.  If these additional samples 
are requested, they will be used to further investigate biomarkers that may explain treatment 
response and resistance mechanisms.  
 
Ex vivo models that mimic the tumor microenvironment are valuable resources to drive 
translational research into understanding sensitivity and resistance to targeted agents. From this 
trial we will collect fresh biopsy material at screening and progression for the establishment of 
ex vivo organoid models. This will enable us to have matched tissues prior to exposure to 
LY3214996 and abemaciclib to give us matched models of both intrinsic and acquired resistance.  
 
 Specimen preparation, handling and shipment: 
The fresh tumor tissue will be placed and delivered in supplemented advanced DMEM/F12 
medium (Gibco, cat. no. 12634-028) in 50-ml Falcon tubes. The supplements are defined as: 1% 
(vol/vol) Penicillin–streptomycin (Gibco, cat. no. 15070063), 1% (vol/vol) HEPES (Gibco, cat. 
no. 15630-056), 1% (vol/vol) Ultraglutamine type I (Lonza, cat. no. BE17-605E) and 1x Primocin 


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(Invivogen, cat. no. PML-40-60) at 4°C. Supplemented advanced DMEM/F12 medium can be 
stored at 4°C for up to 6 months. 
 
In order to arrange the courier collections, the following information will be provided: number of 
samples to be delivered, the name and telephone number of the main contact at Indiana University 
Simon Cancer Center to liaise with the courier company, the exact address of where the samples 
are to be collected from. The courier company will liaise with the main contact at Indiana 
University Simon Cancer Center directly to arrange pick-up of samples.  
 
The packaging must consist of three components to meet the following conditions: 
1. a leak-proof primary receptacle(s) 
2. a leak-proof secondary packaging 
3. An outer packaging of adequate strength for its capacity, mass and intended 
use, and with at least one surface having minimum dimensions of 100mm x 
100mm (4in X 4in). 
 
The following procedure will be used:  
 
A large polystyrene box will be prepared containing ice packages for same-day shipment. All 
samples will be placed into the leak-proof primary receptacle. The primary receptacle will be 
labeled with the de-identified sample ID and date of sample collection. The de-identified sample 
ID will be shared by e-mail at the day of sample collection and shipment. As much air as possible 
will be removed from the secondary packaging before sealing to make it as compact as possible. 
Absorbent material (e.g. tissue paper) must be placed between the primary and secondary 
containers to absorb all potential leakage and entire contents so that no liquid release will reach 
the outer packaging. The polystyrene box lid will be sealed with tape and labeled with the delivery 
details listed below. The outer package must be marked as “Exempt human specimen”. The courier 
will be contacted as soon as the samples are ready for collection. 
 
Delivery Details: 
Karsten Boehnke 
Eli Lilly and Company 
Alexandria Center for Life Science  
East Tower, 12th Floor 
450 East 29th Street 
New York 
NY 10016  
boehnke_karsten@lilly.com 
Phone: +1 646 784 6993 
 
Due diligence will be used and personal identifiers, including the patient’s name and initials, must 
be removed from the institutional pathology report. De-identification and anonymization of 
individual patient data will be applied to meet transparency and disclosure commitments while 
safeguarding the privacy of individuals.  
 


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All tumor biopsy tissue samples will be used for research purposes only per IRB approval. The 
preclinical research conducted at Lilly will be at an early stage being exploratory, and such data 
may not be used for any medical decisions. All samples will be registered at Lilly as anonymized 
data in order to sufficiently devoid of personal information to protect personal privacy and meet 
the requirements of data protection and privacy laws. Upon organoid culture establishment, 
cryovials with organoids will be placed in liquid nitrogen at a dedicated space for human samples 
for long-term storage and detailed logs will generated electronically and manually of all specimens 
stored. 
 Health Economics 
Not applicable.  
 Data Forms and Submission Schedule 
This study will utilize electronic Case Report Form (eCRF) completion in the OnCore® 
database. A calendar of events and required forms are available in OnCore®.  The OnCore® 
database is a comprehensive, web-based, Clinical Trial Management System (CTMS) which 
utilizes an Oracle database. OnCore® was developed by Forte Research Systems, Inc. and is 
used by the IUSCC Clinical Trials Office and supported by the Indiana Clinical and 
Translational Sciences Institute (CTSI). OnCore® properly used is compliant with Title 21 CFR 
Part 11. The system is supported and managed by Forte Research Systems who have developed a 
security program that is compliant with HIPAA and HITECH requirements.  Applications and 
databases are housed off-site at Rackspace, Inc. which is SSAE16 SOC2, ISO 27001, PCI, and 
HITRUST certified.  OnCore provides users secure access with unique IDs/passwords and 
restricts access by assigned roles, from any location, to record, manage, and report on data 
associated with the operation and conduct of clinical trials. 
 Reporting Adverse Events 
The investigator will use Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 or above (NCI 2009) to assign AE terms and severity grades. 
 
