Conditions: Biliary Tract Carcinoma
Keywords: Biliary Tract Carcinoma Abemaciclib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The prognosis of patients with recurrent, late-stage inoperable, or progressed biliary tract carcinoma (BTC) is generally poor. The goal of this clinical study is to determine the effectiveness and safety of abemaciclib in patients with late-stage or progressed BTC that has failed one line of chemotherapy.

Detailed description:
Biliary Tract Carcinoma (BTC) is a leading cause of cancer-related mortality. The newly developed small molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6), abemaciclib, provides a new opportunity of treating patients with BTC. The goal of this clinical study is to determine the efficacy and safety of abemaciclib in patients with advanced or metastatic BTC that has progressed or intolerant to one or more lines of systemic therapy, or treatment-naïve subjects who either decline or being considered not a good candidate first-line systemic chemotherapy per the opinion of the treating physician.

The investigator's objectives for this study are as follows:

Primary Objectives:

• To estimate the objective response rate (ORR)

Secondary Objectives:

* To determine progression free survival (PFS)
* To determine the disease control rate (DCR)
* To determine the overall survival (OS) rate at 6 and 12 months
* To determine quality of life (QoL) using EORTC-QLQ-C30

Arms:
arm 1: Abemaciclib will be given as a single oral agent A sample size of 10 subjects is determined to be minimally sufficient for these pilot study objectives. The starting dose will be 200 mg twice daily. Dosing will continue daily for 28 days, this being one cycle. There will be no protocol scheduled hiatus and daily dosing will be continuous unless there is unacceptable toxicity, disease progression, or death.

Interventions: intervention 1: Abemaciclib
Intervention descriptions: intervention 1: Participant will take 200 mg capsules or tablets orally twice daily. The participant will be instructed to swallow abemaciclib as a whole tablet and not to chew, crush or split capsules or tablets before swallowing. Participants should not ingest abemaciclib tablets if broken, cracked, or otherwise not intact. Doses should be taken at a approximately the same time every day, twice daily. Capsules or tablets can be taken orally with or without food. If the participant vomits or misses a dose of abemaciclib, the participant will be instructed to take the next dose at its scheduled time.

Participants will also be provided with a diary and instructed to keep a twice daily record of the times they have taken their medications and any other events such as vomiting, diarrhea, etc.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version dated:  4/18/2023
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Protocol Title
PSCI 18-052 A Pilot Study to Evaluate the Response and Tolerability of Verzenio
(Abemaciclib)
in Patients with Advanced Biliary Tract Carcinoma
Study Sponsor and Principal Investigator
Nelson Yee, M.D., Ph.D.
Department of Medicine
Pennsylvania State University and Milton S. Hershey Medical Center
T3413, Cancer Institute, 400 University Drive, Hershey, PA 17033
Telephone: (717) 531-0003, extension 280677
E-mail Address: nyee@pennstatehealth.psu.edu
Sub-Investigators
Hongzhang He, Ph.D.
Captis Diagnostics, Inc.,
5000 Forbes Avenue, Scott Hall, 4N211, Pittsburgh, PA 15213
Telephone: (949)878-2679
Email Address: simonhe@captisdx.com
Arthur Berg, Ph.D.
Statistician
Department of Public Health Sciences
Pennsylvania State University College of Medicine
A210, Public Health Sciences, Hershey, PA 17033
Telephone: (717) 531-3039
Email Address: aberg1@pennstatehealth.psu.edu
Funding provided by:  Eli Lilly and Company
Version Date: 4/18/2023
IND#: 142112
Clinicaltrials.gov Registration #: NCT04003896


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TABLE OF CONTENTS
1.0
Study Purpose, Objectives and Endpoints
1.1
Study Purpose
1.2
Study Objectives
1.3
Endpoints
2.0
Background Information
2.1
Introduction
2.2
Biliary Tract Cancers - Cholangiocarcinoma (intra/extrahepatic bile ducts), ampullary
carcinoma, gallbladder carcinoma
2.3
Abemaciclib: Drug Information
2.4
Findings from nonclinical and clinical studies
2.5
Selection of Drugs/Doses
3.0
Selection of Participants/Eligibility
3.1
Inclusion Criteria
3.2
Exclusion Criteria
3.3
Registration Procedures
3.4
Early withdrawal/Discontinuation of the study treatment
3.5
Follow-up
4.0
Recruitment Methods
4.1
Identification/Screening of Subjects
4.2
Recruitment Process
4.3
Recruitment materials
5.0
Consent Process and Documentation
5.1
The Informed Consent process
5.2
Coercion and undue influence
5.3
Consent other considerations
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and
Disclosures of PHI
6.2
Waiver or alteration of authorization statements of agreement
7.0
Study Design and Procedures
7.1
General Design/Phase/Schema
7.2
Study Procedures and Assessments
7.3
Treatment of participants
7.4
Supportive Care Guidelines
7.5
Use in  Special Populations
7.6
Procedures for Monitoring Participant Compliance
7.7
Assessment of Efficacy
8.0
Statistical Plan
8.1
Sample size and power considerations
8.2
Analysis Sets/Populations
8.3
Study Population
8.4
Efficacy Analysis
8.5
Safety Variables and Analysis


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8.6
Safety analysis
9.0
Confidentiality, Privacy, and Data Management
9.1
Patient Identifiers Associated with Data and/or Specimens
9.2
Data Storage
10.0
Assessment of Safety/Adverse Event Reporting
10.1
Adverse Events
10.2
Serious Adverse Events
10.3
Reporting of AEs and SAE
10.4
Pregnancy
11.0
Study Monitoring, Auditing, and Inspection
11.1
Protocol Amendments
11.2
Information to Study Personnel
11.3
Study Monitoring
11.4
Audit and Inspection
12.0
Data Handling, Data Quality Assurance, and Record Keeping
12.1 Data Collection
12.2 Reporting and Publication of Results
13.0
References
Appendix A.
Drugs that could inhibit or induce cytochrome P450 when administered with
Abemaciclib
Appendix B.
Protocol required interventions and assessments
Appendix C.
EORTC QLQ-C30


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Title
A Pilot Study to Evaluate the Response and Tolerability of Verzenio
(Abemaciclib) in Patients with Advanced Biliary Tract Carcinoma
Phase
Pilot study
Objectives
Primary Objectives:
To estimate the overall response rate (ORR)
Secondary Objectives:
To determine progression free survival (PFS)
To determine the disease control rate (DCR)
To determine the overall survival (OS) rate at 6 and 12 months
To determine quality of life (QoL) using EORTC-QLQ-C30 (see
Appendix C)
Exploratory Objectives:
To determine the efficacy and safety of abemaciclib with regard to the
subtypes of biliary tract carcinoma (BTC) including intrahepatic
cholangiocarcinoma (IHCC), extra-hepatic cholangiocarcinoma
(EHCC), ampullary carcinoma, and gall bladder carcinoma (GBC).
Analyze the biopsied tumor tissues for molecular profiling (by Caris
Life Sciences, Inc ®) including genetic mutation in K-RAS, B-RAF,
TP53, INK4A/p16, CDKN1A/p21, cyclin D, and RB by DNA
sequencing (clinical routine).
Correlate the efficacy of abemaciclib with the mutational status of K-
RAS, B-RAF, TP53, INK4A/p16, CDKN1A/p21, cyclin D and RB
genes.
Analyze the collected blood samples for characterization of
extracellular vesicles (EVs).
Study Design
Open label, Pilot Study
Total # of Subjects
N = 10, Approximately up to 20 subjects may be enrolled to attain at least 10
evaluable participants.  
Estimated
Enrollment Period
36 months  
Estimated Study
Duration
48 months
KEY
ELIGIBILITY
CRITERIA
Inclusion Criteria
1.
Male or female, age
18 years at the time of informed consent.
2.
Capable and willing to sign informed consent form prior to performing any


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protocol-related procedures.
3.
Histologic or cytologic evidence of advanced or metastatic biliary tract
cancer, including cholangiocarcinoma (intra-hepatic or extra-hepatic bile
ducts), ampullary carcinoma, or gallbladder carcinoma.
4.
Evidence of recurrent, locally advanced, unresectable, or metastatic disease.
5.
Progressed following or intolerant to one or more lines of systemic therapy,
or treatment-naïve subjects who either decline or being considered not a
good candidate first-line systemic chemotherapy per the opinion of the
treating physician
6.
Per the opinion of the physician investigator, predicted life expectancy > 3
months.
7.
Presence of at least 1 lesion that is measurable or evaluable using Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1.
8.
Eastern Cooperative Oncology Group (ECOG) performance score of
2.
9.
Per the opinion of the physician investigator, acute toxicities relating to any
prior anticancer treatment have improved to Grade 1 or baseline. Exceptions
include residual alopecia or Grade 2 peripheral neuropathy.
10. Ability to swallow capsules.
11. Adequate organ function as evidenced by the laboratory parameters noted in
Section 3.0 Study Eligibility.   
12. Women of childbearing potential (WOCP) defined as not surgically sterile
(hysterectomy, tubal ligation, or oophorectomy), or at least 1 year
postmenopausal, must have a negative serum pregnancy test before study
drug administration on cycle 1 day 1.
13. WOCP must use a medically acceptable method of contraception and must
agree to continue used of this method for the duration of the study and for 3
weeks after last dose of study drug. Acceptable methods of contraception
include abstinence, barrier method with spermicide, intrauterine device
(IUD) known to have a failure rate of less than 1% per year, or steroidal
contraceptive (oral, transdermal, implanted, or injected) in conjunction with
a barrier method.
14. Male, capable of producing offspring, must use a medical acceptable
method of contraception and agree to continued use of this method for the
duration of the study and for 3 weeks after last dose of study drug because
of the possible effects on spermatogenesis. Acceptable methods of
contraception include abstinence, WOCP partner’s use of barrier method
with spermicide, WOCP partner’s use of an IUD known to have a failure
rate of less than 1% per year, WOCP partner’s use of steroidal contraceptive
(oral, transdermal, implanted or injected) or WOCP partner is surgically
sterile or at least 1 year post-menopausal. In addition, male subjects may not
donate sperm for the duration of the study and for 30 days after last dose of
study drug.
15. Must be willing and able to comply with the protocol, including adhering to
study restrictions, remaining at the clinic as required during the study
period, and willing to return to the clinic for the follow-up evaluation.  


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16. Patients who received chemotherapy must have recovered (Common
Terminology Criteria for Adverse Events [CTCAE] Grade
from the
acute effects of chemotherapy except for residual alopecia or Grade 2
peripheral neuropathy.   
17. Patients who received radiotherapy must have completed and fully
recovered from the acute effects of radiotherapy. A washout period of at
least 14 days is required between end of radiotherapy and randomization.
18. Completed last dose of myelosuppressive chemotherapy greater than 21
days prior to first dose of study drug.
19. Completed last dose of non-myelosuppressive biological or monoclonal
antibody therapy greater than 14 days prior to first dose of study drug.
Exclusion Criteria:
1.
Ongoing or active infection requiring systemic antibiotics.
2.
Uncontrolled hypertension despite adequate therapy (systolic blood pressure
higher than 150 mm Hg or diastolic blood pressure higher than 90 mm Hg
found on 2 separate occasions separated by 1 week).
3.
Diabetes mellitus and occurrence of more than 2 episodes of ketoacidosis in
the 12 months prior to the first dose of study drug.
4.
Active second malignancy other than curatively resected basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, in situ
carcinoma of the cervix, or other cancers treated with curative intent, and no
known active disease in the 3 years prior to enrollment.
5.
Primary brain tumor or brain metastases from another primary site.
6.
Known history of human immunodeficiency virus (HIV).
7.
Known active viral hepatitis B or viral hepatitis C.
8.
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. Subjects with controlled atrial fibrillation for more than 30
days are permitted.
9.
Congestive heart failure (New York Heart Association [NYHA] Class III or
IV), or acute coronary syndromes within 6 months of enrollment.
10. Female subjects who are pregnant or breastfeeding.
11. Any other medical, psychiatric, or social condition, which in the opinion of
the physician investigator, would preclude participation in the study, pose an
undue medical hazard, interfere with the conduct of the study, or interfere
with interpretation of the study results. For example, interstitial lung disease,
severe dyspnea at rest or requiring oxygen therapy.
12. Use of an investigational drug within 1 month before the screening visit or
currently participating in another investigational study.
13. Any disorder that may interfere with drug absorption, distribution,
metabolism, or excretion (including extensive gastrointestinal surgery that


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involves removal of the entire stomach or most of the small intestine or
large intestine, bariatric surgery, uncontrolled active Crohn’s Disease or
ulcerative colitis, or preexisting condition resulting in baseline Grade 2 or
higher diarrhea).  History of Whipple’s procedure is permitted.
14. Known hypersensitivity to any of the components in abemaciclib including
micro-crystalline cellulose 102, microcrystalline cellulose 101, lactose
monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon
dioxide. Color mixture ingredients—polyvinyl alcohol, titanium dioxide,
polyethylene glycol, talc, iron oxide yellow, and iron oxide red.
15. The patient has serious and/or uncontrolled preexisting medical condition(s)
that, in the judgment of the investigator, would preclude participation in this
study (for example, interstitial lung disease, severe dyspnea at rest or
requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine
clearance <30ml/min].  
STATISTICS
The data will be summarized in tables listing the mean, standard deviation,
median, minimum, maximum and number of subjects for continuous data, or in
tables listing count and percentage for categorical data where appropriate.  
The primary endpoint is overall response rate (ORR). This pilot study of 10
subjects will generate data preliminary data regarding ORR and tolerability with
this patient population.
The secondary endpoints, which include progression-free survival (PFS),
disease control rate (DCR), and overall survival (OS) rate, will be tabulated and
graphed as appropriate.  The Kaplan-Meier survival curve will be graphed with
confidence intervals.  A 5% level test of the median survival, based on an
exponential maximum likelihood estimator test, will be conducted to determine
if median survival is statistically greater than 2.8 months.  Adverse events (AEs)
and serious adverse events (SAEs) will be annotated and tabulated to allow for a
quantitative assessment of the safety and tolerability of abemaciclib.  Potential
factors associated with the efficacy of abemaciclib, including subtypes of BTC
subtypes, and tumor molecular profiles, will be explored with a Cox
proportional hazards model.  Reproducible statistical reports will be produced.


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1.0 STUDY PURPOSE AND STUDY OBJECTIVES/ENDPOINTS
1.1 Study Purpose:
The primary purpose of this study is to determine the objective response rate of abemaciclib in
participants with biliary tract carcinoma that are locally advanced, unresectable or metastatic and
have failed first-line therapy.  
1.2 Study Objectives
1.2.1 Primary Objectives:
To estimate ORR
1.2.2 Secondary Objectives
To determine PFS
To determine the DCR
To determine the OS rate at 6 and 12 months
To determine QoL using EORTC-QLQ-C30 (see Appendix C)
1.2.3 Exploratory Objectives:
Determine the efficacy and safety of abemaciclib with regard to the subtypes of BTC
including IHCC, EHCC, ampullary carcinoma, and GBC.
Analyze the biopsied tumor tissues for molecular profiling including genetic mutation in K-
RAS, B-RAF, TP53, INK4A/p16, CDKN1A/p21, cyclin D and RB by DNA sequencing
(clinical routine).
Correlate the efficacy of abemaciclib with the mutational status of K-RAS, B-RAF, TP53,
INK4A/p16, CDKN1A/p21, cyclin D, and RB.
Analyze the collected blood samples for characterization of EVs including genetic mutations
and metabolic profiles.
1.3 Study Endpoints
1.3.1 Primary Efficacy Variable and Endpoints:  
ORR as estimated by the proportion of subjects with a best response of CR or PR during
study.
1.3.2 Secondary Efficacy Variable and Endpoints:
PFS as determined by the time interval from the date of first dose of study drug to first
documented disease progression or death from any cause, whichever occurs first, if
evaluable.
DCR as determined by the proportion of subjects with CR, PR, or SD.  
OS rate at 6 and 12 months defined as determined by the proportion of subjects who are
alive at 6 months and 12 months from the date of first dose of study drug, respectively.
QoL as measured from the date of baseline and then every 4 weeks using the EORTC-
QLQ-C30 (see Appendix C).


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1.3.3 Safety Variable and Endpoints:
The safety and tolerability of abemaciclib will be assessed at specified times throughout the
study, at the End of Treatment (EOT) visit and at the follow up visit, by evaluating AEs
(type, frequency, severity, and causality), concomitant medication usage or any subsequent
anticancer therapies (after the EOT visit), clinical laboratory test results, vital sign
measurements, ECG findings, ECOG Performance Status, and physical examination results.          
1.3.4 Exploratory Endpoints:
Efficacy and safety of abemaciclib with regard to the subtypes of biliary tract carcinoma
(BTC) including intrahepatic cholangiocarcinoma (IHCC), extra-hepatic
cholangiocarcinoma (EHCC), ampullary carcinoma, and gall bladder carcinoma (GBC).
Molecular profiles of the biopsied tumor tissues (by Caris Life Sciences®) including
genetic mutation in K-RAS, B-RAF, TP53, INK4A/p16, CDKN1A/p21, cyclin D and
RB by DNA sequencing (clinical routine).
Efficacy of abemaciclib with regard to the mutational status of K-RAS, B-RAF, TP53,
INK4A/p16, CDKN1A/p21, cyclin D, and RB genes.
Genetic mutations and metabolic profiles in the extracellular vesicles from blood-based
biopsies.
2.0 BACKGROUND INFORMATION
2.1 Introduction
BTC is a leading cause of cancer-related mortality.  Except in the patients with localized disease for
which surgical resection with curative intent is feasible, the prognosis of patients with recurrent,
advanced unresectable, or metastatic BTC is generally poor. Standard treatment involves palliative
systemic chemotherapy using gemcitabine and cisplatin, which produces limited benefit of tumor
response and survival.  Typically tumors progress following first-line chemotherapy.  Currently there
is no standard effective second-line treatment.  The molecular basis of chemoresistance is poorly
understood.  Genetic mutations in K-RAS, B-RAF, TP53, RB, and INK4A/p16 are variably present in
BTC, but their contributory roles in resistance to chemotherapy and tumor progression are unclear.  
Targeted therapeutics has been clinically investigated in advanced BTC, but their clinical benefits
remain to be demonstrated.
The newly developed small molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6),
abemaciclib, provides a new opportunity of treating patients with BTC.  The goal of this clinical
study is to determine the efficacy and safety of abemaciclib in patients with advanced or metastatic
BTC that has progressed or intolerant following one line of chemotherapy.  This research work is
important because this is anticipated to generate evidence for supporting the potential use of
abemaciclib as a treatment of patients with advanced BTC by overcoming chemoresistance through
inhibition of CDK4/6, which act downstream of mutant K-RAS, B-RAF, TP53, RB, and INK4A/p16.  
Besides, the data from this study are expected to generate insight into the roles of CDK4/6 in the
pathogenesis of BTC with mutations in K-RAS, B-RAF, TP53, RB, or INK4A/p16.  Moreover,
successful completion of this study is expected to pave the way to future investigation of abemaciclib
in combination with chemo-, targeted, or immuno- therapeutics for improving treatment response and
survival in patients with BTC.


