Conditions: Gastroesophageal Cancer Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This study will test the combination of abemaciclib with pembrolizumab in patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma that is metastatic or cannot be surgically removed, and who have progressed on, or were unable to tolerate, at least 2 earlier courses of treatment for their advanced disease.

Detailed description:
This is a Phase II non-randomized, single arm, open label study of abemaciclib in combination with pembrolizumab in patients with unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma who have received at least two lines of prior therapy. Treatment will be administered in 21-day cycles. Pembrolizumab will be administered intravenously (IV) at a dose of 200 mg on day 1 of each cycle. Abemaciclib will be taken orally twice a day on each day of the cycle, 150 mg per dose. Treatment will continue until disease progression or development of unacceptable toxicities.

Arms:
arm 1: Abemaciclib 150mg days 1-21, and Pembrolizumab 200mg IV, Day 1

Interventions: intervention 1: Pembrolizumab intervention 2: Abemaciclib
Intervention descriptions: intervention 1: Pembrolizumab 200mg IV intervention 2: Abemiciclib 150mg PO

Protocol document:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-GI18-149 
Protocol Title 
Phase II Study of the Combination of Abemaciclib and Pembrolizumab in Locally 
Advanced Unresectable or Metastatic Gastroesophageal Adenocarcinoma:  
Big Ten Cancer Research Consortium BTCRC-GI18-149 
 
Sponsor Investigator 
Nataliya Uboha, MD, PhD 
University of Wisconsin Carbone Cancer Center, Madison WI 
 
 
Co-Investigators 
Howard Hochster, MD 
Rutgers-CINJ  
RWJ-B Health System 
 
 
Statistician 
Jens Eickhoff, PhD, MS 
UW Department of Biostatistics and Medical Informatics 
 
 
Trial Management Provided by  
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Supported by  
Eli Lilly and Company 
 
 
Investigational New Drug (IND) Number: 
Exempted by FDA on 30APR2019 
 
 
 
Initial Protocol Version Date: 22MAY2019 
 
Protocol Amendment Version Date:  
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol title: Phase II Study of the Combination of Abemaciclib and Pembrolizumab in Locally 
Advanced Unresectable or Metastatic Gastroesophageal Adenocarcinoma:  
Big Ten Cancer Research Consortium BTCRC-GI18-149 
 
 
VERSION DATE:  22MAY2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
PLEASE EMAIL COMPLETED FORM TO  
BIG TEN CRC ADMINISTRATIVE HEADQUARTERS 
 
 
 


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SYNOPSIS 
TITLE 
Phase II Study of the Combination of Abemaciclib and Pembrolizumab in 
Locally Advanced Unresectable or Metastatic Gastroesophageal 
Adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-GI18-149
PHASE 
Phase II 
OBJECTIVES OF 
THE STUDY 
Primary Objective:  
 Estimate progression-free survival (PFS) of treatment with abemaciclib 
in combination with pembrolizumab in patients with unresectable or 
metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma. 
 
Secondary Objectives: 
 Estimate progression-free survival (PFS) rate at 6 months in patients with 
unresectable or metastatic gastric, gastroesophageal junction, or 
esophageal adenocarcinoma treated with abemaciclib in combination 
with pembrolizumab. 
 Estimate disease control rate (DCR) in patients with unresectable or 
metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma treated with abemaciclib in combination with 
pembrolizumab. 
 Estimate overall survival (OS) in patients with unresectable or metastatic 
gastric, gastroesophageal junction, or esophageal adenocarcinoma treated 
with abemaciclib in combination with pembrolizumab. 
 Estimate objective response rate (ORR) in patients with unresectable or 
metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma treated with abemaciclib in combination with 
pembrolizumab. 
 Estimate the safety and tolerability of abemaciclib in combination with 
pembrolizumab in patients with unresectable or metastatic gastric, 
gastroesophageal junction, or esophageal adenocarcinoma. 
 
Exploratory Objectives: 
 Correlate PD-L1 expression status with clinical outcomes. 
 Correlate tumor molecular signature from NGS analysis with clinical 
outcomes and treatment response. 
 Collect archival tissue for future studies. 
 Correlate peripheral blood-based biomarkers that will include, but are not 
limited to, circulating tumor DNA and circulating immune markers, with 
clinical outcomes. 
 Correlate saliva microbiome analysis results with clinical outcomes.
STUDY DESIGN 
Phase II, single arm, nonrandomized, open label study of abemaciclib in 
combination with pembrolizumab in subjects with unresectable or metastatic 
gastric, gastroesophageal junction, or esophageal adenocarcinoma who have 
progressed or were intolerant to at least 2 lines of prior therapies for 
advanced disease.


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KEY 
ELIGIBILITY 
CRITERIA  
 Patients age 18 or older. 
 Histologically confirmed unresectable or metastatic gastric, 
gastroesophageal junction, or esophageal adenocarcinoma. 
 Measurable disease by RECIST 1.1 is required.  
 Hematologic parameters:   
o Absolute neutrophil count ≥ 1500/µl 
o Hemoglobin ≥ 8 g/dl 
o Platelet count ≥ 100,000/µl 
 Renal function:  Creatinine  < 1.5x ULN or Cockcroft-Gault calculated 
creatinine clearance ≥ 60 mL/min  
 Hepatic function  
o AST and ALT ≤ 3x upper limit of normal (ULN). 
o Total bilirubin ≤ 1. 5x ULN. Patients with Gilbert’s syndrome with a 
total bilirubin ≤2.0 times ULN and direct bilirubin within normal 
limits are permitted. 
 Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 
 Prior therapy 
o At least two lines of prior systemic therapy for advanced, unresectable 
or metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma.  
 Ability to take oral medications 
 No history of prior therapy with a cyclin-dependent kinases 4 and 6 
(CDK4 and CDK6) inhibitors or prior immune checkpoint inhibitors. 
 No contraindications to immune checkpoint inhibitors. 
STATISTICAL 
CONSIDERATIONS 
In the Phase II study, the primary endpoint for sample size justification is 
progression-free survival (PFS). The null hypothesis that the median PFS is 2 
months or less will be tested against the alternative hypothesis that the median 
PFS is greater than 2 months. A median PFS of at least 4 months will be 
considered sufficient evidence to consider further clinical investigation of the 
proposed treatment combination. A sample size of 31 evaluable subjects is 
required to detect an anticipated increase in the median PFS from 2 months 
(null hypothesis) to 4 months with 80% power at the one-sided 0.05 
significance level.  In order to account for non-evaluable subjects (~10%), a 
total of 34 subjects will be enrolled.
TOTAL NUMBER 
OF SUBJECTS 
N=34 
ESTIMATED 
ENROLLMENT 
PERIOD 
12-18 months  
ESTIMATED 
STUDY 
DURATION  
24 months (18 months for accrual, additional 6 months for primary endpoint 
follow-up) 
 
 


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TABLE OF CONTENTS 
 
List of abbreviations and definition of terms .............................................................................................. 7 
Study Schema.............................................................................................................................................. 8 
1. 
Background and Rationale .................................................................................................................. 9 
1.1 
Disease Background.................................................................................................................... 9 
1.2 
Immunotherapy in the Treatment of Gastroesophageal Cancers ................................................ 9 
1.3 
Rationale for Combining Abemaciclib with Pembrolizumab ..................................................... 9 
2. 
Study Objectives and Endpoints ....................................................................................................... 10 
2.1 
Objectives ................................................................................................................................. 10 
2.2 
Endpoints .................................................................................................................................. 10 
3. 
Eligibility Criteria ............................................................................................................................. 11 
3.1 
Inclusion Criteria ...................................................................................................................... 11 
3.2 
Subject Exclusion Criteria ........................................................................................................ 13 
4. 
Subject Registration .......................................................................................................................... 14 
5. 
Treatment Plan .................................................................................................................................. 14 
5.1 
Pre-medication and Hydration .................................................................................................. 14 
5.2 
Drug Administration ................................................................................................................. 14 
5.3 
Concomitant Medications ......................................................................................................... 15 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 16 
6.1 
Start of a New Cycle ................................................................................................................. 16 
6.2 
Management of Pembrolizumab Associated Toxicities. .......................................................... 16 
6.3 
Management of Abemaciclib Associated Toxicities ................................................................ 26 
6.4 
Dose Delays/Dose Modifications ............................................................................................. 29 
6.5 
Protocol Therapy Discontinuation ............................................................................................ 29 
6.6 
Definition of Evaluable Subject ................................................................................................ 30 
6.7 
Protocol Discontinuation .......................................................................................................... 30 
7. 
Study Calendar & Evaluations .......................................................................................................... 31 
7.1 
Screening Evaluations ............................................................................................................... 33 
7.2 
On Treatment Evaluations ........................................................................................................ 33 
8. 
Biospecimen Studies and Procedures ............................................................................................... 35 
8.1 
Correlative Studies from Tissue................................................................................................ 35 
8.2 
Sample Collection and Banking for Future Unspecified Research .......................................... 36 
8.3 
Confidentiality of Biospecimens ............................................................................................... 36 
9. 
Criteria for Disease Evaluation ......................................................................................................... 36 
9.1 
Overview ................................................................................................................................... 36 
9.2 
Timing of Radiographic Evaluations ........................................................................................ 36 
9.3 
Assessment of Response per RECIST ...................................................................................... 37 
9.4 
Assessment of Response by Immune-Related RECIST ........................................................... 39 
9.5 
Treatment and Assessment After Progression .......................................................................... 40 
9.6 
Definitions for Response Evaluation – RECIST 1.1 and irRECIST ........................................ 41 
9.7 
Safety and Tolerability .............................................................................................................. 41 
10. 
Drug Information .......................................................................................................................... 41 
10.1 
Abemaciclib (Other names: VERZENIO™) ............................................................................ 41 
10.2 
Pembrolizumab (other names: KEYTRUDA®, MK-3475, Anti-PD-1 Antibody MK-3475) . 42 
11. 
Adverse Events ............................................................................................................................. 43 


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11.1 
Definitions................................................................................................................................. 43 
11.2 
Reporting................................................................................................................................... 45 
12. 
Statistical Methods ........................................................................................................................ 46 
12.1 
Study Design ............................................................................................................................. 46 
12.2 
Endpoints .................................................................................................................................. 46 
12.3 
Sample Size and Accrual .......................................................................................................... 47 
12.4 
Assessment of Safety ................................................................................................................ 47 
12.5 
Assessment of Efficacy ............................................................................................................. 47 
12.6 
Data Analysis Plans .................................................................................................................. 48 
13. 
Trial Management ......................................................................................................................... 48 
13.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................... 48 
13.2 
University of Wisconsin Data Safety Monitoring Committee .................................................. 48 
13.3 
Data Quality Oversight Activities ............................................................................................. 49 
13.4 
Compliance with Trial Registration and Results Posting Requirements .................................. 49 
14. 
Data Handling and Record Keeping ............................................................................................. 49 
14.1 
Data Management ..................................................................................................................... 49 
14.2 
Case Report Forms and Submission ......................................................................................... 50 
14.3 
Record Retention ...................................................................................................................... 50 
14.4 
Confidentiality .......................................................................................................................... 50 
15. 
Ethics............................................................................................................................................. 50 
15.1 
Institutional Review Board (IRB) Approval ............................................................................. 50 
15.2 
Ethical Conduct of the Study .................................................................................................... 51 
15.3 
Informed Consent Process ........................................................................................................ 51 
16. 
References ..................................................................................................................................... 52 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
 