Investigators are responsible for: 
 
• Monitoring the safety of patients in 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 appropriate medical care of patients during the study 
• Documenting their review of each laboratory safety report 
• Following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused the 
patient to discontinue study drug before completing the study.  The patient should be 
followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator. 
 


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The investigator will record all relevant AE and SAE information in the eCRF.  After the ICF is 
signed, study site personnel will record via eCRF the occurrence and nature of each patient’s 
preexisting conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study.  In addition, study site personnel will record via eCRF any change in the 
preexisting conditions and any new conditions as AEs.  Investigators should record their 
assessment of the potential relatedness of each AE to study procedure or study treatment via 
eCRF. 
 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies.  A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE. 
 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
 
 Adverse Events 
An adverse event is defined as untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An adverse event can be ANY unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporarily 
associated with the use of a medicinal (investigational) product, whether or not considered 
related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).  Adverse events will be graded according to the NCI 
Common Toxicity Criteria, Version 5.0. 
  Serious Adverse Events 
An SAE is any AE from this study that results in one of the following outcomes: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious, based upon appropriate medical judgment. 
  Adverse Event and Serious Adverse Event Reporting  
All AEs after signing the ICF through 30 days from the last dose of study treatment will be 
recorded in the eCRF. All AEs considered related to trial medication will be followed until 
resolution, return to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
 
SAE reporting begins after the patient has signed the ICF and has received study treatment and 
for at least 30 days after treatment discontinuation. However, if the investigator learns of any 
SAE, including a death, at any time after a patient has been discharged from the study, and 
he/she considers the event reasonably possibly related to the study treatment or study 


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participation, the investigator must promptly notify Lilly. However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure. 
 Reporting to the IRB 
Unanticipated problems involving risks to subjects or others will be reported promptly to the 
IRB if they:  
 
• are unexpected; 
• are related or possibly related to participation in the research; and 
• suggest that the research places subjects or others at a greater risk of harm than 
was previously known or recognized.  
  
If the serious adverse event does not meet all three (3) criteria listed above, the event does not 
have to be promptly reported to the Indiana University IRB.  However, it should be reported at 
the time of continuing review. Prompt reporting of unanticipated problems to the IRB is defined 
as within 5 days from becoming aware of the event. 
 Reporting to the FDA 
Per CFR 312.32 (c), the investigator-sponsor of the IND must notify the Food and Drug 
Administration (FDA) and all participating investigators in a written IND safety report of any 
adverse experience.  There are two types of reports to the FDA: 7-day and 15-day reports. 
 15-Day IND Reports  
The investigator-sponsor of the IND must notify the Food and Drug Administration (FDA) and 
all participating investigators in a written IND safety report of any: 
 
• suspected adverse reaction that is both  
• serious and  
• unexpected   
Each written notification shall be made as soon as possible, and no later than 15 calendar days 
after the investigator-sponsor’s initial receipt of the information.   
 7-Day Reports 
The investigator-sponsor must notify FDA and all participating investigators in a written IND 
safety report of any adverse experience: 
 
• fatal or life-threatening experience that is both 
• associated with use of the drug and 
• unexpected 
The FDA will be notified as soon as possible but no later than 7 calendar days after initial 
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 Report Content 
Each written notification may be submitted on FDA Form 3500A or in a narrative format and 
must bear prominent identification of its contents, i.e., “IND Safety Report”.  For purposes of 
this protocol, the MedWatch Report Form (FDA 3500A mandatory reporting), along with 
FDA Form 1571, and a cover letter submitted to the appropriate FDA division, will serve as 
the written IND safety report.  Follow-up information to a safety report should be submitted as 
soon as the relevant information is available.  
 