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2.2 Biliary Tract Cancers - Cholangiocarcinoma (intra/extrahepatic bile ducts), ampullary
carcinoma, gallbladder carcinoma
Approximately 10,000 new cases of BTC are reported each year within the United States (Siegel et
al, 2017). For patients with BTC, the majority (80-90%) is diagnosed with locally advanced or
metastatic disease, for which surgical resection with curative intent is not feasible (Marks and Yee,
2015a).  Palliative systemic chemotherapy with or without radiation therapy remains the only
treatment option (Wyluda and Yee, 2015).  However, the literature regarding treatment results is
limited because most studies are small, reports consist of treatment of bile duct carcinoma,
gallbladder carcinoma, ampullary carcinoma, and pancreatic or hepatocellular carcinoma due to
paucity of patients.  Despite being in a similar anatomic location, the biological behavior may vary.  
In general, though, no single drug or combination has consistently increased survival beyond the
expected 6-8 months.
The current standard first-line chemotherapy using gemcitabine and cisplatin produces limited
survival benefits, with an overall survival of 12.7 months and progression-free survival of 8 months,
as compared to gemcitabine, 8.1 months and 5 months, respectively (Valle et al, 2010).  Typically,
the disease will progress, and currently there is no standard second-line treatment.  Despite treatment,
the clinical outcomes of patients with BTC are generally poor, with a 2-year survival rate of 13% for
patients with gallbladder carcinoma and less than 5% for cholangiocarcinoma (Marks and Yee,
2015b).
Clinical studies have been attempted to improve treatment response in patients with BTC by using
various combinations of chemotherapeutic drugs and targeted agents, though with limited success
(Wyluda and Yee, 2015; Marks and Yee, 2015a; Marks and Yee, 2015b).  While epidermal growth
factor receptors (ERBB-1, ERBB-2) are aberrantly over-expressed or amplified in BTC, the
combination of either erlotinib or cetuximab with cytotoxic drugs have not produced significant
clinical benefits (Lee et al, 2012; Malka et al, 2014).  Conceivably, resistance of biliary tract tumors
may be related to underlying genetic mutations, particularly K-RAS, B-RAF, TP53, INK4A/p16, and
RB.  Tumors with these mutations are typically aggressive and resistant to chemotherapy-induced
apoptosis.  Currently, there are no actionable agents that effectively target mutated K-RAS, p53,
INK4A/p16, or RB. Targeting the oncogenes and tumor suppressor genes that control tumor growth
may provide new opportunities to improve treatment responses for patients with BTC.  Mutations in
K-RAS, B-RAF, TP53, and INK4A/p16 have been demonstrated in BTC (Chang et al, 2014; Hanada
et al, 1999; Rashid et al, 2002; Robertson et al, 2013; Saetta et al, 2004; Suto et al, 2000; Tannapfel
et al, 2000; Tannapfel et al, 2003; Tian et al, 2006; Marks and Yee, 2015a), and they may play
important roles in development and progression of BTC.  
The incidence of oncogenic mutations in K-RAS has been reported to be 17% to 59% of gallbladder
carcinoma (GBC), 23% to 100% of extra-hepatic cholangiocarcinoma (EHCC), and 0% to 56% in
intra-hepatic cholangiocarcinoma (IHCC).  At a relatively low frequency, mutations in B-RAF were
found in 1% of GBC, 3% of EHCC, and 5% of IHCC.  Similarly, mutations in PI3KCA are present in
14% of GBC, 7% of EHCC, and 5% of IHCC.  The reported incidence of mutations in TP53 is 31%
to 92% in GBC, 33% to 73% in EHCC, and 11% to 37% in IHCC.  In BTC, inactivation of
INK4A/p16 has been shown to occur through distinct mechanisms including deletion or point
mutation of the INK4A/p16 gene, and hypermethylation of the 5’ regulatory regions of INK4A/p16.  


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In particular, 60-80% of BTC exhibit point mutations in the INK4A/p16 gene.  These data suggest
that the mutated K-RAS, p53, and INK4A/p16 are potential therapeutic targets in BTC.
CDK4 and CDK6 are regulated either directly or indirectly by p53 and INK4A/p16, and small
molecule inhibitors targeting CDK4/6 may produce anti-tumor effect in BTC by causing cell cycle
arrest and apoptotic cell death.  The major mitogenic signaling pathways such as those of EGF
typically involve K-RAS that lead to activation of the CDK4/6 and cyclin D1 complex.  This in turns
phosphorylates and inactivates retinoblastoma (RB), enabling the transcription factor E2F to
transcribe the targets genes that promote cell cycle progression, survival, and suppression of
senescence.  Activation of the INK4A/p16-CDKs-retinoblastoma (RB)-E2F pathway has been
demonstrated to induce cell cycle arrest and apoptosis.  This pathway is in parallel to that involves
p53-CDKN1A/p21-mediated cell cycle arrest and apoptosis (Sherr and McCormick, 2002).  By
inhibiting CDKs, one can expect to induce cell cycle arrest and apoptosis in cancer cells that carry
activating mutation in K-RAS and inactivating mutations in p53 and INK4A/p16 (Sherr et al, 2016).  
Thus, CDK inhibitors may be effective for treatment of patients with tumors carrying mutations in K-
RAS, B-RAF, TP53, and INK4A/p16.  Besides, synthetic lethal interaction between oncogenic K-RAS
and CDK4 has been demonstrated (Puyol et al, 2010), such that inhibition of CDK4 in tumors with
mutant K-RAS produces enhanced anti-tumor effect.  
Small molecule inhibitors of cyclin-dependent kinases (CDKs) may produce anti-tumor effect in
BTC by causing cell cycle arrest and apoptotic cell death.  CDK inhibitors such as abemaciclib may
help overcome therapeutic resistance by targeting CDK4/6 that act down-stream of mutated K-RAS,
B-RAF, p53, or INK4A/p16 and impairing cell cycle progression.  These activities have recently
been reported in a variety of malignant diseases, but it has not been investigated in BTC.  Besides,
accumulating evidence indicates that serum metabolites are potential biomarkers of BTC (Liang et al,
2016, Lee et al, 2018).  How serum metabolites are altered in patients treated with CDK inhibitors
such as abemaciclib has not been studied.  These observations form the basis of the hypothesis that
inhibitors of CDKs such as abemaciclib may produce treatment response and prolong survival in
patients with BTC, particularly those tumors that carry mutations in K-RAS, B-RAF, TP53, or
INK4A/p16.
2.3 Abemaciclib: Drug Information
Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4
(cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic
activity. Abemaciclib specifically inhibits CDK4 and CDK6, thereby inhibiting retinoblastoma (RB)
protein phosphorylation in early G2. Inhibition of RB phosphorylation prevents CDK-mediated G1-S
phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and
inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in
certain types of cancer, causes cell cycle deregulation.
2.3.1 Abemaciclib Formulation
Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with
chemical name is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-
[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following
structure:


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Empirical formula: C27H32F2N8 - Molecular weight: 506.59
Abemaciclib capsules are provided as immediate-release oval white, beige, or yellow capsules.
Inactive ingredients are as follows: Excipients—microcrystalline cellulose 102, microcrystalline
cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide.
Color mixture ingredients—polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide
yellow, and iron oxide red.
2.3.2 Pharmacology studies
2.3.2.1 Abemaciclib is currently indicated for the following:
• In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of
postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer.
• In combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive,
human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy.
• As monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or
metastatic breast cancer with disease progression following endocrine therapy and prior
chemotherapy in the metastatic setting.
2.3.2.2 Mechanism of Action:
Cyclin dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle
entry.  Most human cancers contain overactive CDK4/6 cyclin D and thus CDK4/6 specific inhibitors
are now approved for use as anti-cancer therapeutics.  Abemaciclib is an inhibitor of CDK4 and CDK
6.  CDK4 and CDK6, in breast cancer cell lines, promote phosphorylation of the retinoblastoma
protein (RB), cell cycle progression and cell proliferation.  In vitro, continuous exposure to
abemaciclib inhibited RB phosphorylation and thus blocked progressed from G1 into the S phase of
the cell cycle.  This subsequently resulted in cell death/apoptosis.  
2.3.2.3 Drug Metabolism and Pharmacokinetic Studies
The pharmacokinetics of abemaciclib have been characterized in patients with solid tumors,
including metastatic breast cancer, and in normal healthy volunteers.  Following single and repeated


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twice daily administration of 50 mg (0.3 times the approved recommended 150 mg dose) to 200 mg
of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose
proportional.  Steady state was achieved within 5 days following twice daily dose exposure and the
estimated geometric mean accumulation ratio was 2.3 (60% CV) and 3.2 (59% CV) based on Cmax
and AUC, respectively.
The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV).  The
median Tmax of abemaciclib is 8.0 hours (range 4.1-24 hours).  A high fat, high calorie meal  (800-
1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories
from fat) administered to healthy volunteers increased the AUC of abemaciclib plus its active
metabolites by 9% and increased Cmax by 26%.  
In vitro abemaciclib was bound to human plasma proteins, serum albumin and alpha-1-acid
glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL.  In a clinical
study the mean (standard deviation, SD) bound fraction was 96.3% (2.10 for abemaciclib, 93.4%
(2.3) for M2, 96.8% (0.8) for M18 and 97.8% (0.6) for M20.  The geometric mean systemic volume
of distribution is approximately 690.3 L (49% CV).  In patients with advanced cancer, concentrations
of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid were comparable to
unbound plasma concentrations.  The geometric mean hepatic clearance (CL) of abemaciclib in
patients was 26 L/H (51% CV) and the mean plasma elimination half-life for abemaciclib in patients
was 18.3 hours (72% CV).  
Hepatic metabolism is the main route of clearance of abemaciclib.  Abemaciclib is metabolized to
several metabolites primarily by cytochrome P450 3A4 (CYP 3A4) with formation of N-
desethylabemaciclib (M2) representing the major metabolism pathway.  Additional metabolites
include hydroxyabemaciclib (M20), hydroxyl-N-desethylabemaciclib (M18) and an oxidative
metabolite (M1).  M2, M18 and M20 are equipotent to abemaciclib and their AUCs accounted for
25%, 13% and 26% of the total circulating analytes in plasma, respectively.  After a single 150 mg
oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and
approximately 3% recovered in urine.  The majority of the dose eliminated in feces was metabolites.  
2.3.2.4 Toxicology Studies
According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metabolites M2
and M20 did not display mutagenic properties. Abemaciclib was not clastogenic *in vitro* rat bone
marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects
of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses
mg/kg/day in rats and
mg/kg/day in dogs which exceed the recommended therapeutic doses in humans. The findings
included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation,
atrophy and degeneration or necrosis.
From the nonclinical safety report from Eli Lilly on 8/13/2020, the increased incidences of interstitial
(Leydig) cell hyperplasia and interstitial (Leydig) cell adenoma were observed in rats treated with
LY2835219 at clinically relevant LY2835219 exposure levels. Interstitial cell hyperplasia occurred
in male rats at exposures below typical human exposures achieved when administered at 150 mg
twice daily, and benign interstitial cell adenomas occurred in male rats at exposure levels that were
1.5-fold or 1.1-fold higher than typical human exposure at 150 mg or 200 mg twice daily
respectively. Sponsors-Investigators are advised to instruct patients to conduct regular self-


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examination of their testicles and report any new symptoms or changes to their investigator during
clinical trial visits.
2.4 Findings from nonclinical and clinical studies
2.4.1 Nonclinical studies
Pre-clinical studies have demonstrated that inhibitors of CDK4/6 such as abemaciclib, produced anti-
tumor effects by inducing cell cycle arrest and apoptosis and overcoming therapeutic resistance
(Gelbert et al, 2014; Viluda and Rugo, 2016).  Biochemical assays indicate that abemaciclib is a
potent and selective inhibitor of CDK4 (IC50 2 nM) and CDK6 (IC50: 10 nM) by competing for ATP
(KiATP: 0.6 nM and 2.4 nM for CDK4/cyclin D1 and CDK6/cyclin D1, respectively) (Gelbert et al,
2014).  In cancer cells (of colon, breast, acute myelogenous leukemia) and human colorectal
xenografts, abemaciclib produced cellular arrest in G1 phase of the cell cycle with inhibited
phosphorylation of RB (Gelbert et al, 2014).  Studies in mouse xenograft of melanoma with acquired
resistance to vemurafenib that targets B-RAF V600E mutation, abemaciclib induced regression of
tumor growth through targeting the up-regulated cyclin D1-CDK4/6 signaling from MAPK
reactivation (Yadav et al, 2014).  Besides, the human colorectal xenografts model indicates that
chronic dosing of abemaciclib achieved minimum steady-state trough plasma concentrations of 200
ng/ml is required to maintain cell cycle arrest (Tate et al, 2014).  Taken together, the pre-clinical data
support the anti-tumor activity of abemaciclib through inhibition of CDK4/6-cyclin D1 and suggest a
strategy for dosing abemaciclib in the clinical studies. From the Eli Lilly abemaciclib Investigator’s
Brochure (v. 12/2/2021): In a 2-year carcinogenicity study in rats, interstitial (Leydig) cell hyperplasia
and benign interstitial (Leydig) cell adenomas in the testes were observed at clinically relevant
exposure levels. Male patients should be instructed to conduct regular self-examination of their
testicles and report any new symptoms or changes. In rodents, cataracts/lens fiber degeneration,
retinal atrophy, and corneal inflammation have been observed at clinically relevant abemaciclib
exposure levels. Patients who experience changes in vision or develop eye redness and symptoms
such as eye pain should undergo ophthalmological investigations as clinically indicated.2.4.2
Clinical Studies
Abemaciclib is approved to treat: Breast cancer that is hormone receptor positive (HR+) and HER2
negative (HER2-) and is advanced or has metastasized (spread to other parts of the body). It is used
with fulvestrant in women who progressed on prior hormonal therapy.
The safety of abemaciclib (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus
fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to
abemaciclib in 441 patients with HR-positive, HER2-negative advanced breast cancer who received
at least one dose of abemaciclib plus fulvestrant in MONARCH 2.
Median duration of treatment was 12 months for patients receiving abemaciclib plus fulvestrant and
8 months for patients receiving placebo plus fulvestrant.
Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus
fulvestrant. Adverse reactions leading to dose reductions in
of patients were diarrhea and
neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 19% of patients
receiving abemaciclib plus fulvestrant compared to 0.4% of patients receiving placebo and


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fulvestrant. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients
receiving abemaciclib plus fulvestrant compared to no patients receiving placebo plus fulvestrant.
Permanent study treatment discontinuation due to an AE were reported in 9% of patients receiving
abemaciclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse
reactions leading to permanent discontinuation for patients receiving abemaciclib plus fulvestrant
were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal
pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).
Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18
cases (4%) of abemaciclib plus fulvestrant treated patients versus 10 cases (5%) of placebo plus
fulvestrant treated patients. Causes of death for patients receiving abemaciclib plus fulvestrant
included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to
pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.
The most common adverse reactions reported
in the abemaciclib arm were diarrhea, fatigue,
neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting,
and headache (Table 6). The most frequently reported
Grade 3 or 4 adverse reactions were
neutropenia, diarrhea, leukopenia, anemia, and infections.
Table 1: Adverse Reactions
in Patients Receiving Abemaciclib (Verzenio ) plus
Fulvestrant and
Higher than Placebo plus Fulvestrant in MONARCH 2


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a Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort,
abdominal tenderness.
b Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis,
conjunctivitis, sinusitis, vaginal infection, sepsis.
c Includes neutropenia, neutrophil count decreased.
d Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.
e Includes leukopenia, white blood cell count decreased.
f Includes platelet count decreased, thrombocytopenia.
g Includes asthenia, fatigue.


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Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein
thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis,
axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated
with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus
placebo.
Table 2: Laboratory Abnormalities
in Patients Receiving Abemaciclib (Verzenio ) plus
Fulvestrant and
Higher than Placebo plus Fulvestrant in MONARCH 2
Abemaciclib Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1)
Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and
1-2 chemotherapy regimens in the metastatic setting
Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132
women with measurable HR-positive, HER2-negative metastatic breast cancer. Patients received 200
mg abemaciclib orally twice daily until development of progressive disease or unmanageable
toxicity. Median duration of treatment was 4.5 months.
Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each)
abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine
increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and
lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The
most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%),
and fatigue (9%).
Deaths during treatment or during the 30-day follow up were reported in 2% of patients. Cause of
death in these patients was due to infection.
The most common reported adverse reactions
were diarrhea, fatigue, nausea, decreased
appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and
thrombocytopenia (Table 3). Severe (Grade 3 and 4) neutropenia was observed in patients receiving
abemaciclib.
Table 3: Adverse Reactions in
of Patients Receiving Abemaciclib (Verzenio ) in
MONARCH 1


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a Includes asthenia, fatigue.
b Includes neutropenia, neutrophil count decreased.
c Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.
d Includes platelet count decreased, thrombocytopenia.
e Includes leukopenia, white blood cell count decreased.


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Table 4: Laboratory Abnormalities for Patients Receiving Abemaciclib (Verzenio ) in
MONARCH 1
Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion
transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine
(mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing,
remained elevated but stable through the treatment period, and were reversible upon treatment
discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not
based on creatinine, may be considered to determine whether renal function is impaired.
Abemaciclib is also being studied in the treatment of other types of cancer. In a multicenter study
that involved phase I dose escalation followed by tumor-specific cohorts, anti-tumor activity of
abemaciclib was observed in patients with advanced solid tumors. These include breast cancer, non-
small cell lung cancer, colorectal carcinoma, melanoma, ovarian cancer, endometrial cancer, and
glioblastoma.  Importantly, this study demonstrates a better disease control rate in patients with lung
adenocarcinoma carrying K-RAS mutation than in those with wild-type K-RAS treated with
abemaciclib (Patnaik et al, 2016).  Similarly, patients who responded to abemaciclib include one with
metastatic melanoma harboring both N-RAS mutation and loss of INK4A/p16 gene.  In this clinical
study, the dose-limiting toxicity was grade 3 fatigue. Other common treatment-related AEs occurred
in the gastrointestinal, renal, or hematopoietic systems. An acceptable safety profile and antitumor
activity of abemaciclib were also demonstrated in another clinical study (Fujiwara et al, 2016).  This
is a phase I study using dose escalation of abemaciclib as a single agent for Japanese patients with
advanced cancer. In this study of 12 patients, tumor response was demonstrated in two patients, one
with breast cancer and one with neuroendocrine carcinoma. Taken together, abemaciclib produces
anti-tumor effect as a single agent in various malignancies, and it possibly overcomes therapeutic
resistance due to mutations in K-RAS and INK4A/p16.  
It is known that BTC carry mutations in oncogenes and tumor suppressor genes that directly or
indirectly regulate CDK4 and CDK6, but the efficacy of abemaciclib has not been investigated in
BTC. Clinical study (as in this proposal) is indicated to test the hypothesis that abemaciclib prolongs


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PFS in patients with advanced BTC by improving anti-tumor response. Exploring the potential
therapeutic use of abemaciclib and correlation of its efficacy with tumor molecular profiles in
advanced BTC is expected to create new treatment options, and generate insight into the roles of
CDK4/6 in the pathogenesis of BTC.  Furthermore, this study will help pave the way to future
investigation of combination therapy using abemaciclib for improving treatment response and
survival in patients with BTC.
2.5 Selection of Drugs/Doses
When used as monotherapy, the recommended dose of abemaciclib is 200 mg taken orally twice
daily. Abemaciclib may be taken with or without food.
3.0   SELECTION OF PARTICIPANTS/ELIGIBILITY
3.1 Inclusion Criteria:
1.
Male or female, age
18 years at the time of informed consent.
2.
Capable and willing to sign informed consent form prior to performing any protocol-related
procedures.
3.
Histologic or cytologic evidence of advanced or metastatic biliary tract cancer including
cholangiocarcinoma (intra-hepatic or extra-hepatic), ampullary carcinoma, or gallbladder
carcinoma.
4.
Evidence of recurrent, locally advanced, unresectable, or metastatic disease.
5.
Progressed following or intolerant to one or more lines of systemic therapy, or treatment-naïve
subjects who either decline or being considered not a good candidate first-line systemic
chemotherapy per the opinion of the treating physician
6.
Per the opinion of the physician investigator, predicted life expectancy of >3 months.
7.
Presence of at least 1 lesion that is measurable or evaluable using RECIST v1.1.
8.
ECOG performance score
2.
9.
Per the opinion of the physician investigator, acute toxicities relating to any prior anticancer
treatment have improved to Grade 1 or baseline. Exceptions include residual alopecia or Grade
2 peripheral neuropathy.
10. Ability to swallow capsules.
11. Adequate organ function, as evidenced by all of the following:
System
Laboratory value
Hematologic
ANC
Platelets
Hemoglobin
g/dL (Patients may receive erythrocyte transfusions to
achieve this hemoglobin level at the discretion of the
investigator.  Initial treatment may not begin earlier than the
day after the erythrocyte transfusion.)