Abbreviation or special term 
Explanation 
AE 
Adverse event
ALT 
Alanine aminotransferase
ANC 
Absolute neutrophil count
AST 
Aspartate aminotransferase
BUN 
Blood urea nitrogen
CBC 
Complete blood count
cc 
Cubic centimeter
CR 
Complete response
CT 
Computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA
DSMC 
Data and Safety Monitoring Committee
EC 
Esophageal cancer
ECOG 
Eastern Cooperative Oncology Group
EOT 
End of treatment
FDA 
Food and Drug Administration
GC 
Gastric cancer
GEJ 
Gastroesophageal junction
GERD 
Gastroesophageal reflux disease
GI 
Gastrointestinal
ICF 
Informed consent form
IHC 
Immunohistochemistry
irAE 
Immune related adverse event
IV 
Intravenous
Kg 
Kilogram
LFT 
Liver function tests
NCI 
National Cancer Institute
NGS 
Next generation sequencing
ORR 
Objective response rate
PD-1 
Programmed death 1
PD-L1 
Programmed death-ligand 1
PI 
Principal Investigator
PLT 
Platelets
PR 
Partial response 
PRMC 
Protocol Review Monitoring Committee
PS 
Performance status
SAE 
Serious adverse event
SD 
Stable disease
TSH 
Thyroid stimulating hormone
ULN 
Upper limit of normal
UWCCC 
University of Wisconsin Carbone Cancer Center 


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STUDY SCHEMA 
 
 
 
 
 


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1. 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Esophageal cancer is a major health problem in the world.  In Western countries, lower esophagus is the 
most common site for esophageal cancers, and these tumors frequently involve the gastroesophageal 
junction (GEJ).  There are two major histological subtypes of esophageal cancer: squamous carcinoma 
and adenocarcinoma.  Although the incidence of squamous cell esophageal cancer has been declining, 
esophageal adenocarcinoma has one of the fastest growing incidence among solid tumors in the Western 
world.  Esophageal adenocarcinoma is more common in males, but over the last few decades its rates 
among women have been increasing as well1.  Tobacco and alcohol abuse are major risk factors for 
esophageal squamous cell carcinoma, while obesity and gastroesophageal reflux disease (GERD) 
predispose to the development of esophageal adenocarcinoma.  The majority of patients are diagnosed 
with at least stage II disease. Despite aggressive treatments of potentially curative esophageal cancer, 
about 50% of patients ultimately developed recurrent disease 2.  Recurrent and metastatic esophageal 
adenocarcinoma is almost universally fatal.  Overall survival (OS) for metastatic gastroesophageal 
adenocarcinoma remains around 12 months with current treatment strategies 3. Therefore, development 
of novel treatment strategies is needed to improve prognosis of patients with this disease.    
1.2 
Immunotherapy in the Treatment of Gastroesophageal Cancers 
Programmed death-ligand 1 (PD-L1) is a transmembrane protein that is expressed in about 40% of upper 
gastrointestinal (UGI) tumors.  PD-L1 is one of the ligands for programmed death 1 (PD-1), which is an 
inhibitory receptor that belongs to the CD28-B7 family. Binding to PD-1 results in down regulation of 
the T cell immune response allowing PD-L1 positive tumors to evade immune mediated cell death.  
PDL-1 expression has been shown to be associated with greater depth of muscle invasion, the presence 
of lymph node metastasis, and overall worse prognosis4,5.  A number of immunotherapy agents have 
demonstrated activity against metastatic gastroesophageal cancers.  Nivolumab treatment results in 
longer OS compared to placebo in patients with metastatic gastric and GEJ tumors who have received at 
least 2 lines of prior therapies 6.  Pembrolizumab treatment resulted in 15.5% objective response rate 
(ORR) in 259 patients with advanced gastric and gastroesophageal junction cancer that enrolled in a 
phase 2 Keynote-059 trial 7. Avelumab has been found to have encouraging results in a similar setting as 
well, with 15%  ORR in subjects with chemotherapy resistant gastroesophageal cancer 8.  Patients who 
do respond to treatments have durable responses, with median response duration to pembrolizumab of 
8.4 months in this advanced setting.  However, the majority of patients do not respond to these agents. 
Hence, novel approaches are needed to increase activity of immune checkpoint inhibitors in patients 
with esophagogastric malignancies. 
1.3 
Rationale for Combining Abemaciclib with Pembrolizumab 
Combination strategies are key to augmenting activity of immune checkpoint inhibitors against 
gastroesophageal adenocarcinoma (GEA).  CDK4/6 inhibition has been shown to increase anti-tumor 
immunity in preclinical studies9,10. CDK4/6 inhibitors can increase tumor antigen presentation, suppress 
proliferation of regulatory T cells, and increase infiltration and activation of effector T cells.  Moreover, 
combination of CDK4/6 inhibitors and anti-PD1 agents demonstrated synergistic anti-tumor activity in 
spheroid cultures and in mouse models9,10. This effect was seen in preclinical studies evaluating 
abemaciclib and pembrolizumab in particular 11. Moreover, proteins that control cell cycle are frequently 
altered in GEA, and  CDK4 and 6 have been shown to be some of the most frequently upregulated genes 
in GEA12,13.  This suggests that targeting genes that regulate cell cycles may have anti-tumor activity in 


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this disease.  In preclinical setting, CDK4/6 inhibitor, abemaciclib, demonstrated promising activity 
against human esophageal cell lines and a xenograft model 14. Based on the above data, we hypothesize 
that the combination of abemaciclib and pembrolizumab will result in clinically relevant activity in 
patients with advanced GEA. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
 Primary Objective 
 
Estimate progression-free survival (PFS) of treatment with abemaciclib in combination with 
pembrolizumab in patients with unresectable or metastatic gastric, gastroesophageal junction, or 
esophageal adenocarcinoma. 
 Secondary Objectives 
 Estimate PFS rate at 6 months in patients with unresectable or metastatic gastric, 
gastroesophageal junction, or esophageal adenocarcinoma treated with abemaciclib in 
combination with pembrolizumab. 
 Estimate disease control rate (DCR) in patients with unresectable or metastatic gastric, 
gastroesophageal junction, or esophageal adenocarcinoma treated with abemaciclib in 
combination with pembrolizumab. 
 Estimate overall survival (OS) in patients with unresectable or metastatic gastric, 
gastroesophageal junction, or esophageal adenocarcinoma treated with abemaciclib in 
combination with pembrolizumab. 
 Estimate the objective response rate (ORR) to abemaciclib in combination with pembrolizumab 
in subjects with unresectable or metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma. 
 Estimate the safety and tolerability of abemaciclib in combination with pembrolizumab in 
patients with unresectable or metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma. 
 Exploratory Objectives 
 Correlate PD-L1 expression status with clinical outcomes. 
 Correlate tumor molecular profiling results from next generation sequencing (NGS) testing with 
clinical outcomes and treatment response. 
 Correlate peripheral blood-based biomarkers that will include, but are not limited to, circulating 
tumor DNA and circulating immune markers, with clinical outcomes.   
 Correlate saliva microbiome analysis results with clinical outcomes. 
2.2 
Endpoints 
 Primary Endpoints 
 
PFS as determined per RECIST1.1 on treatment with abemaciclib in combination with 
pembrolizumab in patients with advanced, unresectable or metastatic gastric, gastroesophageal 
junction, or esophageal adenocarcinoma. 


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 Secondary Endpoints 
 PFS per irRECIST 
 PFS rate at 6 months (RECIST and irRECIST).  
 DCR (RECIST and irRECIST), which is defined as percent of patients with stable disease, 
partial response and complete response after treatment initiation. 
 OS as measured from the time of treatment initiation until death. 
 ORR as measured as percent of patients who achieved objective response as per RECIST 1.1 and 
irRECIST while on treatment. 
 Safety and tolerability of abemaciclib in combination with pembrolizumab in patients with 
advanced, unresectable or metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma, assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.  
 Correlative Endpoints 
 Correlate PD-L1 status with clinical response. 
 Correlate tumor molecular signature from NGS analysis with clinical outcomes and treatment 
response. 
 Collect archival tissue for future studies. 
 Correlate peripheral blood-based biomarkers that will include, but are not limited to, circulating 
tumor DNA and circulating immune markers, with clinical outcomes.   
 Correlate saliva microbiome analysis results with clinical outcomes. 
3. 
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
Study entry is open to adults regardless of gender or ethnic background. While there will be every effort 
to seek out and include women and minorities, the subject population is expected to be no different than 
that of other advanced solid tumor cancer studies at each participating institution. 
 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
1. Patients with histologically confirmed metastatic or locally advanced unresectable gastric, 
gastroesophageal junction or esophageal adenocarcinoma. 
2. Be willing and able to provide written informed consent for the trial.  
3. Age ≥ 18 years at the time of consent. 
4. Prior treatment with at least two lines of systemic therapy for advanced disease.  Patients who 
have received neoadjuvant or adjuvant therapy or definitive chemoradiation and had recurrence 
during or within 6 months of completion of all treatments may count adjuvant therapy as one 
chemotherapy line. 
5. Presence of measurable disease based on RECIST 1.1 as determined by local site 
investigator/radiology assessment.  
6. ECOG PS 0-1. 
7. Patients must have discontinued all previous treatments for cancer (including cytotoxic 
chemotherapy, molecularly targeted therapy, radiotherapy, and investigational therapy).  


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8. Patients who received chemotherapy must have recovered (CTCAE Grade ≤1) from the acute 
effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy.   A 
washout period of at least 21 days is required between last systemic therapy dose and treatment 
initiation per protocol. 
9. A washout period of at least 14 days is required between end of radiotherapy and treatment 
initiation. 
10. The patient is able to swallow oral medications.  
11. Demonstrate adequate organ function as defined in Table 1. 
 
Table 1. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC)
≥1.5 × 109/L
Platelet count 
≥ 100 × 109/L 
Hemoglobin 
≥ 8 g/dL; transfusions to increase the 
patient’s hemoglobin are permitted; 
however, study treatment must not begin 
until the day after the transfusion. 
Renal 
Calculated creatinine clearance 
< 1.5 x upper limit of normal (ULN) or ≥ 50 
mL/min using the Cockcroft-Gault formula 
Hepatic 
Total bilirubin 
≤ 1. 5 ×  ULN; Patients with Gilbert’s 
syndrome with a total bilirubin ≤2.0 times 
ULN and direct bilirubin within normal 
limits are permitted. 
Aspartate aminotransferase (AST) 
≤3 × ULN 
Alanine aminotransferase (ALT) 
≤3 × ULN 
 
12. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior 
to registration. NOTE: Females are considered of child bearing potential unless they are 
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 
13. Females of childbearing potential must be willing to abstain from heterosexual activity or to use 
2 forms of effective methods of contraception from the time of informed consent until 60 days 
after treatment discontinuation. The two contraception methods can be comprised of two barrier 
methods, or a barrier method plus a hormonal method. 
14. Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of 
contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or 
who could become pregnant during the study must agree to use condoms from the first dose of 
study drug through at least 60 days after the last dose of study drug. Total abstinence for the 
same time period is an acceptable alternative. 
15. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 


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16. Provided written informed consent and HIPAA authorization for release of personal health 
information, approved by an Institutional Review Board (IRB). NOTE: HIPAA authorization 
may be included in the informed consent or obtained separately. 
3.2 
Subject Exclusion Criteria 
1. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
2. History of prior therapy with CDK4 or CDK6 inhibitors or prior immune checkpoint inhibitors.  
3. Patients with known microsatellite instability will be excluded. 
4. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of 
physiologic doses of corticosteroids may be approved after consultation with the study PI. 
5. Serious preexisting medical condition(s) that would preclude participation in this study (for 
example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of 
major surgical resection involving the stomach or small bowel, or a preexisting chronic condition 
resulting in baseline Grade 2 or higher diarrhea). 
6. Symptomatic central nervous system metastasis. Screening of asymptomatic patients is not 
required for enrollment. 
7. Personal history of any of the following conditions: syncope of cardiovascular etiology, 
ventricular arrhythmia of pathological origin (including, but not limited to, ventricular 
tachycardia and ventricular fibrillation), or sudden cardiac arrest.  
8. Known additional malignancy that progressed or required active treatment within the last 2 
years. Exceptions include curatively treated basal cell and squamous cell carcinoma of the skin, 
curatively resected in situ cervical and/or breast cancers, in situ or intramucosal pharyngeal 
cancer, and Gleason 6 prostate cancer with PSA <10.  
9. Patients who have received a live vaccine within 30 days of planned start of pembrolizumab.  
Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; 
however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not 
allowed. 
10. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
11. Active infection requiring systemic therapy. 
12. Patients who are pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 60 days after the last dose 
of pembrolizumab or abemaciclib. (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study.) 
 