Submit 
• MedWatch Report Form (FDA 3500A) 
• FDA Form 1571 
• Cover Letter 
 
The IUSCC Protocol Development Coordinator should be contacted to assist with all FDA 
submissions and will be provided with a copy of all events that are reported to the FDA.  All 
IND submissions will be maintained in a master file in the Clinical Trials Office of the IU Simon 
Cancer Center. 
 Reporting to Lilly 
Study site personnel must notify Lilly of any SAE within 24 hours of investigator awareness of 
the event via the IUSCC SAE form. The form will be submitted with the Lilly study-specific 
cover letter via Lilly’s Investigator Initiated Research (IIR) portal at  
http://LillyInvestigatorResearch.com.  If alerts are issued via telephone, they are to be 
immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information. 
 
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study.  However, if the investigator learns of any SAE, 
including a death, at any time after a patient has been discharged from the study, and he/she 
considers the event reasonably possibly related to the study treatment or study participation, the 
investigator must promptly notify Lilly. 
 
Pregnancy (during maternal or paternal exposure to study treatment does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus. 
  Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidance 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 guidance. 
  Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements. 
 
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
  Treatment of Overdose 
Refer to the relevant IB and/or Product Label for LY3214996 and abemaciclib. 
 Data and Safety Monitoring 
This study will be conducted in accordance with the IU Simon Cancer Center Institutional DSMP for 
High Risk Trials.    
  
Investigators will conduct continuous review of data and subject safety. Weekly review meetings for 
high risk trials are required and will include the principal investigator, clinical research specialist 
and/or research nurse (other members per principal investigator’s discretion). Weekly meeting 
summaries should include review of data and subject safety by including for each dose level: the 
number of subjects, significant toxicities as described in the protocol, dose adjustments and responses 
observed. Study teams should maintain meeting minutes and attendance for submission to the DSMC 
upon request.    
  Data and Safety Monitoring Committee  
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject 
safety, regulatory compliance, and data integrity for this trial.  The DSMC will review this study 
semi-annually to review overall trial progress, toxicity, compliance, data integrity, and accrual per 
the Institutional DSMP.    
  
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business.  Major issues may require further 
DSMC review or action.    
  
For any increase in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the principal investigator will notify the DSMC Chair 
immediately.  The notification will include the incidence of study adverse events, grades, and 
attributions, as well as investigator statements regarding comparison with risks per the IB/ package 
insert.     
  
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance Officer 
must be notified within 1 business day via email, and the IRB must be notified within 5 business 


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days. Alternatively, the DSMC may initiate suspension or early closure of the study based on its 
review.  
  IND Annual Reports   
For trials with an IND held locally by the IU principal investigator or university, the IND Annual 
Report will be prepared and submitted to the Compliance Team.  This report will be reviewed by the 
DSMC at the time of FDA submission.  
  Study Auditing and Monitoring   
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the Institutional 
DSMP. Reports will be reviewed by the full DSMC at the time of study review.   
  Data Management/ Oncore Reporting Requirements  
The DSMC reviews data and study progress directly from Oncore; therefore, timely data entry and 
status updates are vital.  Study data must be entered within Oncore promptly, no later than one week 
from study visit occurrence.  Subject status in Oncore will be updated in real time, as this may affect 
overall trial enrollment status.  Global SAEs and deviations will be reviewed on a monthly basis by 
the DSMC Chair directly from Oncore.    
  Study Accrual Oversight   
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol Progress 
Committee (PPC) reviews study accrual twice per year, while the PPC coordinator reviews accrual 
quarterly.   
  Oncore Safety Reporting  
In addition to protocol- and regulatory-required safety reporting, all serious adverse events (SAEs) 
will be captured in the Oncore system within 1 business day of notification.  Initial SAE reporting 
will include as much detail as available, with follow-up to provide complete information.   
Attributions will be assessed to study drugs, procedures, study disease, and other alternate etiology.      
  Protocol Deviation Reporting   
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the 
DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time of study 
review.  For serious or repetitive protocol deviations, additional action may be required by the 
DSMC.   
 Statistical Considerations 
 Sample Size Determination 
The primary end point is overall response rate (ORR), where overall response is defined as the 
complete or partial response per RECIST criteria. We will use the one stage  design for the phase 
II trial. We will use the one stage design to test the null hypothesis that the true ORR is 5% 
versus the alternative hypothesis that that the true ORR is 19% using a one-sided test with the 
designing parameters type-I error=0.05 and type II error=0.2 (power=80%).  
 


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A total sample size of 28 evaluable patients will be accrued.The trial is considered a success 
when the null hypothesis is rejected, which is determined when 4 or more patients have an 
overall response among the 28 patients. Of note, an evaluable patient is defined as a patient who 
receives at least one dose of the study drug. Assuming a 20% drop-out rate, it is anticipated that 
the total accrual would be 35 patients. 
 