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System
Laboratory value
Hepatic
Serum total bilirubin
times the ULN; Patients with Gilbert’s syndrome with a
total bilirubin
times ULN and direct bilirubin within
normal limits are permitted.
AST and ALT
times the ULN,
5 times ULN for subjects with liver
metastasis
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST =
aspartate aminotransferase; ULN = upper limit of normal.
12. WOCP defined as not surgically sterile (hysterectomy, tubal ligation, oophorectomy) or at least
1 year postmenopausal must have a negative serum pregnancy test before study drug
administration on cycle 1 day 1.
13. WOCP must use a medically acceptable method of contraception and must agree to continued
use of this method for the duration of the study and for 3 weeks after last dose of study drug.
Acceptable methods of contraception include abstinence, barrier method with spermicide,
intrauterine device (IUD) known to have a failure rate of less than 1% per year, or steroidal
contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method.
14. Male subjects capable of producing offspring, must use a medically acceptable method of
contraception and agrees to continued use of this method for the duration of the study and for 3
weeks after last dose of study drug because of the possible effects on spermatogenesis).
Acceptable methods of contraception include abstinence, use of barrier method with
spermicide, WOCP partner’s use of an IUD known to have a failure rate of 1% per year, WOCP
partner’s use of steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction
with a barrier method, or WOCP  partner is surgically sterile or at least 1 year post-
menopausal. In addition, male subjects may not donate sperm for the duration of the study and
for 30 days after last dose of study drug.
15. Must be willing and able to comply with the protocol, including adhering to study restrictions,
remaining at the clinic as required during the study period, and willing to return to the clinic for
the follow-up evaluation.  
16. Patients who received chemotherapy must have recovered (Common Terminology Criteria for
Adverse Events [CTCAE] Grade
from the acute effects of chemotherapy except for residual
alopecia or Grade 2 peripheral neuropathy.   
17. Patients who received radiotherapy must have completed and fully recovered from the acute
effects of radiotherapy. A washout period of at least 14 days is required between end of
radiotherapy and randomization.
18. Completed last dose of myelosuppressive chemotherapy greater than 21 days prior to first dose
of study drug.    
19. Completed last dose of non-myelosuppressive biological or monoclonal antibody therapy
greater than 14 days prior to first dose of study drug.
3.2 Exclusion Criteria:
1. Ongoing or active infection requiring systemic antibiotics.


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2. Uncontrolled hypertension despite adequate therapy (i.e., systolic blood pressure higher than
150 mm Hg or diastolic blood pressure higher than 90 mm Hg found on 2 separate occasions
separated by at least 1 week).
3. Diabetes mellitus and occurrence of more than 2 episodes of ketoacidosis in the 12 months
prior to the first dose of study drug.
4. Active second malignancy other than curatively resected basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or other cancers for which
they are treated with curative intent, and no known active disease in the 3 years prior to
enrollment.
5. Primary brain tumor or brain metastases from another primary site.
6. Known history of HIV.
7. Known active viral hepatitis B or viral hepatitis C.
8. 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. Subjects with controlled atrial fibrillation for
more than 30 days are permitted.
9. Congestive Heart Failure (NYHA Class III or IV), or acute coronary syndromes within
6 months of enrollment.
10. Female subjects who are pregnant or breastfeeding.
11. Any other medical, psychiatric, or social condition, which in the opinion of the investigator,
would preclude participation in the study, pose an undue medical hazard, interfere with the
conduct of the study, or interfere with interpretation of the study results.  For example,
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy.
12. Use of an investigational drug within 1 month before the screening visit or currently
participating in another interventional investigational study.
13. Any disorder that may interfere with drug absorption, distribution, metabolism, or excretion
(including extensive gastrointestinal surgery that involves removal of the entire stomach or
most of the small intestine or large intestine, bariatric surgery, uncontrolled active Crohn’s
disease or ulcerative colitis, or preexisting chronic condition resulting in baseline Grade 2 or
higher diarrhea).  History of Whipple’s procedure is permitted.
14. Known hypersensitivity to any of the components in abemaciclib, including: micro-crystalline
cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium,
sodium stearyl fumarate, silicon dioxide. Color mixture ingredients—polyvinyl alcohol,
titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red.
15. The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the
judgement of the investigator, would preclude participation in this study (for example,
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal
impairment [e.g. estimated creatinine clearance <30ml/min].


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3.3
Registration Procedures
Eligible participants will be enrolled on study by the Penn State Cancer Institute, Clinical Trials
Office (PSCI-CTO) by the designated Research Study Coordinator.  The protocol specific
Eligibility Checklist Worksheet must be completed in its entirety prior to enrollment, and source
documentation verifying each eligibility criterion must be available.  The physician investigator
will sign this document acknowledging accuracy of the data including any subjective variables.   
Following verification of eligibility, it is preferred that participants begin the investigational
treatment as soon as possible.
3.4 Early Withdrawal /Discontinuation of the Study Treatment
A participant will be withdrawn from study treatment for any of the following reasons:
Withdrawal of consent from the study by the participant at any time and for any reason.   
The reason for elective withdrawal will be documented in the research record if known.  
Unacceptable toxicity in the judgement of the Principal Investigator.
Toxicity possibly related to abemaciclib does not resolve in14 days.
Progression of disease requiring alternative systemic treatment.
Significant participant or protocol noncompliance that, in the opinion of the Principal
Investigator, warrants withdrawal of treatment. For example, participant is noncompliant in
taking prescribed study medication or fail to return for scheduled follow up visits.  
Development of intercurrent, non-cancer related illnesses or complications that prevent
either continuation of therapy or regular follow up.
In the opinion of the Principal Investigator, it is inappropriate for the participant to continue
on the study.
Best medical interest of the participant at the discretion of the Principal Investigator.
Subject becomes pregnant.
Participant become lost to follow up.  Participants who are unable to be located despite 3
documented attempts at contact (telephone, mail, or email) followed by a certified letter
will be considered lost to follow up and rendered off study.
Premature study closure.
Every effort should be done to help assure participants who are withdrawn from study
treatment undergo the planned end of study follow up, end of treatment follow-up as
outlined.3.4.1 Follow-up
An EOT visit will occur 30 ± 7 days from the last study treatment. Follow-up visits will
occur every 3 months (+/- 7 days) x2, beginning 3 months after last dose of the study drug,
then every 6 months (± 7 days) thereafter.   
4.0 RECRUITMENT METHODS
4.1 Identification/Screening of Subjects
Patients seen at Penn State Cancer Institute with the disease of study may be pre-screened through
the electronic medical record or in the clinic by research team members for basic variables such as
age and ability to sign consent.  Those patients deemed by this pre-screening effort to meet these
basic criteria will be approached for consideration of participation.   


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This clinical trial will be available for potential patient candidates to view on clinicaltrials.gov.  
Formal screening for participation will not be initiated until an IRB approved informed consent form
has been signed..  All subjects who sign consent will be assigned a study ID number.
Subjects who consent to participate in the clinical trial but who are not subsequently assigned to the
study intervention or registered will be considered screen failures. Subject may be re-screened. All
re-screened subjects will be assigned the same subject ID number as was assigned during the initial
screening.  
4.2 Recruitment Process
Potential participants will be approached for possible participation in the PSCI outpatient clinic or
the inpatient setting if applicable.  The protocol may be initially presented to the patient by the
Principal Investigator or Sub-Investigator.  A member of the study team will discuss the protocol
further with the patient.
4.3 Recruitment Materials
No recruitment materials will be used for the purpose of this clinical trial.
5.0 CONSENT PROCESS AND DOCUMENTATION
5.1 Informed Consent Process
The informed consent process will be carried out in compliance with federal regulations. A copy of
the signed IRB approved consent document will be provided to the patient.  The original document
will be maintained in the protocol specific regulatory files with copies in the Cerner electronic
medical record and research chart.  
5.2 Coercion and Undue Influence
During the consent conference, all patients will be made aware that this is a research investigation
and participation is optional.  Their medical care at Penn State Health will not be affected by their
decision to participate or not participate.
5.3 Consent Other Considerations
5.3.1 Non-English-Speaking Participants
Non-English-speaking patients are eligible for participation in this trial.  Protocol and related
information will be provided to the patient orally in their language using a certified interpreter prior
to and throughout the course of the study.   In the event that a non-English speaking patient is
identified, the consent process and ongoing research process will be carried out in compliance with
federal regulations, as well as the following institutional policies and procedures.   
5.3.2 Cognitively Impaired Adults/Unable to consent
Not applicable.  Eligibility requires that patients are able to understand the requirements for the study
and provide consent themselves.


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6.0 HIPAA RESEARCH AUTHORIZATION AND/OR WAIVER OR ALTERATION OF
AUTHORIZATION
6.1 Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures
of PHI.  Check all that apply:
Not applicable, no identifiable protected health information (PHI) is accessed, used
or disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this
is the only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’
medical records will be accessed to determine eligibility before consent/authorization
has been obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review
studies). [Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of
authorization (verbal authorization will be obtained). [Complete all parts of sections
6.2 and 6.3]
6.2 Waiver or alteration of authorization statements of agreement
Not applicable.
7.0 STUDY DESIGN AND PROCEDURES
This is a open label pilot study of abemaciclib administered orally to participants with recurrent,
locally advanced, unresectable, or metastatic BTC.  This study consists of a screening period of up to
28 days, up to eight 28-day treatment cycles, an EOT visit and follow-up visits every 3 months (± 7
days) 6 months after last dose of the study drug then every 6 months(± 7 days) thereafter until death .
The Principal Investigator will determine whether the participant meets all inclusion/exclusion
criteria.
Each cycle will consist of 28 days of twice daily dosing of abemaciclib.  Participants must receive a
minimum of two 28 day cycles to be considered evaluable for the primary endpoint of ORR unless
they withdraw earlier due to rapid disease progression.  If a participant is deriving clinical benefit, he
or she may receive additional cycles until one of the criteria for discontinuation is met.
Participants who are deriving clinical benefit after completing the treatment period may continue on
additional cycles of therapy at the discretion of the sponsor and the medical monitor from the DSMC.  
Any participant that continues on abemaciclib after completing the treatment period will be
monitored and assessed for tumor response per clinical routine per principal investigator.
Participants who complete treatment or who are withdrawn from treatment early will have an end of
treatment visit. Participants with measurable disease who end treatment on a cycle at which a tumor
response assessment is not planned should have end of treatment CT scans/MRI scans.  Follow up
visits will be performed every three months +/- 7 days 6 months for the subsequent anticancer
therapy and survival then thereafter every 6 months (± 7 days) for survival only till death.  It will be
done by either clinic visit or phone call.


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7.1 General Design/Phase/Schema
This is an open label pilot study to determine the efficacy and safety/tolerability of abemaciclib in
participants with locally advanced, unresectable, or metastatic biliary tract cancer who have failed
one or more lines of systemic therapy, or treatment-naïve subjects who either decline or being
considered not a good candidate first-line systemic chemotherapy per the opinion of the treating
physician7.1.1 Enrollment/Randomization
This is a non-randomized study and thus participants will be enrolled sequentially. Participants will
be screened for eligibility after signing the informed consent form.  
7.1.2 Participant Population
Participants with histologically confirmed advance or metastatic biliary tract cancer including
cholangiocarcinoma (intra-hepatic or extra-hepatic bile ducts), ampullary carcinoma, or gallbladder
carcinoma who progressed following one or more lines of systemic therapy, will be enrolled if they
meet eligibility criteria.  
7.1.3 Number of sites/number of participants
This is a single center study that will be conducted at the Penn State Cancer Institute.  In the future,
additional study sites may be added if needed to assist with accrual numbers.  Any addition of new
sites and related modification to the protocol will be reviewed and approved in advance by the IRB
and other applicable oversight bodies.  Approximately up to 20 subjects may be enrolled to attain at
least 10 evaluable participants.
7.1.4 Sample Size consideration
Refer to section 8.1.
7.1.5 Study Treatment
Abemaciclib will be given as a single oral agent. The starting dose will be 200 mg twice daily.  One
cycle = 28 days.  There will be no protocol scheduled hiatus and daily dosing will be continuous
unless there is unacceptable toxicity, disease progression, or death.  
7.1.6 Dosing Adjustments, Delays and Discontinuation
Abemaciclib Dose Modification for Grade 3 or 4 AEs
Dose Level
Abemaciclib Dose
Recommended starting dose
200 mg twice daily
First dose reduction
150 mg twice daily
Second dose reduction
100 mg twice daily
Third dose reduction
50 mg twice daily
Complete blood counts with differentials and complete metabolic panel will be monitored every 2
weeks for the first 2 months, then monthly for the next 2 months, at the beginning of every cycle.
7.1.7 Subject Evaluability and Subject Replacement


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Approximately up to 20 subjects will be enrolled to attain at least 10 evaluable participants.  
Participants who voluntarily withdraw from the study for a reason other than tumor progression or
inability to tolerate treatment may be replaced.
7.1.8 Safety Analysis
A safety analysis will be requested to review all safety data following the recruitment of 5
participants.  The study may be terminated early if unexpected toxicities are observed.  Following
study termination, the internal PSCI DSMC will complete an expedited review of all efficacy and
safety data; All regulatory bodies will be notified of study termination within no more than 2
business days of such a decision.
7.1.9 Safety Monitoring and Study Stopping Rules
In accordance with administrative, legal and ethical requirements documented in this protocol, safety
monitoring will be performed by an internal Data Safety Monitoring Committee (DSMC).  The
DSMC of PSCI will review safety data per DSMC charter. The principal investigator (PI) will
continuously monitor study progress for safety and will hold routine meetings with the study team
and disease center personnel to review overall conduct and progress of this study.  The frequency of
such meetings will be dependent upon accrual to the trial and issues that arise.  Study team meetings
will include discussion of accrual, adverse events/safety issues, response and overall progress of the
trial. Unexpected and related adverse events will be reported as they arise as well as any significant
literature reporting developments that may affect the safety of participants in this study. Serious and
unexpected adverse events will be reported to PSCI DMSC.
This study will be suspended or terminated prematurely for any of the following reasons:
A death that is unexpected and at least probably related to abemaciclib
Severe anaphylactic reaction to abemaciclib, either active ingredient, metabolites or excipients
Any event, that, in the opinion of the Principal Investigator, or internal monitoring team,
warrant immediate review by the PSCI DSMC
Any other safety finding assessed as related to abemaciclib that, in the opinion of the PSCI
DSMC, contraindicates further dosing of any participant.  
Any interim finding that, in the opinion of the Principal Investigator, suggests that the study
has no clinical benefit for the participants.
7.1.10 Study Duration
Enrollment period: 36 months
Length of study: 48 months
Anticipated length of study for each participant: 6 months
7.1.11 Study Drug
Abemaciclib will be stored in the limited access Penn State Health Investigational Drug Pharmacy.  
Maintenance, secure storage, and accountability of abemaciclib will be ensured according to
institutional policies and procedures for investigational medications.   


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Abemaciclib is stored at room temperature. Refer to package label for specific storage conditions and
instructions. Abemaciclib will be provided in 50 mg capsules in 60 count bottles.   The
Investigational pharmacist may dispense the medication directly to the research participant or the
designated research team member.  
7.2 Study Procedures and Assessments
Refer to Appendix B: Protocol Required Interventions and Assessments.  
7.2.1 Procedures at Screening
A signed and dated informed consent form will be obtained before screening procedures commence.
Evaluations obtained as part of routine medical care and performed during the screening period may
be used for the protocol required evaluations.   
After informed consent is obtained, participants who are screened will be assigned a unique identifier
number such that all participants are given consecutive identification numbers in successive order.
A participant who is screened but not enrolled may be re-screened.  
The following procedures and assessments will be performed within 28 days prior to C1D1 visit:
Obtain histology report confirming diagnosis of malignancy
Review inclusion/exclusion criteria  
Tumor evaluation through diagnostic imaging and RECIST v1.1 reading, including CT or MRI
scans of chest, abdomen, and pelvis with contrast, and brain MRI, or PET CT scan
Archival tumor samples will be collected for subjects for confirmation of diagnosis, as well as,
for determination of exploratory mutational analysis.
If no archival tumor samples are available, fresh biopsy will be collected for subjects for
confirmation of diagnosis, as well as, for determination of exploratory mutational analysis.
Review medical history (to include demographics, tobacco use (if smokes or smoked, and
smoking pack year), surgical and psychiatric history and cancer treatment history)
Review prior medication history (those medications taken within the last 28 days before the
start of study treatment)
Full physical examination including height, weight and vital signs measurements (temperature,
heart rate, respiration rate and blood pressure).
ECOG performance status
Triplicate 12-lead ECG
Clinical laboratory tests include hematology (complete blood counts with differential), serum
chemistry (complete metabolic panel including Na, K, Cl, CO2, blood urea nitrogen,
creatinine, glucose, aspartate aminotransferase, total bilirubin, alkaline phosphatase, alanine
aminotransferase, albumin), coagulation profile including prothrombin time (PT),
international normalized ratio (INR), partial thromboplastin time (PTT), CA 19-9, urinalysis)
The following procedures and assessments will be performed within 7 days prior to C1D1 visit:


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Serum pregnancy test.
Participants who continue to meet all inclusion and exclusion criteria will be enrolled in the study.  
7.2.2 Procedures During Study Drug Treatment
7.2.2.1 Procedures During Treatment Cycles (28-Day Cycles)
Study procedures and assessments will be performed as described below. No extra capsules of
abemaciclib will be distribute to participants for each cycle.
The following procedures and assessments will be performed on C1D1 and C2D1:
Physical examination, including weight and vital signs measurements.
ECOG performance status
AEs
Concomitant medication
12-lead ECG (C1D1 and subsequent cycles  if clinically indicated)
Clinical laboratory tests
EORTC-QLQ-C30 (see Appendix C)
Dispense Abemaciclib
Collect unused Abemaciclib (C2D1 only)
Review participant drug diary and compliance with study medication (C2D1 only)
Extracellular vesicle detection (C1D1 only)
The following procedures and assessments will be performed on C1D15 and C2D15:
Physical examination, including vital signs measurements.
ECOG performance status
AEs
Concomitant medication
Clinical laboratory tests
The following procedures and assessments will be performed on C3-C8D1:
Physical examination, including weight and vital signs measurements. Vital signs include
temperature, heart rate, respiration rate and blood pressure.
ECOG performance status
AEs
Concomitant medication
Tumor evaluations every 8 weeks through diagnostic imaging and RECIST v1.1 reading,
including CT or MRI of abdomen and pelvis with contrast every 8 weeks (± 7 days).
Clinical laboratory tests
EORTC-QLQ-C30


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Dispense Abemaciclib
Collect unused Abemaciclib
Review participant drug diary and compliance with study medication
Extracellular vesicle detection will be performed every 8 weeks (± 3 days) until objective
disease progression or study completion.
7.2.3 Procedures During the End-of-Treatment Visit
For participants who complete the study or withdraw prematurely, final evaluations will be
performed at the EOT visit or on the last day the participant receives the study drug.
Participants with ongoing AEs or clinically significant abnormal laboratory test results (as
interpreted by the Principal Investigator) will be monitored per the Principal Investigator
and AEs will be recorded and reported per protocol Section 10.1.2.  
If a participant withdraws from the study during the treatment period, the reason must be
determined and recorded on the participant’s electronic case report form (eCRF). For
participants who withdraw consent, every attempt will be made to determine the cause.
The following procedures will be performed at the EOT visit (up to 30 days ± 7 days) from
last dose of study drug), unless otherwise specified:
Physical examination including body weight and vital sign measurements
ECOG performance status
AEs
Concomitant medication
Collect unused Abemaciclib
Review participant drug diary and compliance with study medication
Tumor evaluations through diagnostic imaging (CT/MRI/PET) every 8 weeks (± 3 days)
until objective disease progression.
Subsequent post-study treatment anti-cancer therapy
Clinical laboratory tests
12-lead ECG if clinically indicated
EORTC-QLQ-C30
Extracellular vesicle detection will be performed every 8 weeks (± 3 days) until
objective disease progression or study completion
7.2.4 Procedures at Follow-Up Visits
Tumor evaluations: every 3 months (± 7 days) beginning 3 months after the last dose of
study drug for subjects who have not progressed.
Survival/death assessment, including data and cause of death if applicable. Every 3
months (± 7 days) x2, beginning 3 months after last dose of the study drug then
every 6 months (± 7 days) thereafter. The assessment can be performed at standard of
care visits or any other possibly treatments, or via phone calls.