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4. 
SUBJECT REGISTRATION 
All subjects must be registered through Big Ten Cancer Research Consortium (Big Ten CRC) 
Administrative Headquarters’(AHQ) electronic data capture (EDC) system. A subject is considered 
registered when an ‘On Study’ date is entered into the EDC system. 
 
Subjects must be registered prior to starting protocol therapy. Subjects must begin therapy within 5 
business days of registration.  
5. 
TREATMENT PLAN 
This is a Phase II non-randomized, single arm, open label study of abemaciclib in combination with 
pembrolizumab in patients with unresectable or metastatic gastric, gastroesophageal junction, or 
esophageal adenocarcinoma who have received at least two lines of prior therapy.  Treatment will be 
administered in 21-day cycles. Pembrolizumab will be administered intravenously (IV) at a dose of 200 
mg on day 1 of each cycle. Abemaciclib will be taken orally twice a day on each day of the cycle, 150 
mg per dose. Treatment will continue until disease progression or development of unacceptable 
toxicities.  
5.1 
Pre-medication and Hydration 
No pre-medications prior to treatment with pembrolizumab are required. Subjects who develop infusion 
reactions to pembrolizumab while on treatment may receive pre-medication as detailed in table 3 
(section 6.2).  
5.2 
Drug Administration 
Table 2. Abemaciclib + Pembrolizumab Administration 
 
Drug 
Dose1 
Length and route 
of administration 
Frequency of 
administration1 
Cycle 
Length 
Abemaciclib 
150 mg 
PO, BID 
Days 1-21 
21 days 
Pembrolizumab 
200 mg 
30 min (-5/+10); 
IV 
Day 1  
1 A window of ± 3 days may be applied to all study visits to accommodate observed 
holidays, inclement weather, scheduling conflicts etc. Date and time of each drug 
administration should be clearly documented in subject’s chart and electronic case 
report forms (eCRFs). 
 
Dosing will occur in 21-day cycles. Abemaciclib will be dosed at 150 mg PO (bid) on Days 1-21 of each 
21-day cycle. Abemaciclib can be taken with or without food. Patients should be instructed to take their 
doses of abemaciclib at approximately the same times every day. If the patient vomits or misses a dose of 
abemaciclib, patient will take the next dose at its scheduled time. Additional abemaciclib will not be taken 
to account for missed doses. Subjects will swallow abemaciclib tablets whole and not chew, crush, or split 
tablets before swallowing. Patients will record when they take each dose of abemaciclib in a drug diary 


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supplied to them before the beginning of a new cycle.  
 
Pembrolizumab will be administered as a 30 minute intravenous infusion at a dose of 200 mg. Given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min).  
 
Initiation of cycles after Cycle 1 must meet the treatment criteria found in section 6.1. Subsequent cycles 
may begin up to 3 days earlier or later than initially planned to accommodate scheduling issues. Attempts 
will be made not to interrupt abemaciclib dosing if pembrolizumab infusion is delayed. The timing of each 
cycle initiation will be determined by pembrolizumab dosing (i.e. abemaciclib doses will not be made up 
if missed during a 21 day period). 
5.3 
Concomitant Medications 
Concomitant therapy includes any prescription medications or over-the-counter preparations used by a 
patient from the beginning of the screening period.  All concomitant therapy, including anesthetic 
agents, vitamins, homeopathic/herbal remedies, and nutritional supplements, will be recorded on the 
electronic case report form (eCRF) up until the follow up visit after treatment completion.  Medications 
or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing trial.  
 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare, including antiemetics, 
may be administered at the discretion of the investigator per institutional standards. Growth factor 
support is allowed as clinically indicated, but abemaciclib must be suspended for at least 48 hours after 
the treatment.  
 Prohibited Concomitant Medications 
 Administration of anti-cancer agents other than those specified in the protocol is not allowed 
during study participation.   
 Live vaccine administration is prohibited during study participation.  
 The use of immunosuppressive agents is prohibited during study participation, including 
immunosuppressive doses of systemic corticosteroids.   
o Subjects will be allowed to use topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption).   
o Physiologic replacement doses of systemic corticosteroids are permitted at doses of ≤ 10 mg 
of daily prednisone (or equivalent).  
o A brief course of corticosteroids for prophylaxis (e.g., for contrast dye allergy or to prevent 
infusion reaction) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted.   
 Other Concomitant Treatments 
Abemaciclib is predominantly cleared by oxidative metabolism via CYP3A4.  Clinical drug interaction 
studies with a CYP3A inhibitor and CYP3A inducer significantly altered the PK of abemaciclib and its 
circulating major metabolites. Therefore, drugs that are strong and moderate inducers of CYP3A and/or 
strong inhibitors of CYP3A should be avoided or substituted if necessary. 
If concomitant use cannot be avoided, abemaciclib dose adjustments may be required:  


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 Patients who must take CYP3A inhibitors such as clarithromycin, diltiazem, or verapamil should 
reduce the abemaciclib dose to 100 mg twice daily.  
 Patients who must take itraconazole should reduce the abemaciclib dose to 50 mg twice daily.  
 Patients who must take ketoconazole should reduce the abemaciclib dose to 50 mg once daily.  
 Patients should avoid grapefruit or grapefruit juice. 
 Concomitant Radiotherapy 
Limited data are available with abemaciclib and radiotherapy or alternate dosing schedules (e.g. 
induction phase). Thus, caution should be exercised with co-administering abemaciclib with 
radiotherapy.  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed after 
consultation with the sponsor-investigator by contacting the Big Ten CRC project manager.  
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI CTCAE version 5 will be used to grade adverse events.  Subjects enrolled in this study will be 
evaluated clinically and with standard laboratory tests before and at regular intervals during their 
participation in this study as specified in Study Calendar & Evaluations. Subjects will be evaluated for 
adverse events (all grades), serious adverse events, and adverse events requiring study drug interruption 
or discontinuation as specified in Study Calendar & Evaluations. Subjects discontinued from the 
treatment phase of the study for any reason will be evaluated 30 days (± 7) after the last dose of protocol 
therapy.  
 
For toxicities that are clearly attributed to one of the agents, continuation of the other agent is permitted 
at the discretion of the treating physician. Toxicities should be managed as outlined in sections 6.2 and 
6.3. For grade 3 toxicities that have unclear attribution, both agents should be held while with work up is 
ongoing. Treatment can be resumed as outlined in the protocol for each agent based on most likely 
attribution and severity. 
6.1 
Start of a New Cycle 
A new treatment cycle will only be initiated when all of the following conditions are met: 
 
ANC ≥ 1,000× 109/L  
 
platelets ≥ 50 × 109/L  
 
non-hematologic treatment related toxicities have improved to ≤ Grade 2 or to the subject’s baseline 
values (except alopecia) 
 
If toxicities are outside the acceptable threshold, the subject should be assessed weekly (phone or clinic) 
until toxicities are at an acceptable level. If treatment is unable to restart within 6 weeks of the planned 
treatment date, the subject will be permanently discontinued from study therapy. Both pembrolizumab 
and abemaciclib should be stopped at that time.   
6.2 
Management of Pembrolizumab Associated Toxicities. 
 Management of Allergic Reaction/ Hypersensitivity to Pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion reactions including severe hypersensitivity 
or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab-associated infusion reaction are provided in Table 3. 


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Table 3.  Treatment guidelines for subjects who experience an infusion-related reaction associated with 
administration of pembrolizumab. 
NCI CTCAE 
Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and the 
subject should be premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 325-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Additional medications 
are allowed at the 
discretion of the treating 
physician, with the 
exception of 
corticosteroids.
Grades 3 or 4 
 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Subject is permanently discontinued from further trial 
treatment administration.
No subsequent dosing 
Appropriate resuscitation equipment should be available and a physician readily available during the period of 
drug administration. 


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 Management of Pembrolizumab Immune-Related Toxicities. 
Pembrolizumab treatment may result in toxicities related to the activation of immune system and its off-
target effects.  These immune-related AEs (irAEs) may be seen after the first dose or as late as weeks after 
the last dose of pembrolizumab.  Dose reduction of pembrolizumab is not allowed.  Dose delays or treatment 
discontinuation may be necessary depending on the grade and timing of the AE. Early recognition and 
initiation of treatment is critical to reduce complications.  Based on existing clinical study data, most 
irAEs were reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. It is possible that a given 
toxicity is ultimately found to be related to abemaciclib rather than pembrolizumab. In that case 
pembrolizumab can be continued as previously, even if abemaciclib needs to be delayed or dose 
reduced.  However, if pembrolizumab has been held at the onset of toxicity, it may not be resumed until 
AE is at grade ≤1 as detailed in the table 4. Further details regarding toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in the Table 4 below.


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Table 4. Management of Immune-Related Adverse Events. 
GASTROINTESTINAL irAEs 
Severity of Diarrhea/ 
Colitis1 
Initial Management 
Follow-up Management 
Grade 1 
  
 Continue pembrolizumab therapy 
 Symptomatic treatment (for example, loperamide) 
 Close monitoring for worsening symptoms 
 Educate subject to report worsening of symptoms 
immediately 
 If worsens: Treat as Grade 2, 3 or 4 
Grade 2 
  
 Hold pembrolizumab therapy 
 Symptomatic treatment 
 If improves to Grade < 1: Resume pembrolizumab therapy 
 If persists > 5 to 7 days or recurs: Treat as Grade 3 to 4 
 Endoscopy evaluation highly recommended for grade ≥ 2, 
especially since both agents in the study can cause diarrhea.
Grade 3 
 
Hold pembrolizumab for Grade 3. 
  
 1 to 2 mg/kg/day prednisolone IV or equivalent 
 If improves: Continue steroids until Grade < 1 and taper 
over at least 1 month; resume pembrolizumab therapy 
following steroids taper (for initial Grade 3). 
 If worsens, persists > 3 to 5 days, or recurs after 
improvement, treat as grade 4 and add infliximab 5 mg/kg 
(if no contraindication). Note: Infliximab should not be 
used in cases of perforation or sepsis.
Grade 4 
 
Permanently discontinue pembrolizumab therapy for 
Grade 4 or recurrent Grade 3. 
 Steroids and infliximab as above. 
 Additional care per institutional standards.
 