We will add additional early stopping rules for the following subgroups of patients with 
pathogenic alterations in 1) BRAFV600E 2) BRAF nonV600E, RAF1 3) MEK1/2, ERK1/2 and 
4) NF1. We will use the Bayesian posterior probability to monitor the response rates for those 
subgroups. A beta distribution of Beta (0.05,0.05) is assigned as the prior. Then, when every 5 
evaluable patients have been enrolled in the specific subgroup under monitoring, we will 
calculaute the posterior probability that the ORR rate for that subgroup is less than 5%. If this 
posterior probability is greater than 90% during any interim analysis, we will claim that the drug 
is not promising for this subgroup and will stop any future enrollment for that subgroup of 
patients. That is, for the 5th, 10th, 15th, 20th, 25th, 30th, and 35th patients in the subgroup, we will 
determine the enrollment for that subgroup if none of the patients report as tumor response.  If 
the early stopping rule has been triggered, then at the end of the trial we will exclude all the 
patients in that subgroup from final analysis. We will use a binomal exact test to test the 
effectiveness of the drug for the remaining patients.  
 Populations for Analyses 
The following populations will be defined for this study: 
 
Safety population:  will include all enrolled patients who received any quantity of study 
treatment, regardless of their eligibility for the study.  
 
Efficacy Population: will include all enrolled patients who received any quantity of study 
treatment, regardless of their eligibility for the study. 
 
Biomarker population: will include the subset of patients from the safety population from 
whom a valid assay results have been obtained. 
 Statistical Analyses 
Statistical analysis of this study will be the responsibility of Indiana University Department of 
Biostatistics or its designee. 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.  Additional 
exploratory analyses of the data will be conducted as deemed appropriate. 
 Safety Analyses 
For safety analyses, CTCAE Version 5.0 will be used to summarize adverse events in the 
assessment of safety for incorporating LY3214996 in combination with abemaciclib. Summaries 
of treatment related adverse events in the population will be tabulated. All adverse events (AEs) 
will be presented in incidence tables coded by CTC term. An adverse event will be considered 
treatment related if it occurred on or after date of first dose of LY3214996 or abemaciclib and 
was possibly, probably, or definitely related to treatment.  All adverse events will be recorded 


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until off study date. All deaths recoded in this study will be listed and summarized, and the cause 
documented. 
 Efficacy Analyses 
 Endpoints 
Overall response rate is defined as the number of patients who achieve a best overall response of 
complete response (CR) or partial response (PR) divided by the total number of patients treated 
(efficacy population). 
 
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the 
first date of the observed clinical or radiologically documented PD or death due to any cause, 
whichever occurs first.  For patients who are not known to have died or progressed as of the 
data-inclusion cut-off date, PFS time will be censored at the date of the last objective 
progression-free disease assessment prior to the date of any subsequent systematic anticancer 
therapy. 
 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 Analysis Planned 
 
 The Analysis of Primary Endpoint 
The primary end point is overall response rate (ORR), where overall response is defined as the 
complete or partial response per RECIST v1.1 criteria. We will use the one stage design for the 
phase II trial. We will specify the null hypothesis that the true ORR is 5% versus the alternative 
hypothesis that that the true ORR is 19% using a one-sided test with the designing parameters 
type-I error=0.05 and type II error=0.2 (power=80%). 
 The Analysis of Secondary Endpoint 
The safety and tolerability will be summarized and tabulated as in Section 14.3.1. 
 
The secondary endpoint of progression free survival and the duration of response will be 
analyzed using the Kaplan-Meier method.  
 The Analysis of Correlative Obejctives 
To identify potential predictive biomarkers beyond the genomic alteration, exploratory analysis 
of gene expression and DNA mutations will be analyzed to associated with ORR and PFS. In this 
exploratory analysis, the association of DNA mutations in genes and pathways of interest with 
ORR and PFS will be performed using logistic regression, and Cox regression model. High-
dimentional data in these regression models will be dealt using Lasso and Elastic-Net 
Regularized Generalized Linear Models (glmnet package in R)   For gene expression, differential 
expression between responders and non-responders will be identified using the DESeq package 
in R. 
 


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Plasma concentrations of LY3214996, abemacicilib and its metabolites will be summarized 
using descriptive longitudinal and statistics. Further PK/PD analyses will be analyszed using 
linear mixed effect model, in particular, the AUC will be estimated and summarized. However, 
all of these analyses will be exploratory. 
 Patient Disposition 
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients discontinuing (overall and by reason for 
discontinuation).  A listing of all important protocol deviations will be provided. 
 Patient Characteristics 
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval. 
 