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Subsequent post-study treatment anticancer therapy: every 3 months (± 7 days) x2,
beginning 3 months after last dose of the study drug then every 6 months (± 7 days)
thereafter.
7.2.5 Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the request of the participant
or as deemed necessary by the Principal Investigator. The date and reason for the unscheduled visit
will be recorded on the CRF, as well as any other data obtained (e.g. AEs, concomitant medications
and treatments, and results from procedures or tests).
7.3 Treatment of participants
7.3.1 Study Drugs Administered
The investigational drug, abemaciclib, will be administered as 50 mg capsules.
7.3.2 Study drug information
When used as monotherapy, the recommended dose of abemaciclib is 200 mg taken orally twice
daily.   Continue treatment until disease progression or unacceptable toxicity.
7.3.3 Packaging/Preparation/Dispensing/Storage
Abemaciclib 50 mg capsules are oval beige.   Capsules are suppled in 60 count bottles.  Drug is to be
stored at room temperature.
7.3.4 Administration
Participant will be administered a 200 mg dose (i.e., four 50 mg capsules) of abemacilib orally twice
daily.  The participant will be instructed to swallow abemaciclib as a whole capsule and not to chew,
crush or split capsules before swallowing.  Participants should not ingest abemaciclib capsules if
broken, cracked, or otherwise not intact.  Doses should be taken at approximately the same time
every day, twice daily.  Capsules can be taken orally with or without food. If the participant vomits
or misses a dose of abemaciclib, the participant will be instructed to take the next dose at its
scheduled time.
Participants will also be provided with a diary and instructed to keep a twice daily record of the times
they have taken their medications and any other events such as vomiting, diarrhea, etc.  
7.3.5 Overdose
There is no known antidote for abemaciclib.  The treatment of overdose of abemaciclib should
consist of general supportive measures.
7.3.6 Missed doses
If a participant vomits or misses a dose, the participant will be instructed to take the next dose at its
scheduled time.  
7.3.7 Restriction on Concomitant Therapies


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Effect of Other Drugs on Abemaciclib
Strong CYP3A Inhibitors
Strong CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a
clinically meaningful extent and may lead to increased toxicity. all strong CYP3A inhibitors are
excluded from use during this clinical trial. Patients should avoid grapefruit, orange juice, pomelo
products.
Ketoconazole
Avoid concomitant use of the strong CYP3A4 inhibitor ketoconazole. Ketoconazole is predicted to
increase the AUC of abemaciclib by up to 16-fold.
Itraconazole (a strong CYP3A inhibitor) is predicted to increase the relative potency adjusted
unbound AUC of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold. Co-
administration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a
single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage) increased
the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2,
M18, and M20) by 1.7-fold relative to abemaciclib alone in cancer patients.
Moderate CYP3A Inhibitors: Diltiazem and verapamil (moderate CYP3A inhibitors) are predicted to
increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2,
M18, and M20) by 1.7-fold and 1.3-fold, respectively.
Strong CYP3A Inducers
Co-administration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg
dose of abemaciclib decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus
its active metabolites (M2, M18, and M20) by 67% in healthy subjects.
Moderate CYP3A Inducers: The effect of moderate CYP3A inducers on the pharmacokinetics of
abemaciclib is unknown.
Loperamide: Co-administration of a single 8-mg dose of loperamide with a single 400-mg dose of
abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of
abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically
relevant.
Fulvestrant: In clinical studies in patients with breast cancer, fulvestrant had no clinically relevant
effect on the pharmacokinetics of abemaciclib or its active metabolites.
Effects of Abemaciclib on Other Drugs
Loperamide: In a clinical drug interaction study in healthy subjects, co-administration of a single 8
mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150
mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone.
These increases in loperamide exposure are not considered clinically relevant.
Metformin: In a clinical drug interaction study in healthy subjects, co-administration of a single 1000
mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K


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transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150
mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone.
Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%,
respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as
measured by iohexol clearance and serum cystatin C.
Fulvestrant: In clinical studies in patients with breast cancer, abemaciclib had no clinically relevant
effect on fulvestrant pharmacokinetics.
In Vitro Studies
Transporter Systems: Abemaciclib and its major active metabolites inhibit the renal transporters
OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage.
The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition
of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see Adverse Effects (7.1)].
Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic
uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and
OAT3.
Abemaciclib is a substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and
M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide
1B1 (OATP1B1), or OATP1B3.
Abemaciclib inhibits P-glycoprotein (P-gp) and BCRP. The clinical consequences of this finding on
sensitive P-gp and BCRP substrates are unknown.
CYP Metabolic Pathways: Abemaciclib and its major active metabolites, M2 and M20, do not induce
CYP1A2, CYP2B6, or CYP3A at clinically relevant concentrations. Abemaciclib and its major
active metabolites, M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2D6 and CYP3A4. The mechanism of this down regulation and its clinical
relevance are not understood. However, abemaciclib is a substrate of CYP3A4, and time-dependent
changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism was not
observed.
P-gp and BCRP Inhibitors: In vitro, abemaciclib is a substrate of P-gp and BCRP. The effect of P-gp
or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.
Thus, all strong CYP3A inhibitors are excluded from use during this clinical trial. Patients should
avoid grapefruit, orange juice, pomelo products.
Strong CYP3A Inducers
Coadministration of abemaciclib with rifampin, a strong CYP3A inducer, decreased the plasma
concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.  For the
purpose of this study, all CYP3A inducers will not be permitted on this study; please see Appendix A
and refer to crediblemeds.org for a more comprehensive list of prohibited medications.  
7.3.8 Dose Delays/Modifications
Dose Modifications for Adverse Reactions


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The recommended abemaciclib dose modifications for adverse events are provided in table below.
Discontinue abemaciclib for participants unable to tolerate 50 mg twice daily. Once the drug is
reduced, there is no dose re-escalation.
Abemaciclib Dose Modification for Adverse Reactions
Dose Level
Abemaciclib Dose
Recommended starting dose
200 mg twice daily
First dose reduction
150 mg twice daily
Second dose reduction
100 mg twice daily
Third dose reduction
50 mg twice daily
Guidelines for Dose Adjustments and Delays of Abemaciclib
Toxicity Type
Toxicity Profile and
Severity
Dose Modification
Dose Reduction
Hematologic Toxicity
Grade 3
Dose
MUST
be
held until toxicity
resolves to
Grade
2.
Dose MAY be
reduced by 1 dose
level at investigator’s
discretion.
Hematologic Toxicity
(second or more
recurrence)
Grade 3
Dose
MUST
be
held until toxicity
resolves to < Grade
2.
Dose MUST be
reduced by 1 dose
level with each
occurrence.
Discontinue
abemaciclib for
participants unable to
tolerate 50 mg twice
daily
Hematologic Toxicity
Grade 4
Dose
MUST
be
held until toxicity
resolves to < Grade
2.
Dose MUST be
reduced by 1 dose
level. Discontinue
abemaciclib for
participants unable to
tolerate 50 mg twice
daily


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Nonhematologic
Toxicity (except
diarrhea and
ALT increased)
Persistent or recurrent
Grade 2 that does not
resolve with maximal
supportive measures
within 7 days to baseline
or Grade 1
Dose MUST be
held until toxicity
resolves to either
baseline or <
Grade 1.
Dose MUST be
reduced by 1 dose
level. Discontinue
abemaciclib for
participants unable to
tolerate 50 mg twice
daily
Nonhematologic
Toxicity (except
diarrhea and ALT
increased)
Grade 3 or 4 that does not
resolve with maximal
supportive measures
within 7 days to baseline
or Grade 1
Dose MUST be
held until toxicity
resolves to either
baseline or <
Grade 1.
Dose MUST be
reduced by 1 dose
level. Discontinue
abemaciclib for
participants unable to
tolerate 50 mg twice
daily
Diarrhea
Grade 2 that does not
resolve within 24 hrs to at
least Grade 1
Dose
MUST
be
held until toxicity
resolves to <Grade
1.
Dose MAY be
reduced by 1 dose
level.
Diarrhea
Grade 3 or 4 that does
not resolve with maximal
supportive measures
within7 days or requires
hospitalization.
Dose MUST be
held until toxicity
resolves to < Grade
1.
Dose must be
reduced by 1 dose
level - Discontinue
abemaciclib for
participants unable to
tolerate 50 mg twice
daily


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ALT/AST increased
Grade 2 (>3.0-5.0xULN)
that does not resolve
within 7 days to baseline
or < Grade 1
Grade 3 (>5.0-
20.0xULN) with total
bilirubin >2xULN, in the
absence of cholestasis
Grade 4 (>20.0xULN)
Dose MUST be
held until toxicity
resolves to
baseline or Grade
1
Abemaciclib
therapy MUST be
discontinued
Abemaciclib
therapy MUST be
discontinued
Dose MUST be
reduced by 1 dose
level
Abemaciclib therapy
MUST be discontinued
Abemaciclib therapy
MUST be
discontinued
Abbreviations: ALT = alanine aminotransferase, AST=aspartate aminotransferase, ULN = upper
limit of normal.
Monitor ALT, AST, and serum bilirubin prior to the start of abemaciclib therapy, every 2 weeks for
the first 2 months, monthly following cycle 2, and as clinically indicated.
7.4 Supportive Care Guidelines
7.4.1 Guidelines for Diarrhea Management
Clinical trial data indicates the majority of patients who receive abemaciclib will develop diarrhea.
Early identification and intervention for the management of diarrhea has been helpful to patients
At enrollment, participants 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 participant should initiate antidiarrheal therapy (e.g.
loperamide) and notify the investigator for further instructions and appropriate follow-up.
•
Participants 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 Dose Modification Table above for more information on dose modification).
7.4.2 Guidance for Increases in Serum Creatinine and Assessment of Renal Insufficiency
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion
of creatinine without affecting glomerular function. In vitro studies have indicated that abemaciclib
and its major metabolites LSN2839567 and LSN3106726 inhibit the renal transporters OCT2,
MATE1, and MATE2-K at clinically relevant concentrations. Thus, increases in serum creatinine
observed following dosing with abemaciclib, in the absence of simultaneous increases in BUN or


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development of an abnormal urinalysis, are most likely due to inhibition of its tubular secretion via
OCT2, MATE1, and MATE2-K and may not reflect a decline in renal function, making serum
creatinine level an unreliable measurement for renal function.
Increases in serum creatinine occurred within the first 28-day cycle of dosing remained stable
through the treatment period and were reversible upon treatment discontinuation.
If deterioration of renal function is suspected, measures other than those relying on assessment of
serum creatinine should be used to determine renal function. No dosage adjustment is required for
patients with mild or moderate renal impairment (CLcr
mL/min, estimated by Cockcroft-
Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr
<30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown; hold abemaciclib
unless Clcr improves to
mL/min.
7.4.3 General Guidance for Hepatic Monitoring
To ensure patient safety the investigator should collect specific recommended clinical
information and follow-up laboratory tests as shown below in Table 5.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory test
abnormalities. If a study patient experiences elevated ALT 5×ULN and elevated total bilirubin
(TB) 2×ULN, or ALT 8×ULN, liver tests, including ALT, AST, direct bilirubin, gamma-glutamyl
transferase (GGT), and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to
confirm the abnormality and to determine if it is increasing or decreasing. If the abnormality persists
or worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the
hepatic monitoring tests below.
Table 5 Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality.
Hepatic Hematology
Haptoglobin
Hemoglobin
Hematocrit
Hepatic Coagulation
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistry
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody
AST
Anti-actin antibody
GGT
CPK
Anti-smooth muscle antibody


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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.
7.4.4 General Guidance for Hematology Toxicity
7.4.4.1 Neutropenia
Severe (Grade 3 and 4) neutropenia was observed in participants receiving abemaciclib-see Tables 1-
4.  If a participant requires blood cell growth factors, these should be administered according to
ASCO Guidelines. Abemaciclib must be held for at least 48 hours after the last dose of blood cell
growth factors is administered and until toxicity resolves to at least Grade 2. When abemaciclib is
resumed, the dose must be reduced by 1 dose level unless already performed for incidence of toxicity
that led to the use of growth factor.
7.4.5 General Guidance for Interstitial lung disease (ILD)/Pneumonitis events
Interstitial lung disease (ILD) / pneumonitis has been identified as an adverse drug reaction for
abemaciclib. Adverse events reported included events such as interstitial lung disease, pneumonitis,
obliterative bronchiolitis, organizing pneumonia, pulmonary fibrosis. The majority of events were
Grade 1 or Grade 2 with serious cases and fatal events reported.
Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis and please ask
patients to report any new or worsening pulmonary symptoms. Symptoms may include hypoxia,
cough, dyspnea, or interstitial infiltrates on radiologic exams.; these symptoms should be investigated
and treated as per local clinical practice and/or guidelines (including corticosteroids as appropriate).
Infectious, neoplastic, and other causes for such symptoms should be excluded by means of
appropriate investigations. Investigations may include imaging such as high resolution computer
tomography (HRCT), bronchoalveolar lavage (BAL), and biopsy as clinically indicated (see also
Table 7: refer to dose adjustment table for interstitial lung disease/pneumonitis).
Dose Modification and Management — Interstitial Lung Disease/Pneumonitis
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
Hold dose until toxicity resolves to baseline or Grade 1.
Resume at next lower dose.
Grade 3 or 4
Discontinue abemaciclib.
Dose Modification and Management — Nonhematologic Toxicities Excluding Diarrhea, ALT
Increased, and ILD/Pneumonitis


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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
Grade 3 or 4
Hold dose until toxicity resolves to baseline or Grade 1.
Resume at next lower dose.
7.4.6. General Guidance for Concomitant Therapy
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.
CYP3A inducers
Avoid concomitant use of CYP3A inducers and consider alternative agents.
CYP3A inhibitors
Avoid concomitant use of strong CYP3A inhibitors (for example, voriconazole) and use caution with
coadministered moderate (for example, ciprofloxacin) or weak (for example, ranitidine) CYP3A
inhibitors. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the abemaciclib
dose to 100 mg twice daily or, in the case of ketoconazole, reduce the abemaciclib dose to 50 mg
twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse
reactions, further reduce the abemaciclib dose to 50 mg twice daily. Avoid grapefruit or grapefruit
juice. If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-5 half-lives of the
inhibitor) to the dose that was used before starting the inhibitor.
7.4.7 General Guidance for use of Radiotherapy in Combination with Abemaciclib
Limited data are available on the use of radiotherapy in combination with abemaciclib or alternate
dosing schedules (e.g. induction phase). Caution should be exercised with co-administering
abemaciclib with radiotherapy.
7.5 Use in Special Populations
7.5.1 Pregnancy
Risk Summary
Based on findings in animals and its mechanism of action, abemaciclib can cause fetal harm when
administered to a pregnant woman. There are no available human data informing the drug-associated
risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies,
administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal
weight at maternal exposures that were similar to human clinical exposure based on AUC at the
maximum recommended human dose.