1Both study drugs can cause diarrhea. It is recommended that at the onset of diarrhea, diarrhea is initially treated following abemaciclib 
associated diarrhea management guidelines as outlined in section 6.3.1. If diarrhea persists despite measures outlined in section 6.3.1 and 
despite stopping abemaciclib for at least 48 hours, or if it is thought to be more likely to be due to pembrolizumab in an investigator’s opinion 
(for example, it occurred after 3-4 cycles of therapy on stable abemaciclib dose), then it should be treated following guidelines outlined above. 
NOTE:  Abemaciclib should be held for grade 2 diarrhea of any cause that lasts more than 24 hours despite supportive measures. Abemaciclib 
dose reduction is not mandatory once it is resumed if diarrhea is ultimately found to be an irAE. 
 NOTE: For grade 3 diarrhea, both drugs should be held until the cause of diarrhea is determined. Endoscopic evaluation is highly recommended 
to evaluate for possible irAE. 


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HEPATIC irAEs 
Severity of Hepatitis/ 
Liver Tests 
Abnormalities2 
Initial Management 
Follow-up Management 
Grade 1 
  
Continue pembrolizumab therapy with close monitoring 
 Monitor labs at least once weekly. Supportive care as 
appropriate. 
Grade 2 
  
Hold pembrolizumab therapy. 
 
 Monitor labs at least once weekly. Supportive care as 
appropriate. 
 If improves to Grade ≤1 in ≤7 days: Resume 
pembrolizumab therapy. 
 If improves to Grade ≤1 in > 7 days and is thought to be 
abemaciclib related, may resume pembrolizumab therapy. 
At least weekly labs will be required after pembrolizumab 
resumption. 
 If persists for > 7 days, patient develops significant clinical 
symptoms and it is thought to be an irAE or unclear cause.  
administer corticosteroid 0.5-1mg/kg/d prednisone or 
equivalent ,. Pembrolizumab may be restarted if LFTs 
return to grade ≤1 within 7 days of steroid treatment and 
remain stable off steroids for at least 7 days.  
Grade 3 or 43 
 
Permanently discontinue pembrolizumab. 
  
 Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent. 
 If corticosteroid refractory or no improvement after 3 days, 
consider mycophenolate mofetil or azathioprine. 
Laboratories daily or every other day. Corticosteroid taper 
can be attempted around 4-6 weeks. 
 
2Both agents can cause liver test abnormalities, and it may be challenging to determine which drug is the culprit. For subject safety, both 
pembrolizumab and abemaciclib should be held for grade 2 or higher liver test abnormalities. If LFTs improve to grade ≤1 within 7 days, both 
drugs can be restarted with close monitoring of liver tests thereafter (at least once a week). Steroid administration for grade 2 LFT abnormalities 
that last more than 7 days will be determined by a treating investigator and will be indicated if hepatotoxicity is more likely irAE rather than 
abemaciclib related (for example, it occurred after a few cycles on a stable dose of abemaciclib). 
 NOTE: LFTs abnormalities related to abemaciclib are more likely to occur early during treatment, which is why LFTs are monitored twice per 
cycle during the first 3 cycles.  
 
3NOTE: Pembrolizumab can be restarted after grade 3 LFT elevation if LFTs return to grade ≤1 within 7 days and/or are thought to be 
abemaciclib related in the opinion of a treating investigator (i.e. occurred early in the course of treatment).  


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PULMONARY irAEs 
Grade of 
Pneumonitis 
Initial Management 
Follow-up Management 
Grade 1 
 
 Consider withholding pembrolizumab therapy  
 Monitor for symptoms at least twice a week  
 Repeat imaging in 3-4 weeks. Hold if radiologic evidence 
of progression. Re-assess at least every 3 weeks.  
 If worsens: Treat as Grade 2, 3 or 4 
Grade 2 
 
Withhold pembrolizumab therapy 
  
 Prednisone 1-2 mg/kg/d and taper by 5-10 mg/wk over 4-6 
weeks. Consider bronchoscopy with BAL. Consider 
empirical antibiotics 
 Re-assess every 1 to 3 days  
 If improves: When symptoms return to Grade < 1, taper 
steroids over at least 1 month. Resume treatment. 
 If not improving after 2 weeks or worsening: Treat as 
Grade 3 to 4. 
Grade 3 to 4 
Severe new 
symptoms; New / 
worsening hypoxia; 
life-threatening  
 Permanently discontinue pembrolizumab therapy 
 Hospitalize  
  
 1.0 to 2.0 mg/kg/day prednisolone or equivalent. Add 
prophylactic antibiotics for opportunistic infections.  
Consider bronchoscopy and/or lung biopsy. 
 If improves to Grade < 1: Taper steroids over at least 6 
weeks  
 If not improving after 48 hours or worsening: Add 
additional immunosuppression (for example, infliximab, 
cyclophosphamide, IV immunoglobulin, or mycophenolate 
mofetil)  


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RENAL irAEs 
Grade of Creatinine 
Increased 
Initial Management 
Follow-up Management 
Grade 1 
Continue pembrolizumab therapy 
 Continue renal function monitoring  
 If worsens: Treat as Grade 2, 3 or 4
Grade 2 to 3 
Withhold pembrolizumab therapy 
 
 Increase frequency of monitoring to every 3 days. If 
worsening or no improvement over 5-7 days, start 1.0 to 2.0 
mg/kg/day prednisone or equivalent. Consider renal biopsy. 
 If returns to Grade < 1: taper steroids over at least 1 month, 
and resume pembrolizumab therapy following steroids 
taper. 
 If worsens: Treat as Grade 4
Grade 4 
Permanently discontinue pembrolizumab therapy 
 Monitor creatinine daily 
 Start 1.0 to 2.0 mg/kg/day prednisone or equivalent. 
Nephrology consult. Consider renal biopsy. When Cr 
returns to Grade < 1: taper steroids over at least 1 month 
CARDIAC irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac 
signs or symptoms 
and / or new 
laboratory cardiac 
biomarker elevations 
(e.g. troponin, CK-
MB, BNP) or cardiac 
imaging abnormalities 
suggestive of 
myocarditis.  
 Withhold pembrolizumab therapy 
 Hospitalize. 
 In the presence of life threatening cardiac 
decompensation, consider transfer to a facility  
experienced in advanced heart failure and arrhythmia 
management 
 Cardiology consult to establish etiology and rule-out 
immune-mediated myocarditis.  
 Guideline based supportive treatment as per 
cardiology consult.* 
 Consider myocardial biopsy if recommended per 
cardiology consult.
 If symptoms improve and immune-mediated etiology is 
ruled out, re-start pembrolizumab therapy. 
 If symptoms do not improve/worsen, viral myocarditis is 
excluded, and immune-mediated etiology is suspected or 
confirmed following cardiology consult, manage as 
immune-mediated myocarditis. Permanently discontinue 
pembrolizumab. 
Immune-mediated 
myocarditis 
 Permanently discontinue pembrolizumab. 
 Prednisolone 1 to 2 mg/kg/day or equivalent. Once 
improving, taper steroids over at least 1 month. 


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 Guideline based supportive treatment as appropriate 
as per cardiology consult.*
 If no improvement or worsening, consider additional 
immunosuppressants (e.g. azathioprine, cyclosporine A)
*Local guidelines, or e.g. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
ENDOCRINE irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
 Continue pembrolizumab therapy.  
 Endocrinology consult if needed 
 
 Start thyroid hormone replacement 
 therapy (for hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for Type I diabetes mellitus) as 
appropriate. 
 Rule-out secondary endocrinopathies (i.e. hypopituitarism / 
hypophysitis). 
 Continue hormone replacement/suppression and monitoring 
of endocrine function as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
 Withhold pembrolizumab therapy. 
 Consider hospitalization and 
endocrinology consult 
 
 
 Start thyroid hormone replacement therapy (for 
hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for type I diabetes mellitus) as 
appropriate. 
 Rule-out secondary endocrinopathies  (i.e. hypopituitarism 
/ hypophysitis).  Resume pembrolizumab once symptoms 
and/or laboratory tests improve to Grade ≤ 1 (with or 
without hormone replacement/suppression). 
 Continue hormone replacement/suppression and monitoring 
of endocrine function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e.  
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately low 
ACTH): 
 
Refer to endocrinologist for dynamic 
testing as indicated and measurement 
 Resume pembrolizumab once symptoms and hormone tests 
improve to Grade ≤ 1 (with or without hormone 
replacement). 
 In addition, for hypophysitis with abnormal MRI, resume 
pembrolizumab only once shrinkage of the pituitary gland 
on MRI/CT scan is documented. 
 Continue hormone replacement/suppression therapy as 
appropriate.


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of other hormones (FSH, LH, GH/IGF-
1, PRL, testosterone in men, estrogens 
in women) 
 
Hormone replacement/suppressive 
therapy as appropriate 
 
Perform pituitary MRI and visual field 
examination as indicated 
If hypophysitis confirmed: 
 
Continue pembrolizumab if mild 
symptoms with normal MRI. Repeat 
the MRI in 1 month 
 
Withhold pembrolizumab if moderate, 
severe or life-threatening symptoms of 
hypophysitis and/or abnormal MRI. 
Consider hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 1 
month.
DERMATOLOGICAL irAEs 
Grade of Rash 
Initial Management 
Follow-up Management 
Grade 1 to 2  
 
 Continue pembrolizumab therapy  
 Symptomatic therapy (for example, 
antihistamines, topical steroids)  
 
If persists > 1 to 2 weeks or recurs:  
 Withhold pembrolizumab therapy. Consider skin biopsy. 
Consider 0.5 to 1 mg/kg/day prednisolone or oral 
equivalent.  
 Once improving, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume pembrolizumab therapy following 
steroids taper. 
 If worsens: Treat as Grade 3 to 4 
Grade 3 to 4 
 
 Withhold pembrolizumab for Grade 3. 
 Permanently discontinue for Grade 4 or 
recurrent Grade 3. 
 
 1 to 2 mg/kg/day prednisolone or equivalent.  
 Consider skin biopsy. Dermatology consult  
 If improves to < Grade 1: Taper steroids over at least 1 
month , resume pembrolizumab therapy following steroids 
taper (for initial Grade 3) 


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OTHER irAEs (not described above) 
Grade of other irAEs 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive of 
a potential irAE 
Withhold pembrolizumab therapy pending 
clinical investigation 
 If irAE is ruled out, manage as appropriate according to the 
diagnosis and consider re-starting pembrolizumab therapy 
 If irAE is confirmed, treat as Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold pembrolizumab therapy 
 
 For grade 2, monitor closely and start steroids if no 
improvement over 3-5 days. For grade 3, start steroids 
immediately. 
 1.0 to 2.0 mg/kg/day prednisone or equivalent 
 Consider specialty consult as appropriate. 
 If improves to Grade ≤ 1: taper steroids over at least 1 
month and resume pembrolizumab therapy following 
steroids taper.
Recurrence of same Grade 3 
irAEs 
Permanently discontinue pembrolizumab 
therapy 
 
 1.0 to 2.0 mg/kg/day prednisone or equivalent 
 Specialty consult as appropriate. 
 If improves to Grade ≤ 1: Taper steroids over at least 1 
month. 
Grade 4 
Permanently discontinue pembrolizumab 
therapy 
 
 1.0 to 2.0 mg/kg/day prednisone or equivalent and/or other 
immunosuppressant as needed 
 Specialty consult.  
 If improves to Grade ≤ 1: Taper steroids over at least 1 
month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
 Permanently discontinue 
pembrolizumab therapy 
 Specialty consult 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic 
peptide; CK-MB=creatine kinase MB; CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune-
related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for 
Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.