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics.  
 Concomitant Therapy 
A summary of prior and concomitant medications will be reported. 
 Post study-Treatment-Discontinuation Therapy 
The numbers and percentages of patients receiving post study-treatment-discontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy, or systemic 
therapy), and by drug class and/or name, overall and by line of therapy. 
 Treatment Compliance 
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment parts. 
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments.  Study 
treatment taken will be derived from the difference between the total number of pills dispensed 
and returned over the course of the patient’s treatment. 
 Patient Consent and Peer Judgement  
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study.   
Changes to the protocol, as well as a change of principal investigator, must also be approved by 
the Board.  Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Trials 
Office) and are subject to inspection at any time during the study.   
 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 


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Gajewski TF, Lutzky J, Lawson DH, Lao CD, Flynn PJ, Albertini MR, Sato T, Lewis K, 
Doyle A, Ancell K, Panageas KS, Bluth M, Hedvat C, Erinjeri J, Ambrosini G, Marr B, 
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M, Engelman JA. EGFR-mediated re-activation of MAPK signaling contributes to 
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Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford 
K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S. Combined BRAF and MEK inhibition 
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Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
AE 
Adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient 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. 
AUC0-tlast, AUC0-∞ 
area under the concentration-time curve  
ATP 
adenosine triphosphate 
BCOP 
bovine corneal opacity and permeability 
BID 
twice a day 
CDK4 
cyclin-dependent kinase-4  
CI 
confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
apparent clearance  
Cmax 
maximum concentration 
CR 
complete response 
CRC 
colorectal cancer  
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. 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTS 
change in tumor size 
CVw 
coefficients of variations  
DDI 
drug-drug interactions 
DLT 
dose limiting toxicity  


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ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
effective method of 
contraception 
male condom with spermicide, female condom with spermicide, diaphragm with 
spermicide, cervical sponge, or cervical cap with spermicide. 
Also see the definition of highly effective method of contraception. 
EGFR 
epidermal growth factor receptor 
enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment. 
enter 
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
ethical review boards 
ERK 
extracellular signal regulated kinase 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte-colony stimulating factor (G-CSF 
GCP 
good clinical practice 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
interim analysis 
An interim analysis is an analysis of clinical trial data conducted before the final 
reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry  
MAPK 
mitogen-activated protein kinase  
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MN 
micronucleus 
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose 
NF1 
Neurofibromin-1 
NOEL 
no-observed-effect level 
NSCLC 
non-small cell lung cancer  
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamics 
PDAC 
pancreatic ductal adenocarcinoma 
PET 
positron emission tomography 
PFS 
progression free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PR 
partial response 
QD 
once daily 
QTc  
corrected QT interval 
QW 
every week 
RECIST 
Response Evaluation Criteria in Solid Tumors 
reporting database 
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data. 
re-screen 
to screen a patient who was previously declared a screen failure for the same study 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study.  
screen failure 
patient who does not meet one or more criteria required for participation in a trial 


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SUSARs 
Suspected unexpected serious adverse reactions  
t1/2 
half-life 
TEAE 
Treatment-emergent adverse event:  an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment. 
TTR 
time to response 
US 
United States 
V/F 
apparent volume of distribution  
 
 
Appendix 2. 
Study Governance, Regulatory, and Ethical 
Considerations 
Informed Consent 
Investigators are responsible for: 
• ensuring that the patient understands the potential risks and benefits of participating in 
the study 
• ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment. 
• 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. 
Ethical Review 
Documentation of IRB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s). The sponsor-investigator or representative must 
approve the ICF, including any changes made by the IRB, before it is used at the investigative 
site.  All ICFs must be compliant with the International Conference on Harmonisation (ICH) 
guideline on GCP. 
The study site’s IRB should be provided with the following: 
• the current IB or package labeling, Patient Information Leaflet, Package Insert, or 
Summary of Product Characteristics and updates during the course of the study 
• the ICF 
• relevant curricula vitae 


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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  
• applicable ICH GCP Guidelines 
• applicable laws and regulations. 
 
Investigator Information 
Physicians with a specialty in oncology will participate as investigators in this clinical trial. 
Protocol Signatures 
Lilly’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. 
Final Report Signature 
The sponsor-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. If this investigator is unable to fulfill this function, another investigator 
will be chosen by Indiana University to serve as the clinical study report coordinating 
investigator. 
 