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The background risk of major birth defects and miscarriage for the indicated population is unknown.
However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of
miscarriage is 15 to 20% of clinically recognized pregnancies.
Data
Animal Data
In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15
mg/kg/day during the period of organogenesis. Doses
mg/kg/day caused decreased fetal body
weights and increased incidence of cardiovascular and skeletal malformations and variations. These
findings included absent innominate artery and aortic arch, malpositioned subclavian artery,
unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At
4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human
exposure (AUC) at the recommended dose.
7.5.2 Lactation
Risk Summary
There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child
or on milk production. Because of the potential for serious adverse reactions in breastfed infants from
abemaciclib, advise lactating women not to breastfeed during abemaciclib treatment and for at least 3
weeks after the last dose.
7.5.3 Females and Males of Reproductive Potential
Pregnancy Testing
Based on animal studies, abemaciclib can cause fetal harm when administered to a pregnant woman
Pregnancy testing is recommended for WOCP prior to initiating treatment with abemaciclib.
Contraception
Females
Abemaciclib can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during
abemaciclib treatment and for at least 3 weeks after the last dose.
Infertility
Males
Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential [see
Nonclinical Toxicology].
7.5.4 Pediatric Use
The safety and effectiveness of abemaciclib have not been established in pediatric patients.
7.5.5 Geriatric Use


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Of the 900 patients who received abemaciclib in MONARCH 1, MONARCH 2, and MONARCH 3,
38% were 65 years of age or older and 10% were 75 years of age or older. The most common
adverse reactions
Grade 3 or 4 in patients
years of age across MONARCH 1, 2, and 3
were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT
increased. No overall differences in safety or effectiveness of abemaciclib were observed between
these patients and younger patients.
7.5.6 Renal Impairment
No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr
mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with
severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis
is unknown.
7.5.7 Hepatic Impairment
No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-
Pugh A or B).
Reduce the dose when administering abemaciclib to patients with severe hepatic impairment (Child-
Pugh C).
7.6 Procedures for Monitoring Participant Compliance
The Principal Investigator will be responsible for monitoring participant compliance. If the Principal
Investigator determines that the participant is not in compliance with the study protocol, the Principal
Investigator should determine whether the participant should be withdrawn.
The investigator or designee will instruct the participants on how to take the study drug, demonstrate
how to complete the participant’s diary card with a record of the number of capsules of abemaciclib
that he or she has taken daily at home, and instruct him or her to bring the diary card back for each
study visit. The investigator or designee will be responsible for checking the return of study drug and
the participant’s diary card for completeness at each study visit.
7.7 Assessment of Efficacy
Efficacy of treatment with abemaciclib will be assessed by tumor response.  Tumor response
assessments for participants with measurable disease will be performed every 8 weeks ± 7 days for
the duration of the treatment period and compared with assessments performed at screening. Tumor
response is defined for each participant as the best response during the study as determined using
RECIST v 1.1 criteria and tumor specific criteria as described below.    Responses will be confirmed
with a subsequent radiographic evaluation which would be performed 4 weeks after response is
declared.  Responses will be recorded as CR, PR, Stable Disease (SD) or Progressive Disease (PD).
7.7.1 Assessment of Tumors by RECIST v 1.1
Tumor assessments that are made after administration of study drug will be compared with those
obtained at baseline or the smallest sum since treatment started, to determine whether CR, PR, SD or
PD has occurred.
Measurable disease, measurable lesions, and non-measurable lesions are defined as follows:


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Measurable disease: presence of at least 1 measurable lesion after the histological diagnosis and
staging of disease
Measurable lesions: lesions that can be accurately measured in at least 1 dimension as 10 mm or
greater and lymph nodes > 15 mm in shortest axis by CT scan measurements (or MRI, as
appropriate); prior sites of loco-regional therapy (e.g., fibrosis from radiation) should not be
considered measurable lesions
Non-measurable lesions: all other lesions including skin lesions, small lesions (less than 10 mm),
lymph nodes < 15 mm and > 10 mm in shortest axis, ascites, pleural/pericardial effusions, etc.
Documentation of lesions should include date, site, dimensions, description, and diagnostic method.
The same method of assessment and technique should be used at baseline and during follow-up to
characterize each identified and reported lesion.
Baseline documentation of target and non-target lesions is as follows: all measurable lesions up to a
maximum of 5 lesions total and a maximum of 2 lesions per organ representative of all involved
organs should be identified as target lesions.


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Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1)
Measurable
tumor burden
Maximum 5 target lesions in total (up to 2 per organ) can be identified at baseline
and measured through the course of therapy
Minimum
size of
measurable
lesions
mm in LD and 2 times the slice thickness for extranodal lesions
mm in short axis diameter (SAD) for nodal lesions
mm in LD for clinical lesions (must be measured using electronic calipers)
mm in LD for chest X-ray (if clearly defined and surrounded by aerated
lung): CT scan is preferable
Ultrasound cannot be used to measure lesions
Lymph nodes
Lymph nodes are considered pathologically enlarged if >10 mm in SAD. To be
measurable, nodal lesions must be
mm in SAD. Nodal lesions with SAD >10
mm and <15 mm are non-measurable.
The sum of the diameters (LD for extranodal target lesions, SAD for nodal
lesions) is followed through the course of therapy.
Bone lesions
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed on
CT scan/MRI can be measurable if the minimum size criteria are met. Blastic
bone lesions and bone lesions assessed on bone scan, PET, or plain film are non-
measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts are not
malignant. Cystic lesions thought to be metastases can be measurable if they meet
the minimum size criteria. Non-cystic lesions are preferable.
Lesions with
prior local
therapy
Lesions in previously irradiated areas (or areas treated with local therapy) are not
measurable unless the lesion has progressed since therapy. Conditions should be
defined in study protocols.
Too small to
measure
If a target lesion becomes too small to measure, a default value of 5 mm is
assigned. If the lesion disappears, the measurement is recorded as 0 mm.
FDG/PET
New lesions can be assessed using FDG-PET:
(–) PET at baseline and (+) PET at follow-up is PD based on a new lesion.
No PET at baseline and (+) PET at follow-up is PD if the new lesion is confirmed
on CT. If a subsequent CT confirms the new lesion, the date of PD is the date of
the initial PET scan, not the CT scan.
No PET at baseline and a (+) PET at follow-up corresponding to a pre-existing
lesion on CT that is not progressing: not PD
(Eisenhauer et al 2009) LD=longest diameter; SAD=short axis diameter; CT=computed tomography;
MRI=magnetic resonance imaging; PET=positron emission tomography; FDG=fluorodeoxyglucose
Evaluation of Target Lesions
Target lesions will be evaluated as follows:
Response
Criteria
CR
Disappearance of all target lesions
PR
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions,
taking as reference the baseline sum LD


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Response
Criteria
PD
At least a 20% increase in the sum of the LD of target lesions, taking as reference
the smallest sum LD recorded since the treatment started or the appearance of one or
more new lesions
SD
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for
PD, taking as reference the smallest sum LD since the treatment started
Evaluation of Nontarget Lesions
Nontarget lesions will be evaluated as follows:
Response
Criteria
CR
Disappearance of all non-target lesions and normalization of tumor marker level
Incomplete      
response/SD
Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker
level above the normal limits
PD
Appearance of 1 or more new lesions and/or unequivocal progression of existing
non-target lesions. (Although a clear progression of “non-target” lesions only is
exceptional, in such circumstances, the opinion of the treating physician should
prevail and the progression status should be confirmed later on by the review panel
[or study chair].)
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease
progression/recurrence (taking as reference for PD the smallest measurements recorded since the
treatment started). In general, the participant’s best response assessment will depend on the
achievement of both measurement and confirmation criteria, as follows:
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Incomplete response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
Participants 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 CR depends on this determination, it is recommended
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm CR status.


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7.7.2 Primary Efficacy Endpoint
ORR defined above as estimated by the proportion of subjects with a best response of CR or
PR during the study.   
7.7.3 Secondary Efficacy Endpoint
OS rate at 6 and 12 months defined as determined by the proportion of subjects who are alive
at 6 months and 12 months from the date of first dose of study drug, respectively.
PFS as determined by the time interval from the date of first dose of study drug to first
documented disease progression or death from any cause, whichever occurs first, evaluable.
DCR as determined by the proportion of subjects with CR, PR, or SD.  
QoL as measured from the date of first dose of study drug/baseline and then every 4 weeks
using the EORTC-QLQ-C30 (see Appendix C)
7.7.4 Exploratory Efficacy Variables
Determine the Efficacy and safety of abemaciclib with regard to the subtypes of biliary tract
carcinoma (BTC) including intrahepatic cholangiocarcinoma (IHCC), extra-hepatic
cholangiocarcinoma (EHCC), ampullary carcinoma, and gall bladder carcinoma (GBC).
Analyze the biopsied tumor tissues for molecular profiling (by Caris Life Sciences, Inc®)
including genetic mutation in K-RAS, B-RAF, TP53, INK4A/p16, CDKN1A/p21, cyclin D,
and RB by DNA sequencing (clinical routine).
Correlate the efficacy of abemaciclib with the mutational status of K-RAS, B-RAF, TP53,
INK4A/p16, CDKN1A/p21, cyclin D, and RB genes.
Analyze the collected blood samples for characterization of extracellular vesicles
(EVs).Three lavender-top EDTA glass tubes will be used to collect approximately 5 ml of
blood in each tube, and one 10-ml green-top sodium heparin tube will be used to collect
approximately 7.5 ml of blood in the tube.  The collected blood specimens will be processed
as described in the Study 18-052 Lab Manual, and the frozen specimens will be stored in
freezer boxes and sent to Dr. Hongzhang He (phone number 949-878-2679), or Dr. He’s
research staff. The blood specimens will be processed by and stored in Dr. He’s laboratory
(Captis Diagnostics, Inc., 5000 Forbes Avenue, Scott Hall 4N211, Pittsburgh, PA 15213) for
characterization of EVs.
8.0 STATISTICAL PLAN
This is a pilot study to confirm tolerability of abemaciclib and provide an estimate of the overall
response rate. A sample size of 10 subjects is determined to be minimally sufficient for these pilot
study objectives.  The primary objective of this study is objective response rate in locally advanced
and metastatic biliary tract carcinoma that have failed (tumor progression or patient intolerance) one
or more lines of systemic therapies.  All participants will be treated with 200 mg twice daily of oral
abemaciclib for 28 days being one cycle.  Participants will be treated up to 8 cycles or until
progression, untoward toxicities or death.   Antitumor activities will be evaluated using RECIST
v1.1.
8.1 Sample Size and Power Considerations


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The primary endpoints is overall response rate (ORR). A sample size of 10 subjects is determined to
be minimally sufficient for these pilot study objectives.  
8.2 Analysis Sets/Populations
8.2.1 Enrolled Participants
The set of enrolled participants includes all participants who provide informed consent to participate
in the study and who meet all inclusion and exclusion criteria, regardless of whether or not a
participant took any study drug.
8.2.2. Safety Analysis Set
The safety analysis set for this study will include participants who receive 1 or more doses of study
drug.
8.2.3 Data Handling Conventions
For all variables, only the observed data from the participants will be used in the statistical analyses.
There is no plan to estimate missing data. Treated participants without response assessment after
dosing will be considered as non-responders.  
8.3 Study Population
The set of enrolled participants will be used for all study population summaries unless otherwise
noted.
8.3.1 Participant Disposition
Data from participants who are screened, participants screened but not enrolled, reason for non-
enrollment, participants enrolled, participants enrolled but not treated, participants in the safety sets,
participants who complete the study, and participants who withdraw from the study will be
summarized using descriptive statistics. Data from participants who withdraw from the study will
also be summarized by reason for withdrawal using descriptive statistics.
8.3.2 Demographic and Baseline Characteristics
Participant demographic and baseline characteristics, including age, sex, race, medical history,
disease types, biomarkers, prior medications, and ECG and physical examination findings, will be
summarized using descriptive statistics. For continuous variables, descriptive statistics (number [n],
mean, standard deviation, standard error, median, minimum, and maximum) will be provided. For
categorical variables, participant counts and percentages will be provided. Categories for missing
data will be presented if necessary.
8.4 Efficacy Analysis
8.4.1 Primary Efficacy Endpoint
The primary efficacy endpoint is ORR evaluated using RECIST v1.1. A responder is defined as a
participant with a best response of CR and PR during study. Confirmation of CR and PR as assessed
by RECIST v1.1 is needed no sooner than 4 weeks after the initial observation of response.


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8.4.2 Secondary Endpoints
The secondary efficacy endpoints are as follows:
OS rate at 6 and 12 months defined as determined by the proportion of subjects who are alive at 6
months and 12 months from the date of first dose of study drug, respectively.
PFS as determined by the time interval from date of first dose of study drug to first documented
disease progression or death from any cause, whichever occurs first.
DCR as determined by the proportion of subjects with CR, PR, or SD.  
QoL as measured from the date of first dose of study drug/baseline and then every 4 weeks using
the EORTC-QLQ-C30 (see Appendix C).   The EORTC QLQ-C30 is a copyrighted instrument,
which has been translated and validated in over 100 languages and is used in more than 3,000
studies worldwide. Presently QLQ-C30 Version 3.0 is the most recent version.  It is
supplemented by disease-specific modules for e.g. Breast, Lung, Head & Neck, Esophageal,
Ovarian, Gastric, Cervical cancer, Multiple Myeloma, Esophago-Gastric, Prostate, Colorectal
Liver Metastases, Colorectal and Brain cancer which are distributed by the EORTC Quality of
Life Department. Other disease specific modules are under development but not yet validated.
8.4.3 Planned Method of Analysis
The primary and secondary efficacy endpoints, which include PFS, DCR, OS and QoL will be
tabulated and graphed as appropriate.  The Kaplan-Meier survival curve will be graphed with
confidence intervals.  A 5% level test of the median survival, based on an exponential maximum
likelihood estimator test, will be conducted to determine if median survival is statistically greater
than 2.8 months.  Adverse events and serious adverse events will be annotated and tabulated to allow
for a quantitative assessment of the safety and tolerability of abemaciclib.  Potential factors
associated with the efficacy of abemaciclib, including subtypes of BTC subtypes, and tumor
molecular profiles, will be explored with a Cox proportional hazards model.  Reproducible statistical
reports will be produced.
The QLQ-C30 is composed of both multi-item scales and single-item measures including a global
health status/QoL scale, five functional scales and three multi-item symptom scales and six single
item scales. For the multi-item scales, the raw score, RS, is calculated by taking the mean of the
individual item scores. Then a linear transformation is applied to standardize the raw score so that
scores range from 0 to 100. The linear transformations for each scale type
(functional/symptom/global health status) are different and clearly documented in the EORTC QLQ-
C30 Scoring Manual. Descriptive statistics of the QLQ-C30 scales will be reported and Spaghetti
plot graphics will be produced to visualize the responses. No statistical analyses are planned for this
secondary measure.
8.5 Safety Variables and Analysis
8.5.1 Safety Variables
The safety and tolerability of abemaciclib treatment will be assessed throughout the study by
evaluating AEs.
8.5.2 Safety Analysis


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The safety analysis set will be used for all safety analyses.
All AEs will be graded by CTCAE v 5.0. Summaries will be presented for all AEs (overall and by
severity), AEs determined by the investigator to be related or not related to study treatment (overall
and by severity), SAEs, serious treatment-related AEs, AEs leading to withdrawal, and Grade 3 and 4
AEs. Participant listings of AEs, SAEs, Grade 3 and 4 AEs, and AEs leading to withdrawal will be
presented.  
The number and percentage of participants with Grade 3 or 4 values will be tabulated. Summaries of
laboratory values for laboratory parameters will be completed as applicable.  Vital signs
abnormalities will be categorized and tabulated. Summaries of the vital signs measurements will be
provided.
The use of concomitant medications will be summarized by therapeutic class using descriptive
statistics. Concomitant medications will include all medications taken while the participant is treated
with study drug.
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error, median,
minimum, and maximum) will be provided for actual values and changes from baseline to each time
point. For categorical variables, participant counts and percentages will be provided. Descriptive
summaries of SAEs, participant withdrawals due to AEs, and potentially clinically significant
abnormal values (clinical laboratory or vital signs) based on predefined criteria will also be provided.
If any participant dies during the study, a listing of deaths will be provided and all relevant
information will be discussed in the participant narrative.
8.6 Safety Analysis
The data safety monitoring committee (DSMC) will review all safety data following recruitment of
the 5 subjects. If the DSMC requests earlier views of the safety data, the appropriate data will be
cleaned and provided.   The study may be terminated early if unexpected toxicities are observed, but
this should be unanticipated. No interim analyses are planned for this pilot study.
9.0 CONFIDENTIALITY, PRIVACY, AND DATA MANAGEMENT
The Principal Investigator will strictly adhere to the research data security and integrity plan put forth
in the following Penn State Health Institutional policy “HRP-598 – Research Data Plan Review
Form”.
9.1 Patient Identifiers associated with data and/or specimens
Participants will be identified in all reports using a protocol specific unique patient identification
number. A Master list linking these unique identification numbers and the participant is maintained
in the limited access, password protected Cancer Institute OnCore Clinical Trials Management
System (CTMS).
9.2 Data Storage
Data will be maintained in the OnCore CTMS per institutional requirements for data access and
security.  OnCore is a limited access, password protected system maintained in the Cancer Institute.  


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All data will be retained in the CTMS until the time period required by the FDA and institutional
IRB.  Data destruction will be completed according to institutional policies.
10.0 ASSESSMENT OF SAFETY AND ADVERSE EVENT REPORTING
In this study, safety will be assessed by the PI by evaluating results of assessments including but not
limited to verbal inquiries, physical examinations, clinical laboratory test results, vital signs
measurements, ECG findings, and concomitant medication usage.
10.1 Adverse Events
10.1.1 Definition of an AE
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product,
regardless of whether it has a causal relationship with this treatment.
An AE can, therefore, be any unfavorable and unintended physical sign, symptom, or laboratory
parameter that develops or worsens in severity during the course of the study, or significant
worsening of the disease under study or of any concurrent disease, whether or not considered related
to the study drug. A new condition or the worsening of a pre-existing condition will be considered an
AE. Stable chronic conditions (such as arthritis) that are present before the participant signs the
informed consent form and do not worsen during the study will not be considered AEs.
Accordingly, an AE can include any of the following:
Intercurrent illnesses
Physical injuries
Events possibly related to concomitant medication
Significant worsening (change in nature, severity, or frequency) of the disease under study or
other pre-existing conditions. (Note: A condition recorded as pre-existing that is
intermittently symptomatic [e.g., headache] and which occurs during the study should be
recorded as an AE.)
Drug interactions
Events occurring during diagnostic procedures
Laboratory or diagnostic test abnormalities that result in the withdrawal of the participant
from the study, are associated with clinical signs and symptoms or an SAE, or require
medical treatment or further diagnostic work-up, or are considered by the Principal
Investigator to be clinically significant. Note: Abnormal laboratory test results at the
screening visit that preclude a participant from entering the study or receiving study
treatment are not considered AEs, but will be evaluated to monitor data from participants
who do not meet screening criteria.
All events of possible drug-induced liver injury with hyperbilirubinemia (defined as aspartate
aminotransferase [AST] or alanine aminotransferase [ALT]
times the upper limit of the
normal range [ULN], plus either bilirubin
times the ULN or international normalized ratio
[INR]>1.5) or Hy’s Law events require immediate study treatment cessation and reporting as
a SAE.
Disease progression (or progressive disease) or death due to disease progression will not be
considered an AE or a SAE in this study, but will be collected as an efficacy assessment.