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6.3 
Management of Abemaciclib Associated Toxicities 
The most common treatment-related events associated with abemaciclib include diarrhea (63.0%), 
nausea (45.1%), fatigue (40.5%), vomiting (24.9%), white blood cell count decreased (24.9%), platelet 
count decreased (23.1%), neutrophil count decreased (22.5%), anemia (19.7%), anorexia (17.3%), 
creatinine increased (11.0%), and weight loss (10.4%). Dose reductions of abemaciclib are allowed to 
decrease treatment associated toxicities. Doses must be reduced sequentially by one dose level as 
detailed in Table 5. Mid-cycle dose reductions for abemaciclib may be implemented by informing 
patients to reduce the number of 50-mg capsules taken for each dose. For patients requiring a dose 
reduction of abemaciclib, any re-escalation to a prior dose level is permitted only after consultation with 
the study PI.  
 
Table 5. Abemaciclib Dose Modifications for Adverse Reactions 
Dose level 
Dose of Abemaciclib 
Starting Dose 
150 mg (PO), bid 
Dose level (-1) 
100 mg (PO), bid 
Dose level (-2) 
50 mg (PO), bid 
 Management of Abemaciclib Associated Diarrhea. 
Clinical trial data indicate that the majority of patients who receive abemaciclib will develop 
diarrhea. Early identification and intervention for the management of diarrhea is critical for safety 
and best symptom control.  Pembrolizumab can cause diarrhea as well, and it may be challenging to 
differentiate which drug is the culprit. In recent studies, abemaciclib was found to cause diarrhea 
early during treatment (69% of patients experienced diarrhea during cycle 1 in MONARCH 3 
study), and abemaciclib associated diarrhea was low grade (73% were grade 1 or 2 in MONARCH 3 
study)15. Per IB, median time to diarrhea onset ranged from 6 to 8 days in the abemaciclib 
registration studies. At the first onset of diarrhea we recommend following abemaciclib guidelines 
and treat diarrhea as presumed abemaciclib toxicity. In the event when it is very likely that that 
diarrhea is a pembrolizumab associated irAE in the opinion of a treating investigator (for example, 
it occurred after a few cycles of therapy on a stable dose of abemaciclib), pembrolizumab toxicity 
management guidelines in table 4 should be followed. However, even under these circumstances 
abemaciclib should be held for any diarrhea of grade 2 that lasts more than 24 hours. Abemaciclib 
should be not dosed until diarrhea is resolved to ≤ Grade 1. 
 
At enrollment, patients should receive instructions on the prompt management of diarrhea.  In the 
event of diarrhea, supportive care measures should be initiated as early as possible.  These include 
the following: 
 At the first sign of loose stools, the patient should initiate antidiarrheal therapy (e.g. loperamide) 
and notify the investigator for further instructions and appropriate follow-up. 
 Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids per day). 
 Site personnel should assess response within 24 hours.  
 Refer to Table 6 for additional information for diarrhea management and dose modifications 


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Table 6. Management of Abemaciclib Associated Diarrhea 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1  
No dose modification is required.  
Grade 2 
If toxicity does not resolve within 24 hours to ≤ Grade 1, 
suspend treatment until resolution. No dose reduction is 
required. 
Grade 2 that persists > 3 days or 
recurs after resuming the same dose 
despite maximal supportive measures
 Suspend dose until toxicity resolves to ≤Grade 1. 
 Resume at next lower dose. 
Grade 3 or 4 or requires 
hospitalization 
 Suspend dose until toxicity resolves to ≤Grade 1. 
 Resume at next lower dose. 
 Increases in Serum Creatinine and Assessment of Renal Insufficiency 
Elevation of serum creatinine is observed with abemaciclib and is due to a pharmacological inhibitory 
effect of abemaciclib on renal tubular transporters without affecting glomerular function. The rise in 
serum creatinine (mean increase, 0.2 mg/dL) occurs within the first 28 days while on abemaciclib 
treatment and remains elevated but stable throughout the treatment period.  This rise in creatinine is 
reversible upon treatment discontinuation. Alternative markers (such as BUN, cystatin C level, or 
cystatin C calculated GFR) which are not based on creatinine may be considered to determine whether 
renal function is impaired.  
 General Guidance for Hepatic Monitoring 
Elevations in liver enzymes may be seen with abemaciclib use. Liver function tests must be checked 
prior to abemaciclib therapy, twice per cycle during the first 3 cycles of treatment, and at the beginning 
of each cycle afterwards. Management of ALT and AST elevation associated with abemaciclib use is 
detailed in Table 7 below.  Of note, both study agents can cause liver tests abnormalities, and it may be 
challenging to decipher which on is the culprit. Abemaciclib associated liver toxicities tends to occur 
earlier in the treatment course. In a situation when it is impossible to tell which drug is the culprit, 
patient should be treated for possible irAE as detailed in table 4. Both drugs should be held for any LFT 
elevation of grade 2 or above.  
 
Table 7. Management of Abemaciclib Associated ALT and/or AST Elevation.  
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 (>ULN-3.0 x ULN) 
No dose modification or interruption is required. 
Grade 2 (>3.0-5.0 x ULN) 
Hold abemaciclib. Check weekly labs. Resume at 
prior doses when grade ≤1.
Persistent (≥ 21 days) or Recurrent Grade 2, 
or Grade 3 (>5.0-20.0 x ULN) that does not 
resolve with maximal supportive measures 
within 7 days to baseline or Grade 1 
 Suspend dose until toxicity resolves to baseline or 
Grade 1. 
 Resume at next lower dose. 
Grade 4 (>20.0 x ULN) 
Discontinue abemaciclib. 


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To ensure patient safety, labs detailed in Table 8 should be collected in subjects with documented 
hepatotoxicity of any grade. These labs should be checked at the onset of elevated liver function tests 
(LFTs). LFTs should be checked weekly until treatment is restarted per table above.  
Table 8. Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality. 
 
Hepatic Hematology 
Hepatic Chemistry 
Hepatic Serologiesa 
Hemoglobin 
Total bilirubin
Hepatitis A antibody, total
Hematocrit 
Direct bilirubin 
Hepatitis A antibody, IgM
RBC 
Alkaline phosphatase
Hepatitis B surface antigen
WBC 
ALT
Hepatitis B surface antibody
Neutrophils, segmented and bands 
AST 
Hepatitis B Core antibody 
Lymphocytes 
GGT 
Hepatitis C antibody 
Monocytes 
CPK
Hepatitis E antibody, IgG
Eosinophils 
 
Hepatitis E antibody, IgM
Basophils 
 
Platelets 
Hepatic Coagulation 
Anti-nuclear antibody 
 
Prothrombin Time
Anti-actin antibody 
Haptoglobin 
Prothrombin Time, INR
Anti-smooth muscle antibody
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells. 
a Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
 Management of Abemaciclib Associated Hematologic Toxicity 
Hematologic toxicities including neutropenia, leukopenia, anemia, and thrombocytopenia have been 
observed in patients treated with abemaciclib, and causality has been established.  Severe (Grade 3 and 
4) neutropenia has been observed in patients receiving abemaciclib. Complete blood count (CBC) must 
be checked prior to abemaciclib therapy, twice per cycle during the first 3 cycles of treatment, and at the 
beginning of each cycle starting with cycle 4. CBC should include WBC, ANC, hgb and plts. Patients 
should be monitored closely for signs of infection, anemia, and bleeding. Table 9 provides general 
guideline on management of hematologic toxicities. 
Table 9. Management of Abemaciclib Associated Hematologic Toxicities 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required.
Grade 3 
Suspend dose until toxicity resolves to ≤ Grade 2. 
Dose reduction is not required.
Grade 3, recurrent, or Grade 4 
Suspend dose until toxicity resolves to ≤ Grade 2. 
Resume at next lower 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.
 
 


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 General Guidance for Management of Abemaciclib Associated Non-hematologic Toxicities 
(excluding diarrhea and increased ALT and/or AST)  
 Grade 1 or 2:  No dose modification is required. 
 Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures 
within 7 days to baseline or Grade 1: suspend dose until toxicity resolves to baseline or Grade 1. 
Resume at next lower dose. 
 Grade 3 or 4: suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower 
dose. 
Table 10. Management of Abemaciclib Toxicities (excluding diarrhea and ALT/AST) 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required. 
Persistent or recurrent Grade 2 toxicity that 
does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1 
Suspend dose until toxicity resolves to baseline 
or Grade 1. 
Resume at next lower dose. 
Grade 3 or 4 
6.4 
Dose Delays/Dose Modifications 
Unless otherwise noted in the dose modification tables above, treatment may be delayed ≤ 6 weeks from 
the expected day of the next treatment for any reason.  If treatment is delayed ≤ 6 weeks, subjects will 
proceed with the next cycle of treatment at the dose level recommended according to the toxicity dose 
modifications detailed in sections 6.2 and 6.3.  If pembrolizumab treatment is held, abemaciclib may be 
continued with daily dosing as per toxicity management guidelines outlined in section 6.3. Given that 
abemaciclib is taken on a continuous basis, the beginning of each cycle will be determined by the timing 
of the pembrolizumab infusion, i.e. if pembrolizumab is delayed by 7 days, the prior cycle will be 28 
days if abemaciclib is continued. Held or missed doses of abemaciclib will not be made up if it is 
stopped before the 21-day cycle completion.  If a subject is able to resume/continue only one of the 
drugs because of prior AEs, he/she may continue on single agent therapy if there is clinical benefit in the 
opinion of the treating investigator and after the discussion with the study PI.  
6.5 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a subject will 
also be discontinued from protocol therapy and followed up per protocol under the circumstances 
outlined below. The reason for discontinuation of protocol therapy will be documented on the electronic 
case report form (eCRF). 
 
Documented disease progression via RECIST or irRECIST (see section 9 for additional details) 
 
The treating physician thinks a change of therapy would be in the best interest of the subject 
 
The subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or for 
other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), the 
subject should be asked if he or she may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be documented in both the medical 
records and in the eCRF. 


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 
A female subject becomes pregnant. Cases of pregnancy that occur during maternal exposures to 
abemaciclib should be reported. If a patient or spouse/partner is determined to be pregnant 
following abemaciclib initiation, she must discontinue treatment immediately. Data on fetal 
outcome and breast-feeding are to be collected for regulatory reporting and drug safety 
evaluation.  
 
If protocol therapy is interrupted for > 6 weeks from the expected day of the next treatment.  
6.6 
Definition of Evaluable Subject 
Evaluable for response: Any subject who receives at least 75% of abemaciclib during the first 2 cycles 
(i.e. at least 63 of 84 doses of abemaciclib) and 2 doses of pembrolizumab during the first two cycles of 
treatment will be evaluable for response. 
 
Evaluable for toxicity: Any subject who receives at least one dose of treatment on this protocol should 
be evaluable for toxicity. Safety will be assessed the National Cancer Institute (NCI) CTCAE version 5. 
6.7 
Protocol Discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts should be 
made to complete the final study assessments. The site study team should contact the subject by 
telephone or through a clinic visit to determine the reason for the study withdrawal. If the reason for 
withdrawal is an adverse event, it will be recorded on the eCRF. 