The sponsor-investigator and statistician will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
Study and Site Closure 
Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly, the sponsor-investigator, or the IRB of the 
study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP. 
Discontinuation of the Study 
The study will be discontinued if Lilly or the sponsor-investigator judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and GC


 
 
 
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Appendix 3. 
Creatinine Clearance Formula 
 
For serum creatinine concentration 
in mg/dL: 
 
 
 
 
 
 
CrCl =  
(mL/min)  
(140 – agea) × (wt)  ×  0.85 (if female), or × 1.0 (if male) 
72 × serum creatinine (mg/dL) 
 
 
 
 
 
 
For serum creatinine concentration in µmol/L: 
CrCl  = 
(mL/min) 
 (140 – agea) × (wt)  ×  0.85 (if female), or × 1.0 (if male) 
0.81 × serum creatinine (µmol/L) 
a Age in years, weight (wt) in kilograms. 
Source:  Cockcroft and Gault 1976. 
 
 
 


 
 
 
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Appendix 4. 
Dose Modification of LY3214996 & Abemaciclib  
Neutropenia 
Abemaciclib 
LY3214996 
≤ Grade 1/2 
No change in dose. 
No change in dose. 
Grade 3 
Hold* until ≤ Grade 2. Resume at 
same dose level. 
No change in dose. 
Recurrent Grade 3 or 
Grade 4 
Hold* until ≤ Grade 2. Reduce by 1 
dose level. 
No change in dose. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
NOTE: Use of prophylactic granulocyte colony stimulating factor is permitted per investigator discretion. Use of 
ASCO guidelines is recommended. Suspend therapy for at least 48 hours after the last dose of a blood cell growth 
factor was administered and until toxicity resolves to at least Grade 2. 
Abbreviation:  ASCO = American Society of Clinical Oncology 
 
Thrombocytopenia 
Abemaciclib 
LY3214996 
≤ Grade 1/2 
No change in dose. 
No change in dose. 
Grade 3 
Hold* until ≤ Grade 2. Resume at 
same dose level. 
No change in dose. 
Recurrent Grade 3 or 
Grade 4 
Hold* until ≤ Grade 2.  Reduce by 1 
dose level. 
No change in dose. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
 
Anemia 
Abemaciclib 
LY3214996 
Supportive transfusion is permitted after cycle 1, day 1 and future cycles for subjects who do not meet 
hemoglobin parameters for retreatment. 
Hemoglobin 
Abemaciclib 
LY3214996 
Grade 1/2 
No change in dose 
No change in dose. 
Grade 3 
Hold* until ≤ Grade 2. Resume at 
same dose level. 
No change in dose. 
Recurrent Grade 3 or 
Grade 4 
Hold* until ≤ Grade 2.  Reduce by 1 
dose level. 
No change in dose. 
Patient requires 
administration of a 
blood 
cell growth factor  
 
Suspend abemaciclib dose for at least 48 
hours after the last dose of 
blood cell growth factor and until toxicity 
resolves to ≤Grade 2. Resume abemaciclib 
at next lower dose unless the dose was 
already 
reduced for the toxicity that led to the use of 
the growth factor. 
No change in dose. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
Supportive transfusion is permitted after cycle 1, day 1 and future cycles for subjects who do not meet 
hemoglobin parameters for retreatment. 
 


 
 
 
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Recurrent in the context of dose interruptions and delays refer to the same event occurring within 
the next 8 weeks (as measured from the stop date of the first event).  This does not include events 
in the same class (for example, neutropenia followed by anemia 1 month later). 
 
As a general approach, 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 if the patient satisfies the following 
conditions: 
• The patient showed stable hematological counts (≤Grade 2) during that time frame 
• In the absence of any infectious sign or risk factor 
• The patient is getting benefit from study treatment. 
 
Non-Hematologic Toxicity: 
Nausea** 
Abemaciclib 
LY3214996 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Grade 3 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level.  
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
** After optimal anti-emetic therapy.  Please refer to Section 8.6.1.  Use of prophylactic or scheduled antiemetics 
are recommended in future cycles for patients experiencing grade 2 or higher nausea. 
 
Vomiting** 
Abemaciclib 
LY3214996 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Grade 3 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level.  
Grade 4 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
** After optimal anti-emetic therapy.  Please refer to Section 8.6.1.  Use of prophylactic or scheduled antiemetics 
are recommended in future cycles for patients experiencing grade 2 or higher vomiting. 
 