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10.1.2 Recording and Reporting AEs
In this study, any AE occurring after the study participant has signed the informed consent form but
prior to the initiation of study medication will be recorded as medical history.  The commencement
of AE collection will begin at the time of initiation of study medication (Cycle 1, Day 1).  AE
collection will continue up to and including the EOT visit.  Those AEs that are determined to be
related to the study treatment that are ongoing at the time of the EOT visit, will continue to be
monitored until the event resolves or improves to baseline or Grade 1.  For this study, the EOT visit
may occur up to approximately 30 days after the last dose of study drug.   
All AEs that occur during the defined study period must be recorded in the source documentation.   
Signs and symptom will be recorded and entered into the database individually, except when
considered manifestations of a medical condition or disease state.   When such a diagnosis is made,
all related signs, symptoms, and any test findings will be recorded collectively as a single diagnosis.  
A precise medical diagnosis will be recorded whenever possible.
Abnormal laboratory values or diagnostic test results will constitute AEs only if they induce clinical
signs or symptoms or require treatment or further diagnostic tests. Disease progression will not be
recorded as an AE.
When known, the onset and end dates, duration, action taken regarding study drug, and outcome for
each AE should be recorded on the source documentation and entered in the study database.  The
guidelines relating to expectedness of each AE, relationship of each AE to study drug treatment and
study procedures, and the severity and seriousness of each AE, as judged by the investigator, is
described below.
10.1.3 Expectedness of an AE
An AE that is not included in the Listing of Adverse Drug reactions in the Investigator’s Brochure
for Abemaciclib, by its specificity, severity, outcome, or frequency, is considered an unexpected AE.
If necessary, Lilly’s U.S. Pharmacovigilance Department may assist the Principal Investigator,  to
determine the expectedness for SAEs especially in the event it is related, unexpected and of special
interest.
10.1.4 Relationship of an AE to the Study Drug
The relationship of an AE to the study drug is characterized as follows:
Term
Definition
Clarification


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Term
Definition
Clarification
No
reasonable
possibility
(not related)
This category applies to
AEs which, after careful
consideration, are clearly
due to extraneous causes
(disease, environment,
etc.) or to AEs, which,
after careful medical
consideration at the time
they are evaluated, are
judged to be unrelated to
the study drug.
The relationship of an AE may be considered “no
reasonable possibility” if it is clearly due to extraneous
causes or if at least 2 of the following apply:
It does not follow a reasonable temporal sequence
from the administration of the test drug.
It could readily have been produced by the
participant’s clinical state, environmental or toxic
factors, or other modes of therapy administered to
the participant.
It does not follow a known pattern of response to the
test drug.
It does not reappear or worsen when the drug is
re-administered.
Reasonable
possibility
(related)
This category applies to
AEs for which, after
careful medical
consideration at the time
they are evaluated, a
connection with the test
drug administration
cannot be ruled out with
certainty nor felt with a
high degree of certainty to
be related to the study
drug.
The relationship of an AE may be considered
“reasonable possibility” if at least 2 of the following
apply:
It follows a reasonable temporal sequence from
administration of the drug.
It cannot be reasonably explained by the known
characteristics of the participant’s clinical state,
environmental or toxic factors, or other modes of
therapy administered to the participant.
It disappears or decreases on cessation or
reduction in dose. There are important
exceptions when an AE does not disappear upon
discontinuation of the drug, yet drug-relatedness
clearly exists.
It follows a known pattern of response to the test
drug.
10.1.5 Severity of an AE
The severity of each AE will be graded according to the National Cancer Institute Common
Terminology Criteria for AEs, current version 5.0 (NCI CTCAE version 5.0).
AEs that are not included in the NCI CTCAE lists will be graded according to the NCI CTCAE
general guideline for grades as follows:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated


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Grade 2 Moderate; minimal, local intervention, or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living (ADL), e.g., preparing meals,
shopping for groceries or clothes, using the telephone, managing money
Grade 3   Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL, e.g., bathing,
dressing and undressing, feeding self, using the toilet, taking medications, and not
bedridden.
Grade 4    Life-threatening consequences; urgent intervention indicated
Grade 5    Death related to AE
10.2 Serious Adverse Events
10.2.1 Definition of a SAE
A SAE is an AE occurring at any dose that results in any of the following outcomes or actions:
Death
A life-threatening AE (i.e., the participant was at immediate risk of death from the event as it
occurred); does not include an event that, had it occurred in a more severe form, might have
caused death
Inpatient hospitalization or prolongation of existing hospitalization means that hospital
inpatient admission and/or prolongation of hospital stay were required for treatment of an
AE, or that they occurred as a consequence of the event. Hospitalizations scheduled for an
elective procedure or for treatment of a pre-existing condition that has not worsened during
participation in the study will not be considered SAEs.
Persistent or significant disability or incapacity (refers to a substantial disruption of one’s
ability to conduct normal life functions)
A congenital anomaly or birth defect
An important medical event that may not result in death, be life-threatening, or require
hospitalization, but may jeopardize the participant and may require medical intervention to
prevent one of the outcomes listed in this definition. Examples of such events are intensive
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization; or the development of drug dependency or
drug abuse. Note: Any suspected transmission of an infectious agent via a medicinal product
is considered an important medical event.
Reportable AEs, UAP, SAEs and Protocol Violation reporting to DSMC
Type of Event
To whom will it be
reported
Time Frame for
Reporting
How to report?


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10.3 Reporting of AEs and SAEs
10.3.1 Investigator Responsibility
An unanticipated AE is one that is deemed to be unexpected and related (reasonable possibility) to
the investigational medication.  All unanticipated AEs that occur during the protocol specific AE
observation time period must be reported to the Principal Investigator immediately.  If a serious
unexpected AE is believed to be related to the study drug or study procedures, the Principal
Investigator will take appropriate steps to notify all the appropriate regulatory authorities.
All SAEs will be reported to the sponsor within 24 hours of knowledge. SAEs will be reported to the
sponsor using the MedWatch Form 3500A. Updates to the SAE should be made as events change.
The Sponsor-Investigator will submit a written IND Safety Report (i.e., completed FDA Form
3500A) to the responsible new drug review division of the FDA for any observed or volunteered
adverse event that is determined to be a serious and unexpected, suspected adverse reaction.  Each
IND Safety Report will be prominently labeled, “IND Safety Report”, and a copy will be provided to
all participating investigators (if applicable) and sub-investigators.
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no event, later
than 15 calendar days following the Sponsor-Investigator’s receipt of the respective adverse event
information and determination that it meets the respective criteria for reporting.
Death of a research
participant unless the
death is expected
(e.g., due to disease
progression).
PSCI DSMC and
designated IRB, if
applicable per IRB policy.
DSMC: Within 24
hours
DSMC: Email to PSCI-
DSMC@pennstatehealth.psu.edu
Serious Adverse Event,
regardless of relatedness of
expectedness
PSCI DSMC and
designated IRB, if
applicable per IRB policy.
DSMC: Within 10
working days
from the time the
study team
received
knowledge of the
event.
DSMC: Email to PSCI-
DSMC@pennstatehealth.psu.edu
Unanticipated Problems
that are not adverse events
or protocol deviations  
PSCI DSMC and
designated IRB, if
applicable per IRB policy.
DSMC: Within 10
working days
from the time the
study team
received
knowledge of the
event.
DSMC: Email to  PSCI-
DSMC@pennstatehealth.psu.edu


Protocol Version dated:  4/18/2023
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For each written IND Safety Report, the Sponsor-Investigator will identify all previously submitted
IND Safety Reports that addressed a similar suspected adverse reaction experience and will provide
an analysis of the significance of newly reported, suspected adverse reaction in light of the previous,
similar report(s) or any other relevant information.
Relevant follow-up information to an IND Safety Report will be submitted to the applicable review
division of the FDA as soon as the information is available and will be identified as such (i.e.,
“Follow-up IND Safety Report”).
If the results of the Sponsor-Investigator’s follow-up investigation show that an adverse event that
was initially determined to not require a written IND Safety Report does, in fact, meet the
requirements for reporting; the Sponsor-Investigator will submit a written IND Safety Report as soon
as possible, but in no event later than 15 calendar days, after the determination was made.
In addition to the subsequent submission of a written IND Safety Report (i.e., completed FDA Form
3500A), the Sponsor will notify the responsible review division of the FDA of any unexpected, fatal
or life-threatening suspected adverse reaction.
The telephone or facsimile transmission of applicable IND Safety Reports will be made as soon as
possible but in no event later than 7 calendar days after the Sponsor-Investigator’s receipt of the
respective adverse event information and determination that it meets the respective criteria for
reporting.
Unexpected and related AEs as defined by Penn State IRB (regardless of grades) and SAEs will be
reported to the Penn State IRB expeditiously per their requirements.    The study funder, Eli Lilly,
will be notified within one business day of Investigator and/or Institution receiving notification of
any “serious” adverse event experienced by a patient participating in the Study and receiving Study
Drug.  For purposes of this requirement, “serious” means:  (1) death; (2) in-patient hospitalization or
prolonged hospitalization; (3) life-threatening; (4) persistent or significant disability or incapacity;
(5) congenital anomaly or birth defect; or (6) other serious events that may jeopardize the patient and
may require medical or surgical intervention to prevent one of the other five listed outcomes.  Serious
adverse events should be reported to Lilly using a MedWatch 3500A Form (FAX #: 866-644-1697).  
Investigator and Institution further agree to make available promptly to Lilly such records as may be
necessary and pertinent for Lilly to further investigate an adverse event in the Study that is possibly
associated with the Study Drug.
Based on the unanticipated toxicity, the Sponsor/Investigator, Dr Nelson Yee may take the following
steps where applicable:
Amending the current protocol
Discontinuing or suspending the study
Altering the process of informed consent by modifying the existing informed consent form and
informing current study participants of any new findings.  This includes modifying listings of
expected toxicities to include AEs newly identified as related to the study medication.
The Principal Investigator must ensure that the IRB and DSMC are also informed of the event, in
accordance with local regulations.
10.4 Pregnancy


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All pregnancies (pregnancies of women participating in the study and partners of men participating
in the study) that occur during the study, or 30 days after last dose of the study drug, are to be
reported immediately to the individual identified in the clinical study personnel contact information
section of this protocol, and the Principal Investigator must provide the Eli Lilly’s USA
Pharmacovigilance Department with MedWatch 3500A   form (FAX: 866-644-1697). Although
pregnancy is not a SAE, the process for reporting a pregnancy is the same as that for reporting a
SAE.
Any participant becoming pregnant during the study will be withdrawn. All participants (or partners)
who become pregnant will be monitored to the completion or termination of the pregnancy. If the
pregnancy continues to term, the outcome (health of the infant up to 8 weeks of age), including
spontaneous or voluntary termination, details of birth, and presence or absence of any birth defect,
congenital abnormalities, or maternal and newborn complications, will be reported to Eli Lilly. Any
complication of pregnancy will be reported as an AE or SAE, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:
For a spontaneous abortion, report as a SAE.
For an elective abortion due to developmental anomalies, report as a SAE.
For an elective abortion not due to developmental anomalies, report on the pregnancy form.
11.0 STUDY MONITORING, AUDITING, AND INSPECTION
11.1 Protocol Amendments
No changes from the final approved protocol will be initiated without the prior written approval or
favorable opinion of a written amendment by the IRB/IEC, except when necessary to address
immediate safety concerns to the participants or when the logistical or administrative changes are
required.
11.2 Information to Study Personnel
The Principal Investigator is responsible for administering information about the study to all staff
members involved in the study or in any element of participant management, both before starting the
study and during the course of the study (e.g., when new staff become involved). The Principal
Investigator must assure that all study staff members are qualified by education, experience, and
training to perform their specific responsibilities. Study staff members must be listed on the
Delegation of Authority Log, which includes a clear description of each staff member’s
responsibilities. This list must be reviewed and updated throughout the study, as necessary.
The Principal Investigator is responsible for explaining the protocol to all study staff, including any
sub-investigators, and for ensuring they comply with the protocol. Additional information will be
made available during the study when new staff becomes involved in the study.
At monthly intervals, routinely scheduled meetings with the study staff members will be conducted at
the Penn State Cancer Institute. All sub-Investigators and study staff members will be notified of new
information regarding the safety of the study drug and presented updates on the study. Written
documentation of such notifications will be maintained in the regulatory files of the Clinical Trials
Office.


Protocol Version dated:  4/18/2023
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11.3 Study Monitoring
The Principal Investigator will ensure that this study is conducted and that the data are collected,
documented, and reported in compliance with this protocol, federal regulations, institutional and IRB
policies and procedures. Good Clinical Practice guidelines and any other applicable regulatory
requirements.  The study will be monitored by the PSCI Quality Assurance Department. The
monitors will provide an independent review of the regulatory and subject records and associated
data collected to assure appropriate compliance, ensuring human subject’s protection, examine the
quality, reliability, and integrity of data collected and provide opportunities for corrective action
while the study is ongoing. Comprehensive monitoring will be conducted by a PSCI Quality
Assurance monitor specifically for the PSCI-CTO and planned visits will start at Site Initiation Visit
(SIV), a visit will take place within two weeks after the first subject receives protocol treatment;
every 6-8 weeks until the last subject is enrolled, and thereafter every 4-6 months until all subjects
have come off active treatment. Once all subjects are on long term follow-up monitoring visits will
occur annually; the remaining visits will happen for close out; and ad-hoc for any study based on
findings.
The investigational site will provide direct access to all trial-related sites, source data/ documents,
and reports for the purpose of auditing by the DSMC, and inspection by local and regulatory
authorities.
11.4 Audit and Inspection
The Principal Investigator will allow for auditing and inspecting by all applicable federal, state and
local entities at any time.   Lilly Pharmaceuticals, the pharmaceutical manufacturer of abemaciclib
who is providing funding for this study, may audit the investigational center to evaluate study
conduct and compliance with protocols, SOPs, GCPs, and applicable regulatory requirements. The
Quality Assurance Unit at Lilly, independent of the PSCI Quality Assurance will be responsible for
determining the need for (and timing of) an investigational center audit.
The Principal Investigator and Sub-Investigators must accept that regulatory authorities and Eli Lilly
representatives may conduct inspections to verify compliance of the study with GCP guidelines.
The DSMC, study monitors from Penn State Cancer Institute Quality Assurance Department, any
auditors, the PSCI IRB, or any other health authority inspectors (or their agents) will be given direct
access to source data and documentation (e.g., medical charts/records, laboratory test results,
printouts, videotapes) for source data verification, provided that participant confidentiality is
maintained.
The Principal Investigator and any Sub-investigator must maintain all original source documents of
each participant’s data at all times. Examples of source documents are hospital records, office visit
records, examining physician’s finding or notes, consultant’s written opinion or notes, laboratory
reports, drug inventory, study drug label records, diary data, protocol required worksheets, and
eCRFs that are used as the source.


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12.0 DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD KEEPING
12.1 Data Collection
Direct data entry into to the Penn State Cancer Institute OnCore CTMS will be utilized for this study.  
In addition to demographics, medical history, concomitant medications, and safety data, only those
data needed to answer the study objectives will be included in the study database.  The assessments
and interventions noted in the Protocol Required Interventions and Assessments (Appendix B) will
not be entered into the database. This data includes dates and results of physical examinations, vital
signs, performance status, and laboratory results (CBC, Chemistry).  Any abnormal results of the
assessments will be captured as an AE according to the criteria noted in Section 10.  Any
concomitant medications administered for the purpose of procedures (anesthetics, etc.) will not be
included in the data collection. AEs and SAEs will be recorded after the start of study drug until 30
days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever
occurs first. AE that are ongoing at time will be checked or ongoing with no stop date. Unanticipated
SAEs (ie. Serious, unexpected, and related (even remotely)) will be reported on the SAE Submission
Form and entered in Oncore within 1 business day of discovery of the event.  All other SAEs will be
entered in the Oncore system within 5 business days. For screen failures (participants who sign the
informed consent form but do not meet eligibility criteria), data relating to failure reason and
demography will be captured.
Data will be reviewed for consistency by Data Management using both automated logical checks and
manual review.   The data collected will be reviewed and approved by the Principal Investigator or
designated Co-investigator on an approximately quarterly basis depending on enrollment.  Evidence
of the Principal Investigator or Co-investigator review and approval may be done electronically in
the OnCore CTMS.  This approval acknowledges the Principal Investigator’s review and acceptance
of the data as being, to the best of his knowledge, complete, accurate, and current per the date
documented on the form. Data will be verified using source documentation by the Study Monitor.
12.2 Reporting and Publication of Results
The Principal Investigator is responsible for ensuring that the public has access to the appropriate
information about the study by conforming to requirements for registration and publication of results.
The data of this study will be submitted to American Society of Clinical Oncology Gastrointestinal
Cancers Symposium and American Society of Clinical Oncology Annual Meeting for presentation.
In addition, the data will be written in a manuscript and submitted to journals such as Journal of
Clinical Oncology, Cancer, Lancet Oncology, World Journal of Gastroenterology, and World Journal
of Clinical Oncology.
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significances of EGFR, KRAS and BRAF mutations in biliary tract carcinomas in Taiwan. J
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Yamamoto S, Kajiyama G. Gene mutations of K-ras in gallbladder mucosae and gallbladder
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advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.
Lancet Oncology 2014; 15:819-828.
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Journal of Gastroenterology 2015a; 22:1335-1347.
Marks EI, Yee NS. Immunotherapeutic approaches in biliary tract carcinoma: Current status and
emerging strategies. World Journal of Gastrointestinal Oncology 2015b; 7:338-346.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Onc 1982; 5:649-655.
Patnaik A, Rosen LS, Tolaney SM,Tolcher AW, Goldman JW, Gandhi L, Papadoupoulos KP,
Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS,
Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY,
Shapiro GI. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with
breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discovery 2016; 6:1-14.
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between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinma.
Cancer Cells 2010; 18:63–73.
Rashid A, Ueki T, Gao YT, Houlihan PS, Wallace C, Wang BS, Shen MC, Deng J, Hsing AW. K-ras
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Anders RA. The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and
their correlation with clinical outcome. Human Pathol 2013; 44: 2768-2773.
Saetta AA, Papanastasiou P, Michalopoulos NV, Gigelou F, Korkolopoulou P, Bei T, Patsouris E.
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Garg P, Chaudhary SP. Best supportive care compared with chemotherapy for unresectable gall
bladder cancer: a randomized controlled study. Journal of Clinical Oncology 2010; 28: 4581-4586.
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Discovery 2016; 6:353-367.
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the K-ras, p53, and APC genes in extrahepatic bile duct cancer. J Surg Oncol 2000; 73: 158-163
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of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut
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Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind
C. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut
2003; 52: 706-712 [PMID: 12692057 DOI: 10.1136/gut.52.5.706]
Tate SC, Cai S, Ajamie RT, Burke T, Beckmann RP, Chan EM, De Dios A, Wishart GN, Gelbert
LM, Cronier DM. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor
activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor
xenografts. Clinical Cancer Research 2014; 20: 3763-3764.
Tian Y, Ding RY, Zhi YH, Guo RX, Wu SD. Analysis of p53 and vascular endothelial growth factor
expression in human gallbladder carcinoma for the determination of tumor vascularity. World J
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APPENDIX B – PROTOCOL REQUIRED INTERVENTIONS AND ASSESSMENTS
BASELINE ASSESSMENTS
DAYS PRIOR TO C1D1
COMMENTS
Informed Consent
X
Assessment of eligibility
X
Enrollment path report
X
Diagnostic Imaging for
Tumor Evaluation–RECIST
v. 1.1 Reading
X
Baseline CT or MRI scans of chest,
abdomen, and pelvis with contrast,
brain MRI or PET CT scans with
contrast are performed if symptomatic.
If hypersensitivity or known serious
allergic reaction to CT contrast,
consider MRI scans with gadolinium,
or alternatively chest CT scans without
contrast and abdomen/pelvic MRI
scans with contrast.
Medical History
X
including demographics, tobacco use
(if smokes or smoked, and smoking
pack year), surgical and psychiatric
history and cancer treatment history
Physical Examination
X
Height, weight and vital signs
(temperature, heart rate, respiration
rate, blood pressure).
Concomitant Medications
X
ECOG Performance Status
X
Triplicate 12-lead ECG
X
Any ECG abnormalities at baseline
will be followed up according to
standard of care.
Hematology
X
Serum Chemistry
X
Complete metabolic profile
Coagulation Profile
X
Urinalysis
X
Basic and microscopic if abnormal
sample is collected.
CA 19-9
X
Archival Tumor Samples
X
Formalin-fixed paraffin-embedded
tumor is requested following
confirmation of study eligibility.
Fresh Tumor Samples
X
If archival tissue is unavailable or
insufficient, repeat biopsy of tumor is
as clinically indicated.
Pregnancy Test
X
WOCP must have a negative serum
pregnancy test between Day -7 to Day
-1.
Notes:
Physical examination, including body weight
Hematology: complete blood counts with differential