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7. 
STUDY CALENDAR & EVALUATIONS 
Cycle = 21 days
Screen 
Cycle 12 
Cycle 2-32 
Cycle 4+2 
Safety 
follow up2,3
Long-term 
Follow up4
-28 days1 
D12
D8 
D1 
D8 
D1 
30 days post 
last dose
Q 3 months 
(±14 days)
REQUIRED ASSESSMENTS 
 
Informed consent 
X
 
Patient demographics 
X
 
Medical history5 
X
 
Diagnosis and Staging6 
X
 
Physical exam, height (screen only), weight
X
X
X 
X
X
Vital signs, ECOG Performance status7
X
X
X
X 
X
X
AEs & concomitant medications 
X
X
X
X 
X
X
Drug Diary review 
X
X
X 
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count (CBC)8
X
X1
X
X 
X
X
X
Comprehensive Metabolic Profile (CMP)8,9
X
X1
X 
X
X
TSH, Free T410 
X
X 
X
AST, ALT, Total Bilirubin 
X
 
X
Cortisol10 
X 
 
 
X 
 
X 
 
 
Pregnancy test (serum or urine) WOCBP11
-7 days
 
DISEASE ASSESSMENT12 
 
CT or MRI of chest, abdomen, and pelvis12
X
 
Q3 cycles12
X12
TREATMENT EXPOSURE 
 
Abemaciclib 
 
Pembrolizumab  
X
X 
X
CORRELATIVE SPECIMEN COLLECTION
 
Archival Tissue for PD-L1, NGS or prior results13
X
 
Saliva for Microbiome14 
X
 
pre-C4
X
Plasma for ctDNA15 
X
 
pre-C4
X
BANKING SPECIMEN COLLECTION 
 
Unstained Slides (if available)16 
X
 
Whole Blood17 
X
 
pre-C4
X
Serum and Plasma17 
X
 
pre-C4
X
FOLLOW-UP 
 
Survival status, subsequent therapy 
 
X


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Key to Footnotes  
1If screening (baseline) labs were performed within 7 days of D1 of treatment these do not need to be repeated. 
2A window of 3 days will be applied to all treatment study visits (with the exception of tumor imaging, see footnote 12). 
3The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, or at 
discretion of site investigator) and should be performed within 30 days (+/-7 days) after the last dose of treatment. All AEs considered related to 
study drug(s) will be followed until the AE resolves to ≤ grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever is earlier. 
4Long-term follow up will occur every 3 months (90 days) starting after safety follow up visit for up to 2 years and may be conducted via 
telephone. Subjects who have ongoing Grade 4 AE or SAE at the time of discontinuation from treatment, and those who come off treatment 
prematurely for safety reasons will continue to be followed until the event is resolved or deemed irreversible by the site investigator. 
5Medical history to include demographics, prior treatments, radiation and surgical history, previous PD-L1 testing results, previous NGS testing 
results. 
6Diagnosis and staging to include pathology report. 
7Vital signs to include blood pressure, heart rate, weight, and height (screening only) and ECOG performance status. 
8If labs are drawn within the time window allotted, but do not meet criteria for treatment, they can be repeated and can be used for treatment 
decisions. 
9CMP to include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium. 
10Cortisol, TSH and free T4 should be checked during screening and before each odd cycle starting with cycle 3.  
11For women of childbearing potential: serum βhCG within 7 days prior to treatment initiation if clinically appropriate. 
12Tumor response assessment will consist of evaluation by CT or MRI scans of chest, abdomen and pelvis. Additional imaging scans may be 
performed as clinically indicated in the opinion of the treating physician. Assessments will be performed at screening, and every 3 cycles starting 
with cycle 4. Tumor imaging may take place within 7 days prior to the study visit. Tumor imaging to be done at treatment discontinuation due to 
progression. If tumor assessments are available for subjects who have not yet experienced progressive disease (PD) at the time treatment is 
discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD or death is confirmed, or until another treatment is 
initiated. 
13If prior PD-L1 and NGS testing was performed, submit results. If prior PD-L1 and NGS testing has not been performed, it should be ordered as 
standard of care. If testing cannot be performed as standard of care, fixed paraffin-embedded blocks or unstained slides will be requested from 
tumor specimen in all subjects, if available. See section 8 and CLM. 
14Saliva samples for microbiome analysis will be collected before Cycle 1 Day 1, Cycle 4 Day 1 and at EOT visit. 
15Plasma samples for ctDNA analysis will be collected before Cycle 1 Day 1, Cycle 4 Day 1 and at EOT visit. 
16Fixed paraffin-embedded blocks or unstained slides will be requested from tumor specimen in all subjects (optional). 
17Whole blood, serum, and plasma samples for circulating biomarkers (to be specified at a later time point) will be collected before Cycle 1 Day 1, 
Cycle 4 Day 1 and at EOT visit (optional). 


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7.1 
Screening Evaluations 
 Within 28 days prior to registration for protocol therapy 
 Informed Consent 
 Medical history to include demographics, prior treatments, radiation and surgical history 
 Physical exam 
 Vital signs: blood pressure, heart rate, weight and height 
 ECOG performance status 
 Baseline signs and symptoms 
 Concomitant medications 
 Complete blood count (CBC): hematocrit, hemoglobin, total white cell count with differential, 
and platelet count. 
 Comprehensive metabolic panel (CMP): albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, 
sodium. 
 Thyroid stimulating hormone (TSH) and free T4. 
 Cortisol level 
 Within 7 days of Cycle 1 Day 1 serum βhCG pregnancy test for women of childbearing potential 
(WOCP).   
 Disease assessment to include evaluation by CT or MRI scans of chest, abdomen and pelvis. 
Additional imaging scans may be performed as clinically indicated in the opinion of the treating 
physician. 
7.2 
On Treatment Evaluations 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting protocol 
therapy. 
 Cycle 1 Day 1 
 Physical exam 
 Vital signs: blood pressure, heart rate, weight 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 
 Drug diary instructions 
 CBC with differential 
 CMP 
 Abemaciclib Days 1-21, bid 
 Pembrolizumab IV Day 1 
 Cycle 1, Day 8 (±3 days) 
 Vital signs: blood pressure, heart rate 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 


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 Drug diary instructions 
 CBC with differential 
 AST, ALT, total bilirubin 
 Cycle 2+, Day 1 (±3 days) 
 Physical exam 
 Vital signs: blood pressure, heart rate, weight 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 
 Drug diary review 
 CBC with differential 
 CMP 
 TSH, free T4 (on day 1 of odd numbered cycles only, starting with cycle 3) 
 Cortisol (on day 1 of odd numbered cycles only, starting with cycle 3) 
 Abemaciclib (Days 1-21, bid) 
 Pembrolizumab Day 1 
 Cycle 2 and 3, Day 8 (±3 days) 
 CBC with differential 
 AST, ALT, total bilirubin 
 Every 3 Cycles (±7 days) starting with Cycle 4 Day 1  
 Disease assessment with CT or MRI scans of chest, abdomen and pelvis. Additional scans may 
be ordered by the treating physicians as clinically indicated and depending on the known sites of 
disease. 
 Safety Follow-up Evaluations: 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated 30 days (± 
7) after the last dose of study drug or before the initiation of a new anti-cancer treatment, whichever 
comes first. 
 Physical exam 
 Vital signs: blood pressure, heart rate, weight 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 
 CBC with differential 
 CMP 
 Long Term Follow Up (every 90 days +/- 14 days) from Safety Follow Up Visit 
Subjects will be followed for survival and disease progression after completing the end of treatment 
visit.  Survival follow up should continue for 2 years (+/- 2 months) after EOT visit or until death, 
whichever is sooner.  When possible, the following information will be obtained: 
 Date of disease progression (if known) 
 Anti-cancer therapy received since EOT visit 


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 Date of death 
 
Follow up may be accomplished via clinic visit, phone call, medical record review, or other avenues as 
appropriate. 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please refer to the Correlative Laboratory Manual for collection, processing, and shipping details. 
8.1 
Correlative Studies from Tissue 
 PD-L1 Immunohistochemistry (IHC) 
All subjects would ideally have had standard of care PD-L1 testing using PD-L1 22C3 pharmDx 
qualitative immunohistochemical assay.  Assessment of PD-L1 in gastroesophageal cancer is determined 
using combined positive score (CPS). CPS represents percentage of all cells in tumor microenvironment 
that express PD-L1 (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells.  
 
If PD-L1 testing has been performed prior to study enrollment, results should be submitted. If subjects 
have not had PD-L1 testing done, it should be ordered as standard of care with the 22C3 antibody, if 
possible. The results will be collected for further correlative evaluations. If PD-L1 results with 22C3 
antibody are not available, archival tissue samples should be submitted if available.  
 Tumor Molecular Profiling via Next Generation Sequencing 
All subjects would ideally have had standard of care NGS testing already performed. If NGS testing has 
been performed prior to study enrollment, results should be submitted. If subjects have not had NGS 
testing done, it should be ordered as standard of care if possible. The results will be collected for further 
correlative evaluations. If NGS cannot be performed as standard of care, archival tissue samples should 
be submitted if available.  
 Circulating Biomarkers 
8.1.3.1 Plasma for Circulating Tumor DNA (ctDNA) 
Plasma samples will be collected for ctDNA analysis prior to treatment on Cycle 1 Day 1, prior to 
treatment on Cycle 4 Day 1 visit, to coincide with restaging scans, and at EOT visit. 
 Saliva Collection 
Saliva samples will be collected for microbiome analysis prior to treatment on Cycle 1 Day 1, prior to 
treatment on Cycle 4 Day 1 visit, to coincide with restaging scans, and at EOT visit. 
 Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific correlative 
research. Hoosier Cancer Research Network (HCRN), as Administrative Headquarters for the Big Ten 
CRC, will manage the banked samples. Samples will be banked indefinitely in the Hoosier Cancer 
Research Network Biorepository and used for future unspecified cancer-related research.  


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8.2 
Sample Collection and Banking for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified Big Ten Cancer 
Research Consortium studies. HCRN will manage the banked samples. Samples will be banked 
indefinitely in the HCRN Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1, before Cycle 4 
Day 1, and at EOT visit.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment on 
Cycle 1 Day 1, prior to treatment on Cycle 4 Day 1 visit, to coincide with restaging scans, and at 
EOT visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on Cycle 
1 Day 1, prior to treatment on Cycle 4 Day 1 visit, to coincide with restaging scans, and at EOT visit. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin fixed 
paraffin embedded tumor sample if available. Repeat biopsy will not be mandatory if archival tumor 
tissue is not available.  
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, labeling, 
and shipping instructions. 
8.3 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and only 
identified by the subject’s Big Ten CRC sequence number. 
9. 
CRITERIA FOR DISEASE EVALUATION 
9.1 
Overview 
Both RECIST 1.1 and irRECIST will be used for disease evaluation. RECIST has some limitations 
when applied to immunotherapy and oncology. Tumors that initially progress per RECIST may 
subsequently regress. As such, in cases of radiologic progression per RECIST 1.1 but with clinical 
stability or benefit, irRECIST criteria will be applied. Subjects may continue on treatment past 
radiological progression on the first set of restaging scans. Disease status will be re-evaluated with 
repeat scans 4-9 weeks later compared to new baseline established on treatment.  
9.2 
Timing of Radiographic Evaluations 
All subjects will undergo serial radiographic assessments to assess tumor response. Initial tumor 
imaging at screening must be performed within 28 days prior to the date of the first dose of study 
treatment. Scans performed prior to the signing of the ICF as part of routine clinical management are 
acceptable for use as initial tumor imaging if they are of diagnostic quality and performed within 28 
days prior to first dose date. 
 
The first on-study imaging assessment should be performed prior to initiation of cycle 4. Subsequent 
tumor imaging should be performed every 3 cycles (±7 days) or more frequently if clinically indicated 
and at the time of suspected disease progression.   