 
 
 
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Diarrhea** 
Abemaciclib 
LY3214996 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 (1st episode) 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Hold* until ≤ Grade 1. Resume at same 
dose level. 
Grade 2 (Persistent or 
recurrent following 
resumption of 
therapy) 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Grade 3 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level.  
Grade 4 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
** After optimal anti-diarrheal therapy.  Please refer to Section 8.6.1.  Use of prophylactic or scheduled anti-
diarrheals are recommended in future cycles for patients experiencing grade 2 or higher diarrhea. 
 
Hepatotoxicity is a known adverse drug reaction of abemaciclib. Additional information is in the 
IB. Should a patient experience ≥ Grade 2 increase in AST and/or ALT we recommend holding 
therapy with dosing guidelines below. Please follow AST, ALT, and total bilirubin at least 
weekly until ≤ Grade 1 prior to re-initiating study therapy. Liver function can be monitored more 
frequently per investigator discretion.  
 
AST and/or ALT 
Elevations** 
Abemaciclib 
LY3214996 
≤ Grade 1  
(>ULN-3.0x ULN) 
No change in dose. 
No change in dose. 
Grade 2  
(>3.0-5.0 x ULN)  
(without increase in 
total bili > 2 x ULN) 
Hold* until meets treatment criteria. 
Resume at same dose level. 
Hold* until meets treatment criteria. 
Resume at same dose level. 
Grade 2 (without 
increase in total bili 
>2 x ULN; recurrent 
or persistent) 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Grade 3 
(>5.0-20.0 x ULN) 
(without increase in 
total bili > 2 x ULN) 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Hold* until ≤ Grade 1. Reduce by 1 dose 
level. 
Grade 2 (with increase 
in total bili > 2x ULN) 
Discontinue therapy 
Discontinue therapy 
Grade 3 (with increase 
in total bili >2 x ULN) 
Discontinue therapy 
Discontinue therapy 
Grade 4 (>20.0 x 
ULN) 
Discontinue therapy 
Discontinue therapy 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
** Use ULN unless baseline is greater than ULN, then use baseline for grading. 
 


 
 
 
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Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib.  Additional information is available in the IB. 
 
Ask your patients to report any new or worsening respiratory symptoms such as cough, dyspnea, 
fever, and investigate and treat as per your local clinical practice, including corticosteroids as 
appropriate.  If interstitial lung disease/pneumonitis is suspected, investigations may include 
imaging, such as high-resolution CT scans, bronchoalveolar lavage, and biopsy as clinically 
indicated. Please refer to dosing guidelines below for respiratory toxicity.  
 
ILD/Pneumonitis 
Abemaciclib 
LY3214996 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 (>7 days 
despite maximal 
supportive measures 
or recurrent) 
Hold* until ≤ Grade 1 or baseline. 
Reduce by 1 dose level.  
Hold* until ≤ Grade 1 or baseline. Resume 
at same dose level. 
Grade 3/4 
Discontinue therapy. 
Discontinue therapy. 
*Patients requiring a delay of all protocol therapy > 3 weeks due to toxicity should go off protocol therapy. 
 
 
Cutaneous toxicity should be managed per guidelines in Section 8.6.1.1. In the event of grade 3 
or higher dermatologic toxicity, hold abemaciclib and LY3214996 until dermatologic toxicity 
resolves to ≤ grade 2 or pre-treatment baseline. Subsequent LY3214996 treatment should be dose 
reduced by one dose level. Abemaciclib does not require dose reduction. Treatment may be held 
for up to 21 days. If the toxicity is not improved to ≤ grade 2 or pre-treatment baseline within the 
21-day period, the patient will discontinue therapy. Additionally, a one level dose reduction of 
LY3214996 is permitted for intolerable grade 2 dermatologic toxicity, at the discretion of the 
treating physician. Such dose reductions should be undertaken in conjunction with management 
of cutaneous toxicity as described in Section 8.6.1.1.  
 
For any grade 3 or 4 toxicity, not mentioned above, the treatment should be withheld until the 
patient recovers to grade 1 or less toxicity. The treatment may then be resumed at one dose level 
reduction. For intolerable grade 2 toxicities, withhold treatment until the patient recovers, then 
resume treatment at a one dose level reduction. Dose reduction will be done for the drug that is 
most likely to have caused the toxicity. For grade 1 or tolerable grade 2 toxicities or clinically 
insignificant laboratory changes, no dose reduction should be made. 
 