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Serum Chemistry:  complete metabolic panel including Na, K, Cl, CO2, blood urea nitrogen,
creatinine, glucose, aspartate aminotransferase, total bilirubin, alkaline phosphatase, alanine
aminotransferase, albumin Coagulation Profile = PT,INR, PTT
Urinalysis - In case of abnormal parameters microscopic evaluation should be performed.
Tumor Samples (clinical routine) - Archival or fresh tumor tissue is required for subjects with
confirmation of diagnosis, as well as, for determination of exploratory mutational analysis as
described in Section 1.3.4.   
Biomarker Blood Sample (extracellular vesicles (EV) isolation) - will be collected at baseline
(within 28 days prior to C1D1 visit) and every 8 weeks (at the onset of every 3rd cycle).  Three
lavender-top EDTA glass tubes will be used to collect approximately 5 ml of blood in each tube,
and one 10-ml green-top sodium heparin tube will be used to collect approximately 7.5 ml of
blood in the tube.
ON STUDY TREATMENT SCHEDULE OF ASSESSMENTS
Cycle
1
Cycle
1
Cycle
2
Cycle
2
Cycle
3 – 8
Day within Cycle
1(+/-
3)
15(+/-
3)
1(+/-
3)
15(+/
-3)
1(+/-
3)
Instructions
Physical Examination
X
X
X
X
X
Including vital signs (temperature, heart
rate, respiration rate, blood pressure).
Weight
X
X
X
ECOG Performance
Status
X
X
X
X
X
Adverse Events
X
X
X
X
X
CTCAE 5.0
Concomitant
Medication
X
X
X
X
X
Diagnostic Imaging
for Tumor Evaluation
–RECIST v1.1  
Reading
X
CT or MRI scans of chest, abdomen and
pelvis with contrast are performed
every other cycle (every 8 weeks ± 7
days). If hypersensitivity or known
serious allergic reaction to CT contrast,
consider MRI scans with gadolinium;
alternatively chest CT scans without
contrast and abdomen/pelvic MRI scans
with contrast.
12-lead ECG
X
ECG as a baseline and subsequently if
clinically indicated.
Hematology
X
X
X
X
X
3 days prior to day 1 of each cycle,
unless more frequent assessment is
clinically indicated.
Serum Chemistry
X
X
X
X
X
3 days prior to day 1 of each cycle,
unless more frequent assessment is
clinically indicated.
CA 19-9
X
X
X
EORTC-QLQ-C30
X
X
X


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Dispense
Abemaciclib
X
X
X
Abemaciclib is taken orally every 12
hours on days 1 through 28 of each
cycle regardless of food intake.
Collection of Unused
Study Drug
X
X
Study Drug Diary
X
X
Extracellular vesicles
X
X
Every 8 weeks (±3 days) until disease
progression or End of Treatment visit.
Participants who are deriving clinical benefit after completing the treatment period may
continue on additional cycles of therapy at the discretion of the sponsor and medical monitor.  
Any participant on abemaciclib after completing the treatment period will be monitored and
assessed for tumor response .
POST-TREATMENT FOLLOW-UP SCHEDULE OF ACTIVITIES
EOT a
Long-Term
Follow-Up c
Instructions
Physical Examination
X
Including vital signs measurements
(temperature, heart rate, respiration rate,
blood pressure).
Weight
X
ECOG Performance Status
X
Adverse Events
X
Only collected for unresolved AEs
Grade 3 and related to the study drug.
Concomitant Medication
X
Collection of Unused
Study Drug
X
Diagnostic Imaging –for
Tumor Evaluation
RECIST v.1.1
Reading
X
X
Every 3 months (± 7 days) beginning 3
months after last dose of the study drug for
subjects who have not progressed.
Survival information
X
Every 3 months (± 7 days) x2, beginning 3
months after last dose of the study drug
then every 6 months (± 7 days) thereafter.
Post-Study Treatment
Anti-Cancer Therapy
X
X
Every 3 months (± 7 days) x2, beginning 3
months after last dose of the study drug,
then every 6 months (± 7 days) thereafter.
Hematology
X


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Serum Chemistry
X
Coagulation Profile
X
Urinalysis
X
CA 19-9
X
12-lead ECGb
X
EORTC-QLQ-C30
X
Collection of Unused
Study Drug
X
Study Drug Diary
X
Extracellular vesicles
X
a End-of-treatment (EOT) visit will be completed up to 30 days (± 7 days) after last dose study drug.   
b as clinical indicated.
c. A follow-up visit will be conducted every 3 months (± 7 days) x2, beginning 3 months after last
dose of the study drug then every 6 months (± 7 days) thereafter.


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APPENDIX C.  EORTC QLQ-C30


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ICF_001.pdf: 
Page 1 of 16 (v.12/19/2018)
IRB STUDY00010946
PSCI # 18-052
Version Date:  18APR2023
CONSENT FOR RESEARCH
Penn State College of Medicine
Penn State Health
Title of Project:
A Pilot Study to Evaluate the Response and Tolerability of Verzenio
(Abemaciclib) in Patients with Advanced Biliary Tract Carcinoma
Principal Investigator and Study Sponsor:
Nelson Yee, M.D., Ph.D.
Address:
Penn State Cancer Institute – Clinical Trials Office
Rm T2200, MC: CH56
500 University Drive
Hershey, PA 17033
Telephone Numbers: Weekdays: 8:00 a.m. to 5:00 p.m. (717) 531-8678. After hours call (717) 531-
8521. Ask for the Hematology/Oncology doctor on 24-hour call.
Subject’s Printed Name: __________________________________________________________
We are asking you to be in a research study.
Whether or not you take part is up to you. You can choose not to take part. You can
agree to take part and later change your mind. Your decision will not be held against you,
and there will be no penalty or loss of benefits to which you are entitled.
This form gives you information about the research. Please ask questions about
anything that is unclear to you and take your time to make your choice.
KEY INFORMATION
The following is a short summary of this study to help you decide whether or not to be a
part of this research. More detailed information is provided later in this form. If you have
any questions, be sure to ask the study team.
Why am I being invited to take part in this research study?
You have been asked to participate in this study because you have advanced biliary tract
carcinoma that has progressed (worsened) despite initial treatment, or you did not tolerate the
previous chemotherapy, or you are considered not a good candidate for first-line systemic therapy.
What is the purpose of this research study?
The purpose of this voluntary research study is to investigate the use of a medication called
Verzenio™or Abemaciclib for your disease. Abemaciclib is a medicine that targets certain
proteins in cancer cells and stops the cancer cells from growing.
How long will the research study last?
If you agree to take part, it will take you about 3 years to complete this research study. You may
continue to take part in the study until your disease progresses (or gets worse), you experience
serious side effects or you decide to withdraw from the study.


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What will I need to do?
If you choose to participate there is a screening period, treatment period and a long term follow up
period. You will need to take the study medication by mouth twice a day as directed, you will be
asked to keep a study drug diary while you are taking the study medication, you will need to come
to all your scheduled study visits, and make sure you talk to your study doctor or study staff about
any side effects you are experiencing while participating in this study.
What are the main risks of taking part in the study?
You may have side effects while on the study. There are side effects of the study drug Abemaciclib.
In addition, you may have side effects from other medication you are receiving as part of your routine
care for your disease. Some of the common side effects are as follows: loose stools, belly pain or
swelling, lack of energy, weakness, fatigue, feeling sick to the stomach, low appetite, decreased
number of white blood cells, low red blood cell count, decreased number of platelets, bruising,
difficulty with blood clotting, or bleeding easily, dry mouth, inflammation or ulcers inside the mouth,
taste changes or bad taste in the mouth, hair loss, headache, jaundice (or the yellowing of the eyes
and skin), fever, joint pain, cough, and dark-colored urine.
Everyone taking part in the study will be watched carefully for any side effects. However,
researchers don’t know all the side effects that may happen. You may experience none, some, or
many of the side effects listed below. Side effects may be mild or very serious, including a risk of
death. Your health care team may give you medicines to help lessen side effects.
What are the possible benefits to me that may reasonably be expected from being in the
research?
There is no guarantee that you will benefit from this research. It is possible that the medication
Abemaciclib may help to prevent your cancer from growing. However, the information from this
study will help investigators learn more about the medication Abemaciclib and its effect on
advanced biliary tract carcinoma.
What happens if I do not want to be in this research?
Participation in research is completely voluntary. You can decide to participate or not to participate.
Instead of participating in this research, you could:
Be part of a different research study, if one is available.
Receive standard of care treatment that is FDA approved.
Choose not to be treated for your medical condition and only receive care to make you
more comfortable.
DETAILED INFORMATION
The following is more detailed information about this study in addition to the information
listed above.
1. Why is this research study being done?
You have been asked to participate in this study because you have advanced biliary tract
carcinoma that has progressed (worsened) despite initial treatment, or you did not tolerate the
previous chemotherapy.   We are studying the use of a medication called Verzenio™or
Abemaciclib for your disease.  Abemaciclib is a medicine that targets certain proteins in cancer
cells and stops the cancer cells from growing.   


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The United States Food and Drug Administration (FDA) has approved Abemaciclib as a type of
treatment for patients with advanced breast cancer.   Researchers have found that some of the
genetic mutations (changes in DNA) present in breast cancer cells are also found in biliary tract
cancer.  For this reason, the doctors would like to find out if use of Abemaciclib can help stop
the growth of your disease.   Because Abemaciclib has not been FDA approved for biliary tract
carcinoma, use of this medication for your disease is considered research (or investigational).   
We expect about 10 people will take part in this research study at Penn State Cancer Institute in
Hershey, PA over the next few years.
2. What will happen in this research study?
Study Screening:
If you agree to participate, the research team will evaluate you to see if you are able (or eligible) to
take part in this study. As part of this screening you will need to have the following exams and tests.
These exams and tests are part of regular cancer care and may be done even if you did not join the
study. If you have had some of them recently, they may not need to be repeated.
Your doctors will ask you about your medical history, surgical and psychiatric history, any
previous cancer treatments, smoking history, and other medications you are taking.
A physical examination, which includes your vital signs (heart rate, breathing rate,
temperature, and blood pressure), height, weight
How you are performing in terms of your activities of daily living (called a “performance status
assessment”), and your overall health status (heart, lungs, kidneys, liver, etc.).
Blood tests to look at how your blood, immune system, kidneys, and liver are functioning.
About 2 teaspoons of blood are needed for these tests.
A urinalysis used to test for abnormalities like infection or kidney problems.
Females who are able to have a child will be required to take a pregnancy blood test within
7 days prior to the study treatment. About 1 teaspoon of blood is needed for this test.
A 12-lead electrocardiogram (also called ECG, an electrical tracing of your heartbeat) and
echocardiogram (sound waves to make pictures of your heart, which helps show how well
your heart pumps blood) to check for signs of heart disease.
Tumor evaluation include CT scans (Computerized series of x-rays), and/or MRI scans of
your chest, belly, pelvis and brain (Magnetic resonance imaging, body pictures created by
using magnetic energy rather than x-ray energy. To have the scans, you will lie on a table
that slides into the scanner, which is like a large tube). A PET/CT (uses a small amount of a
radioactive drug to show differences between healthy tissue and tumor tissue) can also be
used to scan your chest, upper belly and lower belly to measure your disease.
You either had or will have a tumor biopsy taken for your routine care. If there is enough
sample left over, a piece of the tumor biopsy sample taken for your routine care will be
requested for research testing. If there is not enough tissue from previous tumor samples
then a fresh biopsy will be collected for diagnosis and to analyze the mutation of your cancer
cells.
On the day you start the study medication-Abemaciclib
Before you receive your first dose of Abemaciclib, the following assessments are required:
A physical examination including your weight, and vital signs which include temperature,
heart rate, breathing rate and blood pressure
Your performance status assessment


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Blood tests to look at how your blood, immune system, kidneys, and liver are functioning and
if there are any changes that may be related to the study medication. About 2 teaspoons of
blood are needed for these tests
ECG (12-lead electrocardiogram, as clinically indicated)
Your doctors will ask you about other medications you are taking
Your doctor will ask about any symptoms you might experience.
A questionnaire about your health called EORTC-QLQ-C30. You may skip any questions on
this questionnaire that you would prefer not to answer
A blood test for biomarkers. Biomarkers are proteins found in the blood and on cancer cells
that can tell your doctors how your body and disease are responding to different types of
treatment. This test will require about 4.5 teaspoons of blood.
Study Medication - Abemaciclib
How do I take Abemaciclib?
Take this study medication twice a day for 28 days (a “cycle’) as ordered by your study doctor.
Follow all instructions closely.
Take with or without food.
Take at a similar time of day, twice daily.
Swallow as a whole capsule and do not chew, crush or split capsules before swallowing.
Do not use if the capsule is broken or cracked.
To gain the most benefit, do not miss doses.
Keep taking this drug as directed, even if you feel well.
Drink lots of liquids every day (about 8-10 glasses of clear liquid) unless told to drink less
liquid by your doctor.
Avoid grapefruit and products that contain grapefruit juice, orange juice or pomelo products
during treatment with Abemaciclib. These products, such as grapefruit juice decreases the
body’s ability to breakdown the study drug resulting in increased blood level of the study drug
that may result in the risk for new or worsened side effects.
Do not take a medication called ketoconazole or any medication containing ketoconazole.
If you throw up after taking a dose, do not repeat the dose. Take your next dose at your
normal time.
Write in your diary the dates and times of taking the drug and any symptoms you might
experience.
For your safety, you must tell the study doctor or nurse about all the prescription drugs, herbal
products, over-the-counter drugs (OTC), vitamins and other supplements you are taking.
Check with the study doctor before starting any new medicines (including prescription, OTC
drugs, vitamins and herbal supplements) or changing doses of medications that you are
already taking.
What do I do if I miss a dose?
Skip the missed dose and go back to your normal time.
Do not take 2 doses at the same time or extra doses to make up for missing a dose.
How do I store and/or throw out Abemaciclib?
Store at room temperature.
Store in a dry place. Do not store in a bathroom.
Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
Return unused drug to the next clinic visit.


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During Treatment Cycles (28-Day cycles)
The following procedures and assessments will be performed on days 1 (±3 days) of cycle 1 and 2.
Review of all prescription drugs, herbal products, over-the-counter drugs, vitamins and other
supplements and supplements you have taken along with Abemaciclib.
Performance status
Physical examination
Body weight
Vital signs measurements (including temperature, heart rate, breathing rate, and blood
pressure)
ECG (C1D1 only, as clinically indicated)
Blood tests that include how your blood, immune system, kidneys, and liver are functioning
and if there are any changes that may be related to the study medication. About 2 teaspoons
of blood is needed for these tests
A blood test for biomarkers. Biomarkers are proteins found in the blood and on cancer cells
that can tell your doctors how your body and disease are responding to different types of
treatment. This test will require about 4.5 teaspoons of blood (C1D1 only).
Receipt of Abemaciclib on day 1 of each cycle
Write in your diary the dates and times of taking the drug and any symptoms you might
experience.
Review of your diary (C2D1 only)
Return any unused Abemaciclib (C2D1 only).
A questionnaire about your health called EORTC-QLQ-C30. You may skip any questions on
this questionnaire that you would prefer not to answer
Your doctor will ask about any symptoms you might experience
The following procedures and assessments will be performed on day 15 (±3 days) of cycle 1 and
2.
Review of all prescription drugs, herbal products, over-the-counter drugs, vitamins and other
supplements and supplements you have taken along with Abemaciclib.
Performance status
Physical examination
Vital signs measurements (including temperature, heart rate, breathing rate, and blood
pressure)
Blood tests that include how your blood, immune system, kidneys, and liver are functioning
and if there are any changes that may be related to the study medication. About 2 teaspoons
of blood is needed for these tests
Your doctor will ask about any symptoms you might experience
The following procedures and assessments will be performed on cycle 3 through cycle 8 or
subsequent cycles should you have clinical benefit, unless otherwise noted.
Review of all prescription drugs, herbal products, over-the-counter drugs, vitamins and other
supplements and supplements you have taken along with Abemaciclib.
Performance status
Physical examination
Vital signs measurements (including temperature, heart rate, breathing rate, and blood
pressure)


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Blood tests that include how your blood, immune system, kidneys, and liver are functioning
and if there are any changes that may be related to the study medication. About 2 teaspoons
of blood is needed for these tests
A blood test for biomarkers. Biomarkers are proteins found in the blood and on cancer cells
that can tell your doctors how your body and disease are responding to different types of
treatment (every 8 weeks until end of treatment visit). This test will require about 4.5
teaspoons of blood.
Tumor evaluation, including CT/MRI/PET of your chest, belly, pelvis and brain as applicable,
every other cycle (every 8 weeks)
Receipt of Abemaciclib on day 1 of each cycle
Write in your diary the dates and times of taking the drug and any symptoms you might
experience.
Review of your diary
Return any unused Abemaciclib and study diary on day 1 of each cycle except cycle 1.
A questionnaire about your health called EORTC-QLQ-C30. You may skip any questions on
this questionnaire that you would prefer not to answer
Your doctor will ask about any symptoms you might experience
End of Treatment (up to 30 days (± 7 days) after last dose study drug)
If you complete the study or withdraw prematurely, final evaluations will be performed at the end-of-
treatment visit or on the last day the you take Abemaciclib. The following procedures will be
performed:
Physical examination including body weight
Vital signs measurements
Performance status
ECG (as clinically indicated)
Your doctor will ask about any symptoms you might experience
Your doctors will ask you about other medications you are taking
Your doctors will ask you any anti-cancer therapy you had after completion of this study
Blood tests that include how your blood, immune system, kidneys, and liver are functioning
and if there are any changes that may be related to the study medication. About 2 teaspoons
of blood are needed for these tests
A blood test for biomarkers. This test will require about 4.5 teaspoons of blood.
A urinalysis used to test for abnormalities like infection or kidney problems.
Tumor evaluation, including CT/MRI/PET of your chest, belly, pelvis and brain as applicable
Return any unused study medication Abemaciclib and study diary.
A questionnaire about your health called EORTC-QLQ-C30. You may skip any questions on
this questionnaire that you would prefer not to answer
Long Term Follow-Up Visits
A follow-up visit will be conducted every 3 months +/- 7 days x2 beginning 3 months after the last
dose of Abemaciclib then every 6 months +/- 7 days thereafter. The following procedures will be
performed at the follow-up visit:
Tumor evaluation, including CT/MRI/PET of your chest, belly, pelvis and brain as applicable
every 3 months until your disease progression.
Your doctors will ask you have had any anti-cancer therapy.
Research Testing