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Per RECIST v1.1, complete response (CR) or partial response (PR) should be confirmed by a repeat 
tumor imaging assessment. The tumor imaging for confirmation of response may be performed at the 
earliest 4 weeks after the first indication of response, or at the next scheduled scan (i.e., 3 cycles after 
the previous scan), whichever is clinically indicated. Additionally, progressive disease (PD) should also 
be confirmed a minimum of 4 weeks and up to 9 weeks after the first PD assessment; patients may 
remain on study treatment while awaiting confirmation provided the patient is clinically stable. 
 
Subjects who discontinue treatments for reasons other than disease progression (clinical or radiographic) 
will not be required to continue getting imaging per schedule outlined in the protocol. 
9.3 
Assessment of Response per RECIST 
 Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable lesions are 
defined as those that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  If 
lymph nodes are to be included in the sum, then only the short axis is added into the sum.  The baseline 


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sum diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline.  Measurements 
of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up. 
 Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to  
<10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
 Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 
mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they 
must normalize for a subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the sponsor investigator. 
 


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 Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
9.4 
Assessment of Response by Immune-Related RECIST 
RECIST v1.1 will be adapted to account for the unique tumor response characteristics seen 
during treatment with CTLA-4 and PD-1/PD-L1 inhibitors. irRECIST will be used by local site 
investigators to assess tumor response and progression and make treatment decisions. 
 
irRECIST adaptations compared to RECIST v1.1: 
 If repeat imaging shows < 20% increase in tumor burden compared with nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved non-target disease (if 
identified as cause for initial PD), treatment may be continued / resumed, and the next tumor 
imaging should be conducted according to the protocol schedule of every 3 cycles (± 7 days)  
 If repeat imaging confirms PD due to any of the scenarios listed below, patients will be discontinued 
from study therapy. In determining whether or not the tumor burden has increased or decreased per 
irRECIST, the local site Investigator should consider all target and non-target lesions, as well as any 
incremental new lesion(s). 
 
 


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If ANY of the following occur by irRECIST on repeat imaging, PD is confirmed: 
 Tumor burden remains ≥ 20% and at least 5-mm absolute increase compared with nadir 
 Non-target disease resulting in initial PD is worse (qualitative) 
 New lesion resulting in initial PD is worse (qualitative) 
 Additional new lesion(s) since last evaluation 
 Additional new non-target progression since last evaluation 
 
Table 10: Imaging and Treatment after First Radiologic Evidence of Progressive Disease via irRECIST 
Tumor Assessment 
Confirmation of Response 
irCR 
Disappearance of all measurable and non-measurable 
lesions. Lymph nodes must have reduction in short axis 
to < 10 mm. 
Required 
irPR 
At least 30% decrease in the sum of diameters of 
measurable lesions, taking as reference the baseline sum 
diameters. 
Required 
irSD 
Shrinkage does not qualify for irCR/irPR or increase 
does not qualify for irPD. 
Nor required 
irPD 
At least 20% increase and absolute increase of at least 5 
mm in sum of the diameters of measurable lesions. The 
appearance of new lesions is not considered PD but are 
to be included in the sum diameters. 
Confirmation required at least 4 
weeks after the first irPD 
assessment provided the patient 
is considered clinically stable 
Abbreviations: irCR=immune-related complete response; irPR=immune-related partial response; 
irSD=immunerelated 
stable disease; irPD=immune-related progressive disease; PD=progressive disease 
9.5 
Treatment and Assessment After Progression 
There is accumulating evidence indicating clinical benefit in a subset of patients treated with 
immunotherapy despite initial evidence of PD per RECIST. During study treatment, a subject with 
initial evidence of radiological PD per RECIST may continue on study treatment until repeat imaging is 
obtained (at least 4 weeks and up to 9 weeks later). Investigator’s decision to continue treatment beyond 
the initial assessment of progression should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data. A subject may receive study 
treatments while waiting for confirmatory imaging if he/she is clinically stable per the following criteria: 
 Absence of signs and symptoms indicating clinically significant progression of disease, including 
worsening of laboratory parameters 
 No decline in performance status 
 Does not have rapid progression of disease 
 Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases, cord compression) 
 
 Whenever possible, patients should not be discontinued until progression is confirmed. 


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9.6 
Definitions for Response Evaluation – RECIST 1.1 and irRECIST 
 Progression-Free Survival 
A measurement from the date of the start of treatment until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs.  PFS will also be measured as the time of first documentation of 
disease progression per irRECIST as a secondary endpoint. 
 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according to 
RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 6 months PFS Rate  
6 months PFS rate is defined as the proportion of subjects who have experienced no progressive disease 
at a 6 month time point from time of treatment initiation using RECIST and irRECIST criteria.  
 Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 16 weeks, or partial 
response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the start of treatment). RECIST and irRECIST criteria will be applied 
 Overall Survival 
Overall survival is defined by the date of the start of treatment to date of death from any cause. 
9.7 
Safety and Tolerability 
Safety and tolerability of abemaciclib in combination with pembrolizumab by NCI CTCAE version 5.   
10. 
DRUG INFORMATION 
10.1 
Abemaciclib (Other names: VERZENIO™) 
Please refer to the latest version of the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and/or on the manufacturer’s website. 
 
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are 
activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin 
D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and 
cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and 
blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In 
breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in 
combination with antiestrogens resulted in reduction of tumor size.  
 Supplier/How Supplied 
Eli Lilly and Company will supply abemaciclib at no charge to subjects participating in this clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 


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 Preparation  
Please refer to the package insert for instructions on preparation of abemaciclib.  
 Storage and Stability 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).  
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 Handling and Disposal 
Please refer to the package insert for instructions on proper handling of abemaciclib. 
 Dispensing 
Abemaciclib must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Abemaciclib should be stored in a secure area according to local 
regulations.  It is the responsibility of the site investigator to ensure that study drug is only dispensed to 
subjects.   
 Adverse Events 
Most common adverse reactions (incidence ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, 
infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia. 
Please refer to the package insert for the comprehensive list of adverse events. 
 
10.2 
Pembrolizumab (other names: KEYTRUDA®, MK-3475, Anti-PD-1 Antibody MK-3475) 
Please refer to the latest version of the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and/or on the manufacturer’s website. 
 
Pembrolizumab is a highly selective humanized monoclonal IgG4 antibody directed against the 
programmed death-1 (PD-1) receptor on the cell surface. The drug blocks the PD-1 receptor, preventing 
binding and activation of programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). 
This mechanism causes the activation of T-cell mediated immune responses against tumor cells. 
 Supplier/How Supplied 
Commercial supplies of pembrolizumab will be used in this study and billed to third party payers or the 
subject.   
 Pembrolizumab for injection is supplied as a white to off-white lyophilized powder: carton 
containing one 50 mg single-dose vial.  
 Pembrolizumab injection is supplied as a clear to slightly opalescent, colorless to slightly yellow 
solution: carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial. 
 Preparation  
Please refer to the package insert for instructions on preparation of pembrolizumab.  


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 Storage and Stability 
Pembrolizumab does not contain a preservative. Store vials under refrigeration at 2°C to 8°C (36°F to 
46°F). 
 
Store the reconstituted and diluted solution from the KEYTRUDA 50 mg vial either: 
 At room temperature for no more than 6 hours from the time of reconstitution. This includes room 
temperature storage of reconstituted vials, storage of the diluted solution, and the duration of 
infusion. 
 Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
 
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: 
 At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the diluted solution, and the duration of infusion. 
 Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
dilution. 
 
If refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard 
after 6 hours at room temperature or after 24 hours under refrigeration. Do not freeze. 
 Handling and Disposal 
Please refer to the package insert for full instructions on proper handling of pembrolizumab. 
 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. Pembrolizumab should be disposed at the site following procedures 
for the disposal of anticancer drugs. 
 Adverse Events 
Most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, 
decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and 
abdominal pain. For more detailed information on adverse reactions, warnings, and precautions please 
refer to the pembrolizumab package insert. 
11. 
ADVERSE EVENTS 
11.1 
Definitions 
 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug that 
appears to change in intensity during the course of the study. The following are examples of AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 


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Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical signs or 
symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE (e.g., 
surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen by the 
site investigator. 
 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a SAE, 
unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as administration 
of chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; 
or the development of drug dependency or drug abuse. 
 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency from 
information provided in the current IB, package insert, or when it is not included in the informed 
consent document as a potential risk. Unexpected also refers to AEs that are mentioned in the IB as 
occurring with a class of drugs or are anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation.   
 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  


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Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
11.2 
Reporting 
 Adverse Events 
 AEs will be recorded from time of signed informed consent until 30 days after discontinuation of 
study drug(s). 
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 Asymptomatic laboratory abnormalities that do not require treatment will not be collected as 
adverse events. 
 
 Serious Adverse Events (SAEs) 
Site Requirements for Reporting SAEs to Big Ten CRC Administrative Headquarters 
 SAEs will be reported from time of signed informed consent until 30 days after discontinuation 
of study drug(s).  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the EDC 
system within 1 business day of discovery of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
The site will submit the completed SAE Submission Form (see SPM) to Big Ten CRC AHQ within 1 
business day of discovery of the event.  The form will be sent electronically to Big Ten CRC AHQ at 
safety@hoosiercancer.org.  The site investigator is responsible for informing the IRB and/or other local 
regulatory bodies of the SAE as per local requirements. 
 
The original copy of the SAE Submission Form and the email correspondence must be kept within the 
study file at the study site. 
 
Once the SAE has resolved, sites must electronically submit a follow up SAE Submission Form within a 
reasonable timeframe to Big Ten CRC AHQ at safety@hoosiercancer.org. 


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Big Ten CRC AHQ Requirements for Reporting SAEs to Eli Lilly and Company  
Big Ten CRC AHQ will report SAEs to Eli Lilly and Company within 1 business day of receipt of the 
SAE Reporting Form from a site.  Follow-up information will be provided to Eli Lilly and Company as 
it is received from a site.   
 
Big Ten CRC AHQ will fax all SAE reports and any other relevant safety information to Eli Lilly and 
Company (Attn: Global Patient Safety; FAX 866-644-1697 or 317-453-3402). 
 
Big Ten CRC AHQ will provide follow-up information to Eli Lilly and Company Global Patient Safety 
as reasonably requested.  
Sponsor-Investigator Responsibilities 
Big Ten CRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
Big Ten CRC AHQ Responsibilities for Reporting SAEs to FDA 
The FDA has concluded this protocol is exempt from the requirements of an IND. Big Ten CRC AHQ 
will continue to facilitate compliance of applicable requirements for the sponsor-investigator in relation 
to this study. This includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, 
and pertinent sections of the Public Health Service Act and FDAAA. 
IND Safety Reports Unrelated to this Trial 
Eli Lilly and Company will provide Big Ten CRC AHQ with IND safety reports from external studies 
that involve the study drug(s) per their guidelines. Big Ten CRC AHQ will forward the safety reports to 
the sponsor-investigator who will review these reports and determine if revisions are needed to the 
protocol or consent.  Big Ten CRC AHQ will forward these reports to participating sites within 1 
business day of receiving the sponsor-investigator’s review. Based on the sponsor-investigator’s 
review, applicable changes will be made to the protocol and informed consent document (if required). 
All IND safety reports will also be made available to sites via the EDC system. 
 