Dose adjustments as outlined in the table below are allowed both within a cycle and between 
cycles for abemaciclib.  Abemaciclib must be reduced sequentially by 1 dose level. 
Dose Adjustment 
Oral Dose 
Frequency 
0 
150 mg 
Q12H 
-1 
100 mg 
Q12H 
-2 
50 mg 
Q12H 
 
Dose adjustments as outlined in the table below are allowed both within a cycle and between 
cycles for LY3214996.  LY3214996 must be reduced sequentially by 1 dose level. 


 
 
 
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Dose Adjustment 
Oral Dose 
Frequency 
0 
200 mg 
Daily 
-1 
100 mg 
Daily 
 
If a patient receiving the 50-mg Q12H dose of abemaciclib requires further dose reduction, 
abemaciclib should be discontinued.  Patients may remain on single agent treatment with 
LY3214996 if the investigator determines the patient is receiving clinical benefit. 
Dose omissions are allowed within a cycle.  If a patient requires omission of more than 25% of 
doses during a cycle for tolerability, then treatment may continue if the investigator determines 
the patient is receiving clinical benefit. 
 
 


 
 
 
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Appendix 5. 
Sensitive CYP3A Substrates and Narrow 
Therapeutic Range Drugs 
The information in this table is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated. 
Strong Inducers of CYP3A 
Carbamazepine 
Dexamethasone 
Phenobarbital/phenobarbitone 
Phenytoin 
Rifapentine 
Rifampin 
Rifabutin 
St John’s wort 
 
Moderate Inducers of CYP3A 
Bosentan 
Lenisurad 
Modafinil 
Primidone 
Telotristat ethyl 
 
Strong Inhibitors of CYP3A 
Aprepitant 
Ciprofloxacin 
Clarithromycin 
Conivaptan 
Diltiazem 
Erythromycin 
Fluconazole 
Itraconazole 
Ketoconazole 
Nefazodone 
Posaconazole 
Troleandomycin 
Verapamil 
 
This table is prepared to provide examples of clinical CYP3A-sensitive substrates and narrow 
therapeutic range drugs that are CYP3A substrates and is not intended to be an exhaustive list. 
Concomitant therapy with sensitive substrates of CYP3A4, particularly those that also have a 
narrow therapeutic range, should be used with caution for all patients. 


 
 
 
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Appendix 6. 
Patient Dosing Instructions and Diary  
Subject ID: _____________Cycle:_________________ 
 
Date Medication Dispensed ______/______/_________  
LY3214996 ___________ 
Abemaciclib Dose: _________ 
 
Dosing Instructions 
 
LY3214996 
• You will take LY3214996 once daily on days 1 through 28 of your 28 day cycle 
• LY3214996 can be taken with or without food 
• You should take your dose about the same time each day (± 2 hours) as much as 
possible 
• If you miss or vomit a dose, you should not take another dose to try and make it up 
• LY3214996 should be taken at the same time as either the a.m. or p.m. dose of 
abemaciclib 
 
Abemaciclib 
• You will take abemaciclib twice a day on days 1 through 28 of your 28 day cycle  
• You should take your doses 12 hours apart (±2 hours) and at about the same time each 
day 
• Abemaciclib can be taken with or without food 
• If you miss or vomit a dose, you should not take another dose to try and make it up 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Dosing Diary  
 
Subject ID: ________________Cycle:_____________________ 
 
Use the table below to record each dose of LY3214996 and each dose of Abemaciclib you take. 
Record the date and the time of each dose in the space provided. Return your diary to the 
study team at the end of each cycle.  
 
Day 
LY3214996 
Abemaciclib 
Day 
LY3214996 
Abemaciclib 
Example 
Day 1 01/01/2001 
8:00  am 
8:00  am 
8:00 pm 
 
 
 
Day 1: ___/___/____ 
_____:____ 
_____:_____ 
_____:_____ 
Day 15:___/___/____ _____:____ 
_____:_____ 
_____:_____ 
Day 2: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 16:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 3: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 17:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 4: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 18:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 5: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 19:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 6: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 20:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 7: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 21:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 8: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 22:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 9: ___/___/____ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 23:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 10: ___/___/___ 
_____:_____ 
_____:_____ 
_____:_____ 
Day 24:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 11:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 25:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 12:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 26:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 13:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 27:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 
Day 14:___/___/____ _____:_____ 
 
_____:_____ 
_____:_____ 
Day 28:___/___/____ _____:_____ 
_____:_____ 
_____:_____ 


 
 
 
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