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In addition to all the other blood tests you will undergo at your visits, we will obtain some additional
blood for research purposes only.
One blood test will be done every 8 weeks.
A total of 4.5
teaspoons of blood is needed for this test each visit. This test will be obtained at the same time as
your routine blood testing. For this reason, no additional needle sticks should be required.
A blood test will be done to look at different blood biomarkers called extracellular vesicles.
When certain cells in the body grow, they produce (secrete) proteins called extracellular
vesicles into the bodily fluids (blood, urine). Biliary tumors produce specific extracellular
vesicles that can be found in the blood. The research doctors would like to find out if checking
these extracellular vesicles will help show if the cancer is growing.
2a. What are my responsibilities if I take part in this research?
In order to obtain useful, complete data about how Abemaciclib works with your disease, you will
be expected to do the following:
Attend all of your routine visits as scheduled by your physician
Let your physician know if you are having any new health concerns and when they
started.
For example, if you have recently started to have red patches on your skin,
you should let your physician know as soon as possible and when it started.
Tell your physician or research team member if you have any changes in medications
or allergies while you are taking part on this study.
Follow the directions of your treating physicians and research team
Do not participate in other research studies while you are a subject in this study
Tell the research team member if you wish to stop being in the study.
Avoid consumption of grapefruit, grapefruit juice, orange juice and pomelo products
while taking the study drug due to possible drug interactions.
At the first sign of loose stools, start an antidiarrheal therapy as instructed by the study
doctor and notifying the study doctor or study staff for further instructions and
appropriate follow up.
Drink plenty of fluids, it is recommended about 8-10 glasses of clear fluids each day.
For your safety, you must tell the study doctor or nurse about all the prescription drugs,
herbal products, over-the-counter drugs (OTC), vitamins and other supplements you
are taking. Check with the study doctor before starting any new medicines (including
prescription, OTC drugs, vitamins and herbal supplements) or changing doses of
medications that you are already taking.
Males: are advised to instruct patients to conduct regular self-examination of their
testicles and report any new symptoms or changes to their investigator during clinical
trial visits.
If you experience vision changes, you are advised to see an eye doctor.
3. What are the risks and possible discomforts from being in this research study?  
You may have side effects while on the study. There are side effects of the study drug Abemaciclib
as noted below. In addition, you may have side effects from other medication you are receiving as
part of your routine care for your disease.
Everyone taking part in the study will be watched carefully for any side effects.
However,
researchers don’t know all the side effects that may happen. You may experience none, some, or
many of the side effects listed below. Side effects may be mild or very serious, including a risk of
death. Your health care team may give you medicines to help lessen side effects.
Side Effects of Abemaciclib


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Very Common side effects (10% to 90%): (may occur in 10 or more of every 100 people taking
the medication)
Loose stools, may be severe
Belly pain or swelling
Lack of energy, weakness or fatigue
Feeling sick to the stomach with a sense of wanting to throw up
Low appetite
Decreased number of white blood cells count in the blood; this may make infections more
likely to occur
Low red blood cell count in the blood that may make you feel more tired
Decreased number of platelets in the blood; this may cause bruising, difficulty with clotting
of blood, or bleeding easily
Dry mouth
Inflammation or ulcers inside the mouth
Taste changes or bad taste in the mouth
Hair loss
Headache
Jaundice (or the yellowing of the eyes and skin)
Fever
Joint pain
Cough
Dark-colored urine
Diarrhea
Uncommon side effects (1% to 5%): (may occur in less than 5 of every 100 people taking the
medication)
Decreased number of lymphocytes in the blood; this may make infections more likely to
occur
Rare but severe inflammation of the lungs causing coughing and difficulty breathing
Deep vein thrombosis (blood clot in the lower leg or thigh) which could be indicated by
pain, swelling, redness or warmth in the area of the clot
Pulmonary embolism (blood clot in the lung) which could be indicated by dry cough,
lightheadedness, chest pain, shortness of breath
Very often, increases in creatinine levels, a substance in the blood that measures kidney function,
were noted by laboratory testing. While Abemaciclib does not decrease kidney function, creatinine
increases may indicate the need for other tests of kidney function.
In mice and rats, when abemaciclib was taken in doses that caused similar exposures to doses used
in this study for three or six months, respectively, it caused cataracts and retinopathy. We are not
sure how this applies to humans.
Risks in Women of Childbearing Potential and Nonsterile Men
Abemaciclib has been studied in animals to understand possible harmful effects. Information on
harmful effects in animals can indicate possible risks to people. This information may be useful to
you in considering whether to participate in the study.


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Abemaciclib may harm a developing embryo, fetus, or child. When Abemaciclib was tested on
pregnant rats, it was found to cause heart and bone birth defects and to decrease the weight of
developing fetuses. No effects on female reproductive organs in mice, rats, or dogs
were observed. No effects on female fertility and early embryonic development in rats were
observed. Women with childbearing potential should use highly effective contraception during
treatment and for 3 weeks after the last dose of Abemaciclib.
The effect of Abemaciclib on a fetus (unborn baby) or nursing children is unknown. For that reason
if you are pregnant or breastfeeding, you will not be able to participate in this study. If you become
pregnant while on study, the Abemaciclib will be stopped and you and your child will be followed
closely until completion of the study.
Male animals given Abemaciclib had injury to their testes. Abemaciclib may affect your ability to
have children, both while you are taking this drug and in the future.
Abemaciclib may cause fertility problems in males. This may affect your ability to father a child. Talk
to your healthcare provider if this is a concern for you.
In rats, when abemaciclib was taken in doses that caused similar exposures to doses used in this
study, it caused an increase in the number of Leydig cells in the testicles. When rats were exposed
to similar or higher doses than used in this study, it caused an increase in non-cancerous tumors
made of these cells. We are not sure how this applies to humans.
Risk of Venipuncture
There may be a risk related to obtaining the blood for the research tests. However, we will obtain
the blood for those tests at the same time that your routine blood tests are obtained. For this reason,
the physical risks for these blood tests are no more than what you would have in your daily life.
Risk of loss of confidentiality
There is a risk of loss of confidentiality if your information or your identity is obtained by someone
other than the investigators, but precautions will be taken to prevent this from happening. The
confidentiality of your electronic data created by you or by the researchers will be maintained as
required by applicable law and to the degree permitted by the technology used. Absolute
confidentiality cannot be guaranteed.
New Information
You have the right to know about new information concerning the study and the medication involved
that may affect your health, welfare, or your willingness to take part. You will be informed in writing
in a timely manner of any new information or findings that become available that may affect your
choice to continue to take part in this study. You will be asked to sign a new (updated) informed
consent form as soon as possible to document that this new information has been explained to you.
4. What are the possible benefits from being in this research study?
4a. What are the possible benefits to me?
There is no guarantee that you will benefit from this research. It is possible that the medication
Abemaciclib may help to prevent your cancer from growing.
4b. What are the possible benefits to others?
The information from this study will help investigators learn more about the medication
Abemaciclib and its effect on advanced biliary tract carcinoma.   


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5. What other options are available instead of being in this research study?
You do not have to take part in this study to be treated for your condition. Instead of participating in
this research, you could:
Be part of a different research study, if one is available.
Receive standard of care treatment that is FDA approved.
Choose not to be treated for your medical condition and only receive care to make you
more comfortable.
Before you decide if you want to be in this research, we will discuss the other choices that are
available to you. We will tell you about the possible benefits and risks of these choices. Because it
is investigational, it’s important that you know that the study drug Abemaciclib offered in this
research is not available to you without taking part in this research study.
6. How long will I take part in this research study?
If you agree to take part, it will take you about 4 years to complete this research study. You will
be asked to return to the Cancer Center Clinic several times throughout the study as noted
above. You may continue to take part in the study until your disease progresses (or gets worse),
you experience serious side effects or you decide to withdraw from the study.
7. How will you protect my privacy and confidentiality if I decide to take part in this
research study?
7a.  What happens to the information collected for the research?
Efforts will be made to limit the use and sharing of your personal research information. In our
research files at The Milton S. Hershey Medical Center (HMC) and Penn State College of
Medicine (PSU), we will include these identifiers your name, dates (e.g. date of birth), medical
record number, and a code number.
A list that matches your name with your code number will be kept in a limited access,
password protected computer system within the Cancer Institute Clinical Trials
Office.
Your research records will be labeled with: your code number, your initials, & dates
and will be kept in a secure area of the Cancer Institute Clinical Trials Office.
Your research blood samples will be labeled with: a code number, and your initials,
and kept in a secured limited access lab in the Penn State Cancer Institute. Your
samples and data will be sent for processing at the laboratory of Penn State
University at University Park.
A copy of this signed consent form will be included in your HMC medical record. This
means that other HMC healthcare providers will know you are in this study.
Results of some of the research-related tests may be kept in your HMC medical
record
For research records and specimens sent to Dr. He’s laboratory at Captis Diagnostics, Inc,
5000 Forbes Avenue, Scott Hall 4N211, Pittsburgh, PA 15213, you will be identified by a code
number.
In the event of any publication or presentation resulting from the research, no personally
identifiable information will be shared.


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7b. What will happen to my research information and/or samples after the study is
completed?
We may use your research information and your biological samples in future studies or may
share your information or biological samples with other investigators for future research
without your additional informed consent. Before we use or share your information or
samples we will remove any information that shows your identity.
Researchers can do studies that are more powerful when they share with each other the
data or information they get from research studies. They share this information with each
other by putting it into scientific databases. Your coded research information may be put in
one or more databases and used for future research. Your information stored in these
databases will not include any identifying information such as your name, address,
telephone number, or social security number. Your research data will only be available to
researchers who have received approval from data access committees and/or Institutional
Review Boards. Some of these databases are maintained by PSH/PSU, some are
maintained by the federal government, and some are maintained by private companies and
other institutions.
Most tests done on samples in research studies are only for research and have no clear
meaning for health care. If the research with your identifiable information or samples gives
results that do have meaning for your health, the researchers will not contact you to let you
know what they have found.
7c. How will my identifiable health information be used?
In general, under federal law (including the Health Insurance Portability and Accountability Act
– HIPAA or privacy laws) your health information is private. By signing this form, you are
authorizing us to collect, use, and disclose your identifiable health information, sometimes
referred to as “Protected Health Information” or “PHI” under HIPAA, for the purposes of this
research study. We will use and disclose your information only as described in this form, in the
PSH Privacy Notice, and as may be required or allowed under the applicable privacy laws.
The research team may use the following health information:
Past, present, and future medical records, including identifiable information
New health information from tests, procedures, visits, interviews, or forms filled out as
part of this research study.
The following people/groups may see, use, and share your identifiable health information:
PSH/PSU research staff involved in this study
The PSH/PSU Institutional Review Board (IRB), a group of people who review the
research study to protect subjects’ rights and welfare
The PSH/PSU Human Subjects Protection Office
The PSH/PSU Research Quality Assurance Office
Non-research staff within PSH/PSU who need this information to do their jobs (such as
for treatment, payment (billing), or health care operations)
Federal and state agencies (such as the U.S. Food and Drug Administration, the Office
for Human Research Protections, the Department of Health and Human Services, the
National Institutes of Health, and other U.S. or foreign government bodies that oversee
or review research)


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People or groups that we hire to do work for us, such as data storage companies,
insurers, and lawyers
Organizations that provide independent accreditation and oversight of hospitals and
research
Public health and safety authorities (for example, if we learn information that could
mean harm to you or others, we may need to report this, as required by law)
The PSH/PSU pharmacy
Representatives from Eli Lilly and Company, the manufacturer of the study drug
Abemaciclib used in this study.
Researchers at the lab of Dr. He at Captis Diagnostics, Inc.
Representatives from the diagnostic lab, Captis Diagnostics, Inc.
A group that oversees the data (study information) and safety of this research
These groups may also review and/or copy your original PSH/PSU records while looking at the
results of the research study. It is possible that some of the other people/groups who receive
your health information may not be required by Federal privacy laws to protect your
information. We share your information only when we must, and we ask anyone who receives it
from us to protect your privacy.
Sometimes a Principal Investigator or other researcher moves to a different institution. If this
happens, your identifiable health information and samples may be shared with that new
institution and their oversight offices. PHI will be shared securely and under a legal agreement
to ensure it continues to be used under the terms of this consent and HIPAA authorization.
We may remove identifying information from your protected health information. Once we do
this, the remaining information will not be subject to the privacy laws. Information without
identifiers may be used or disclosed with other people or organizations for purposes besides
this study.
Because research is an ongoing process, your permission for the use, storage and sharing of
your health information will continue indefinitely.
Your privacy rights:
You have the right to refuse to sign this form that allows us to use and share your
health information for research; however, if you don’t sign it, you will not be able to take
part in this research study.
You have the right to withdraw your permission for us to use or share your health
information for this research study. If you want to withdraw your permission, you must
notify the person in charge of this research study in writing using the address on the
front of this form. Once permission is withdrawn, you cannot continue to take part in the
study.
If you withdraw your permission, we will stop collecting health information about you for
this study; we may continue to use and share your health information that we already
have if it is necessary for safety and scientific soundness of the research study; and we
will not be able to take back information that has already been used or shared with
others.
You have the right to see and get a copy of your health information that is used or
shared for treatment or for payment. However, you may not be allowed to see or copy
certain health information that is a part of this research study. This is only for the period


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of the study. You will be allowed to see that information when the entire research study
is complete.
8. What are the costs of taking part in this research study?
8a. What will I have to pay for if I take part in this research study?
You and/or your insurance company will not be charged for the cost of Abemaciclib and any
tests or procedures that are required as part of the research and are outside the standard of
care (what is normally done) for your condition. This includes the following:
The study drug Abemaciclib will be provided by the manufacturer, Eli Lilly and
Company, at no cost to you while you take part in this study.
The research-related tests and procedures that will be provided at no cost to you
including the research blood tests noted above in Section 2, Research Testing.
For costs of medical services for care you would receive even if you were not in this
research study:
You and/or your insurance company will be responsible for the costs of routine
medications and the tests and procedures that you would receive even if you were not
in this research.
You and/or your insurance company will be billed for the costs of these routine tests
and procedures in the usual manner.
You will be responsible for any co-payments, co-insurance and deductibles that are
standard for your insurance coverage.
You will be responsible for any charges not reimbursed by your insurance company.
Some insurance companies may not pay for routine costs for people taking part in
research studies. Before deciding to be in this research you should check with your
insurance company to find out what they will pay for.
If you have any questions about costs and insurance, ask the research study doctor or a
member of the research team.
8b. What happens if I am injured as a result of taking part in this research study?
It is possible that you could develop complications or injuries as a result of being in this
research study. If you experience a side effect or injury and emergency medical treatment is
required, seek treatment immediately at any medical facility. If you experience a side effect
or injury and you believe that emergency treatment is not necessary, you should contact the
principal investigator listed on the first page of this consent form as soon as possible and the
principal investigator will arrange for medical treatment. You should also let any health care
provider who treats you know that you are in a research study.
PSH/PSU compensation for injury
There are no plans for PSH/PSU to provide financial compensation or free medical
treatment for research-related injury.
If an injury occurs, medical treatment is available at the usual charge.
Costs will be charged to your insurance carrier or to you.
Some insurance companies may not cover costs associated with research injuries.
If these costs are not covered by your insurance, they will be your responsibility.
When you sign this form you are not giving up any legal right to seek compensation for injury.


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9.
Will I be paid to take part in this research study?
You will not receive any payment or compensation for being in this research study.
It is possible that your research information and/or specimens may be used to develop products
or tests that could be patented and licensed. There are no plans to provide financial compensation
to you should this occur.
10. Who is paying for this research study?
The cost for carrying out this study is being paid for by the Penn State Cancer Institute.  Eli Lilly
and Company, the manufacturer of Abemaciclib, will provide some financial support.  In
addition, they will provide the medication to Penn State Cancer Institute at no cost to the
institution or to you.  
The Pennsylvania State University has a beneficial interest in a company which
licenses the technology used in or developed by this research. This interest has been
reviewed by the University’s Institutional Conflict of Interest Committee and is being
managed by the University
11. What are my rights if I take part in this research study?
Taking part in this research study is voluntary.
You do not have to be in this research.
If you choose to be in this research, you have the right to stop at any time.
If you decide not to be in this research or if you decide to stop at a later date, there will be
no penalty or loss of benefits to which you are entitled.
You may withdraw from the study at any time. If you decide to withdraw, your study doctor will
discuss your treatment options with you and your future medical care will not be affected.
If you stop being in the research, already collected data may not be removed from the study
database. You will be asked whether the investigator can collect medical information from your
routine medical care. If you agree, this data will be handled the same as research data. If you
withdraw completely from the research study, no further information will be collected and your
participation will end. You may discontinue taking part at any time without penalty or loss of
benefits to which you are otherwise entitled.
Your research doctor Dr. Nelson Yee may take you out of the research study without your
permission.
Some possible reasons for this are:  continuing the research would be harmful, your
condition has become worse, you become pregnant, you did not follow the
instructions of the study doctor, or you experience serious side effects.
Also, Penn State Cancer Institute could decide to end the research study early.
If your participation ends early, you may be asked to visit the research doctor for a
final visit.
During the course of the research you will be provided with any new information that may affect
your health, welfare or your decision to continue participating in this research.
12. If I have questions or concerns about this research study, whom should I call?
Please call the head of the research study (principal investigator), Dr. Nelson Yee at 717-531-8678
or the Hematology/Oncology doctor on 24-hour call at 717-531-8521 if you:
Have questions, complaints or concerns about the research.


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Believe you may have been harmed by being in the research study.
You may also contact the research protection advocate in the PSH Human Subjects Protection
Office (HSPO) at (717) 531-5687 if you:
Have questions regarding your rights as a person in a research study.
Have concerns, complaints or general questions about the research.
Have questions about your privacy and the use of your personal health information.
You may also call this number if you cannot reach the research team or wish to offer input
or to talk to someone else about any concerns related to the research.
You may visit the Penn State College of Medicine’s Clinical Research web site at
http://med.psu.edu/clinical-research/faqs for:
Information about your rights when you are in a research study;
Information about the Institutional Review Board (IRB), a group of people who review the
research to protect your rights; and
Links to the federal regulations and information about the protection of people who are in
research studies. If you do not have access to the internet, copies of these federal
regulations are available by calling the HSPO at (717) 531-5687.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will
include a summary of the results. You can search this Web site at any time.
INFORMED CONSENT AND AUTHORIZATION TO TAKE PART IN RESEARCH
Signature of Person Obtaining Informed Consent
Your signature below means that you have explained the research to the subject or subject
representative, provided the subject or subject representative an opportunity to discuss and
consider whether or not to participate in the research, and have answered any questions about
the research.
______________________________
__________
______
________________
Signature of person who explained this research
Date
Time
Printed Name
Signature of Person Giving Informed Consent and Authorization
Before making the decision about being in this research you should have:
Discussed this research study with an investigator,
Read the information in this form, and
Had the opportunity to ask any questions you may have.
Your signature below means that you have received this information, have asked the questions you
currently have about the research and those questions have been answered. You will receive a copy
of the signed and dated form to keep for future reference.
Signature of Subject


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By signing this consent form, you indicate that you voluntarily choose to be in this research and
authorize your information to be used and shared as described above.
___________________________
__________
______
________________
Signature of Subject
Date
Time
Printed Name
Witness to Consent for Limited English Speaking Subjects (Using a “Short Form” written in
the subject’s own language)
Witness Statement: As someone who understands both English and the language spoken by the
subject or subject representative, your signature indicates that the English version of the consent
form was presented orally in the language of the subject or subject representative, and that the
subject or subject representative was given the opportunity to ask questions.
_______________________
__________
______
____________________
Witness Signature
Date
Time
Printed Name
Witness to Consent of Subjects Who Cannot Read or Write
Witness Statement: Your signature indicates that you were present during the informed consent
discussion of this research for the above named subject, that the information in the consent form
and any other written information was presented orally to the subject or subject representative,
that the subject or subject representative was given the opportunity to ask questions, that the
informed consent decision was freely made by the subject or subject representative who indicated
consent and authorization for participation by (check the box as applicable):
  Making a mark
  Other means: ____________________________________________________
(fill in above)
_______________________
__________
______
____________________
Witness Signature
Date
Time
Printed Name