Upon receipt from Big Ten CRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
12. 
STATISTICAL METHODS 
12.1 
Study Design 
This is a multi-institutional Big Ten CRC single arm, phase II study of the combination of abemaciclib 
and pembrolizumab in subjects with advanced, unresectable or metastatic gastric, gastroesophageal 
junction, or esophageal adenocarcinoma.  
12.2 
Endpoints 
 Primary Endpoints 
 PFS is defined as the time of treatment initiation until the criteria for disease progression per 
RECIST1.1 are met or until the date of a death event (any cause).  


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 Secondary Endpoints 
 OS is defined as the time of treatment initiation until death from any cause.  
 ORR as measured as percent of patients who achieved objective response per RECIST 1.1 and 
irRECIST criteria while on treatment 
 DCR is defined as percent of patients with stable disease, partial response and complete response 
after treatment initiation per RECIST 1.1 and irRECIST. 
 PFS per irRECIST is defined as the time of treatment initiation until the criteria for disease 
progression per irRECIST are met or until the date of a death event (any cause). 
 PFS rate at 6 months (RECIST and irRECIST) is defined as the percent of patients without a 
progression (or death event) at month 6 after treatment initiation.   
 Safety and tolerability of abemaciclib in combination with pembrolizumab in patients with 
advanced, unresectable or metastatic gastric, gastroesophageal junction, or esophageal 
adenocarcinoma, assessed by NCI CTCAE version 5. 
12.3 
Sample Size and Accrual 
The primary efficacy endpoint is used to determine the sample size for this study. The primary efficacy 
endpoint is PFS.  A median PFS of 2 months has been reported in this patient population in patients 
treated with pembrolizumab alone. If the addition of abemaciclib results into a median PFS at most 2 
months, then the efficacy of the proposed combination therapy will be considered as unacceptably low. 
Hence, the null hypothesis that the median PFS is 2 months or less will be tested against the alternative 
hypothesis that the median PFS is greater than 2 months. A median PFS of at least 4 months will be 
considered sufficient evidence to consider further clinical investigation of the proposed treatment 
combination. A sample size of 31 evaluable subjects is required to detect an increase in the median PFS 
from 2 months (null hypothesis) to 4 months with 80% power at the one-sided 0.05 significance level. 
This calculation is based on the non-parametric Brookmeyer-Crowley method for time to event 
endpoints16, assuming that the accrual follows a uniform distribution with an accrual period of 12-18 
months and a minimum follow-up period of 6 months for each subject. Analogously, a median PFS of 5 
months will be detected with 92% power while a median PFS of only 3 months will be detected with 
51% power. In order to account for non-evaluable subjects (~10%), a total of 34 subjects will be 
enrolled. 
12.4 
Assessment of Safety 
The safety population consists of all eligible study participants who received at least one dose of 
abemaciclib or pembrolizumab. Toxicities will be defined by the NCI Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v5. 
12.5 
Assessment of Efficacy 
The efficacy population consists of all evaluable study participants. A study participant is evaluable for 
efficacy assessment if (1) the subject completes at least one cycle of the abemaciclib (Day 1-
21)/pembrolizumab (Day 1) therapy and (2) and completes at least one post-baseline disease assessment. 


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12.6 
Data Analysis Plans 
 Analysis Plans for Primary Objective 
PFS will be analyzed using the Kaplan-Meier method. The median PFS will be reported along with the 
corresponding two-sided 95% confidence interval which will be constructed using the non-parametric 
Brookmeyer-Crowley method16. 
 Analysis Plans for Secondary Objectives 
OS will be analyzed using the Kaplan-Meier method. The median OS will be reported along with the 
corresponding 95% confidence interval which will be constructed using the non-parametric 
Brookmeyer-Crowley method16. ORR, DCR, and PFS rate at 6 months will be summarized in tabular 
format and reported along with the corresponding two-sided 95% confidence intervals which will be 
constructed using the Wilson score method. The number and frequencies of toxicities will be 
summarized in tabular format. 
 Analysis Plans for Exploratory Objectives 
Univariable and multivariable Cox proportional hazard regression analyses will be conducted to evaluate 
whether PD-L1 status and molecular signatures from NGS analysis predict PFS or OS. Analogously, 
univariable and multivariable Cox proportional hazard regression analyses will be conducted to evaluate 
whether PD-L1 status and molecular signatures from NGS analysis predict ORR, DCR or PFS rate at 
month 6. Age, disease type, stage, performance status and tumor CSP score (0 vs. 1-9 vs. 10+) will be 
included as covariates in the multivariable analyses. Due to the small sample size, these analyses will be 
considered exploratory. 
 Other Planned Analyses  
Descriptive statistics will be provided to summarize demographics and baseline characteristics 
parameters of all study participants. Categorical data will be summarized as frequency and its 
corresponding percentage. For continuous data, frequency (n), mean, standard deviation, median (as 
appropriate), minimum, and maximum will be provided for each of the parameters. 
13. 
TRIAL MANAGEMENT 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The University of Wisconsin Carbone Cancer Center’s Data Safety Monitoring committee will oversee 
the conduct of this study. 
 
Big Ten CRC AHQ oversight activities include: 
 Review all adverse events requiring expedited reporting as defined in the protocol 
 Notify participating sites of adverse events requiring expedited reporting 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator 
 Submit data summary reports to the lead institution Data Safety Monitoring Committee for review as 
per their DSMP 
13.2 
University of Wisconsin Data Safety Monitoring Committee  
The DSMC will review the following: 


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 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The University of Wisconsin DSMC will review AE data twice a year.  Documentation of DSMC 
reviews will be provided to sponsor-investigator and Big Ten CRC AHQ. Issues of immediate concern 
by the DSMC will be brought to the attention of the sponsor-investigator and other regulatory bodies as 
appropriate.  The sponsor-investigator will work with Big Ten CRC AHQ to address the DSMC’s 
concerns.   
13.3 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the life 
cycle of the study. A summary report (QC Report) of these checks together with any queries resulting 
from manual review of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel. 
 
Monitoring visits to the trial sites will be made periodically during the trial to ensure key aspects of the 
protocol are followed. On-site for-cause monitoring visits will occur as necessary. Source documents 
will be reviewed for verification of agreement with data entered into the EDC system.  It is important for 
the site investigator and their relevant personnel to be available for a sufficient amount of time during 
the monitoring visits or audit, if applicable. The site investigator and institution guarantee access to 
source documents by Big Ten CRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by Eli Lilly and Company or its designee as 
well as inspection by appropriate regulatory agencies. 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All results of primary and 
secondary objectives must be posted to CT.gov within a year of completion. The sponsor-investigator 
has delegated responsibility to Big Ten CRC AHQ for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Management 
Big Ten CRC AHQ will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web-based clinical research platform compliant with Good Clinical Practices and Federal 
Rules and Regulations. Big Ten CRC AHQ personnel will coordinate and manage data for quality 


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control assurance and integrity. All data will be collected and entered into the EDC system by study site 
personnel from participating institutions.   
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results will be 
captured in the EDC system or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. Select 
standard of care data will also be captured in the EDC system, according to study-specific objectives. 
Please see the Data and Safety Oversight Process (DSOP) guidelines for further details.  
 
The completed dataset is housed at Big Ten CRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written permission 
from the sponsor-investigator and Big Ten CRC AHQ. After the initial publication, the complete data 
set will be available to all Big Ten CRC institutions. 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/Big Ten CRC AHQ, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition.  All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with local and federal regulations. No records will be 
destroyed until Big Ten CRC AHQ confirms destruction is permitted. 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, 
will not be made publicly available. Information collected will be maintained on secure, password 
protected electronic systems. Paper files that contain personal information will be kept in locked and 
secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, Big Ten CRC AHQ, Eli Lilly and Company, IRB, or government agencies, 
like the FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in accordance with 
local data protection laws. 
 
If the results of the study are published, the subjects’s identity will remain confidential. 
15. 
ETHICS 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in writing 
by an IRB.  The site investigator must submit written approval by the IRB to Big Ten CRC AHQ before 
he or she can enroll subjects into the study.   
 


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The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to recruit 
subjects for the study.  The protocol must be re-approved by the IRB as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to the IRB according to local 
regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration of 
Helsinki. Conduct of the study will be in compliance with ICH Good Clinical Practice, and with all 
applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study.  Subjects must also be notified they are free 
to discontinue from the study at any time.  The subject should be given the opportunity to ask questions 
and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study.  The site investigator must store the original, signed informed consent form.  
A copy of the signed informed consent form must be given to the subject. 
 
 
 


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16. 
REFERENCES 
 
1. 
Raman R, Deorah S, McDowell BD, et al: Changing incidence of esophageal cancer 
among white women: analysis of SEER data (1992-2010). Contemp Oncol (Pozn) 19:338-40, 2015 
 
2. 
Shapiro J, van Lanschot JJ, Hulshof MC, et al: Effectiveness of neoadjuvant 
chemoradiotherapy for early-stage esophageal cancer. J Clin Oncol 33:288-9, 2015 
 
3. 
Fuchs CS, Shitara K, Bartolomeo MD, et al: RAINFALL: A randomized, double-blind, 
placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without 
ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction 
(G-GEJ) adenocarcinoma. Journal of Clinical Oncology 36 
 
4. 
Tanaka K, Miyata H, Sugimura K, et al: Negative influence of programmed death-1-
ligands on the survival of esophageal cancer patients treated with chemotherapy. Cancer Sci 107:726-33, 
2016 
 
5. 
Ohigashi Y, Sho M, Yamada Y, et al: Clinical significance of programmed death-1 
ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 
11:2947-53, 2005 
 
6. 
Kang Y-K: Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or 
later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-
blinded, randomized, phase III trial. J Clin Oncol 35, 2017 
 
7. 
Fuchs CS, Doi T, Jang RW, et al: Safety and Efficacy of Pembrolizumab Monotherapy in 
Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 
Clinical KEYNOTE-059 Trial. JAMA Oncol 4:e180013, 2018 
 
8. 
chung HC: Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), 
an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer. journal 
of Clinical Oncology 34:Abstr 167, 2016 
 
9. 
Deng J, Wang ES, Jenkins RW, et al: CDK4/6 Inhibition Augments Anti-Tumor 
Immunity by Enhancing T Cell Activation. Cancer Discov, 2017 
 
10. 
Goel S, DeCristo MJ, Watt AC, et al: CDK4/6 inhibition triggers anti-tumour immunity. 
Nature 548:471-475, 2017 
 
11. 
Dempsey J, Huber L, Forest A, et al: Abstract 583: The CDK4/6 inhibitor abemaciclib 
induces synergistic immune activation and antitumor efficacy in combination with PD-L1 blockade. 
Cancer Research 77:583-583, 2017 
 
12. 
Cancer Genome Atlas Research N: Comprehensive molecular characterization of gastric 
adenocarcinoma. Nature 513:202-9, 2014 
 
13. 
Su P, Wen S, Zhang Y, et al: Identification of the Key Genes and Pathways in 
Esophageal Carcinoma. Gastroenterol Res Pract 2016:2968106, 2016 
 
14. 
Omstead AN, Kosovec JE, Biedka MJ, et al: Dual CDK 4/6 inhibitor demonstrates potent 
antitumor efficacy in vitro and in vivo against esophageal adenocarcinoma. Annals of Oncology, 2017 
 
15. 
Johnston S, Martin M, Di Leo A, et al: MONARCH 3 final PFS: a randomized study of 
abemaciclib as initial therapy for advanced breast cancer. NPJ breast cancer 5:5-5, 2019 
 
16. 
Brookmeyer R, Crowley J: A Confidence Interval for the Median Survival Time. 
Biometrics 38:29-41, 1982