Phase II Clinical Trial of Abemaciclib in Combination With Androgen Deprivation Therapy for Locally Advanced Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Alabama at Birmingham

CLINICAL PROTOCOL 
Title: 
RAD 1805/UAB 1917: Phase II Clinical Trial of Abemaciclib in 
Combination with Androgen Deprivation Therapy for Locally Advanced 
Prostate Cancer 
Protocol Number: 
RAD 1805/UAB 1917 (I3Y-US-IO0I) 
Study Sponsor: 
UAB Department of Radiation Oncology 
Study Support: 
Eli Lilly and Company 
Principal Investigator: 
Eddy S. Yang, MD, PhD 
Co-Investigators: 
Mollie DeShazo, MD 
Lakshminarayanan Nandagopal, MD 
John Fiveash, MD 
Robert Kim, MD 
Rojymon Jacob, MD 
Michael Dobelbower, MD 
Andrew McDonald, MD 
Soroush-Rais Bahrami, MD 
Jeffrey Nix, MD 
Biostatistician 
Sejong Bae, PhD 
Signature & Date: 
 
Signed: 
Print: 
Dated: 
I I 
Page 1 of 86 

 
 
 
 
 
Page 2 of 86 
CLINICAL PROTOCOL 
Version Date: 
Amendment # 4     13 April 2021 
Amendment # 3    12 March 2021 
Amendment # 2:  13 February 2020 
Amendment # 1:    6 February 2020 
Protocol Update:   6 September 2019 
Original Protocol: 10 December 2017 

 
 
 
 
 
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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Medical Monitor 
Sharon Spencer, MD 
University of Alabama at Birmingham 
(UAB) Department of Radiation 
Oncology 
1700 6th Avenue South, Suite 2232F 
Birmingham, Alabama 35249 
Phone#: (205) 934-2762  
Secondary Medical 
Monitor 
 
 
 

 
 
 
 
 
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1. 
SYNOPSIS 
Name of Company: Eli Lilly Pharma.  
Name of Investigational Product: Abemaciclib 
Name of Active Ingredient: Abemaciclib 
Title of Study:  
Phase II Clinical Trial of Abemaciclib in Combination with Androgen Deprivation Therapy for 
Locally Advanced Prostate Cancer 
 
Study center(s): This study will be performed at University of Alabama at Birmingham 
(UAB).   
Principal Investigator: Dr. Eddy S. Yang, MD, PhD 
Studied period:  
Date first patient enrolled: April 2020 
Estimated date endpoint obtained: April 2024 
Estimated date last patient completed: April 2023 
Total number of estimated patients: 30 
Estimated duration of treatment per patient: Until toxicity, 
progression, withdrawal or maximum of 24 months of 
Androgen Deprivation Therapy (ADT). 
Phase of Development: 2 
Rationale:  
 
Recently, CDK4/6 inhibition in combination with the anti-estrogen fulvestrant was found in a 
randomized phase III study to prolong the progression free survival of patients with advanced 
hormone receptor positive, HER2 negative breast cancer refractory to previous endocrine therapy 
compared to fulvestrant alone, irrespective of the menopausal status of patients enrolled in the study1. 
A prolonged progression free survival was also found in a randomized phase II study in combination 
with letrozole in the front-line setting compared to letrozole alone2.  The basis of this synergy 
involves the dependence of estrogen receptor positive breast cancers to CDK4/6 for growth and 
proliferation.  Additionally, activation of growth factor receptor signaling is a hallmark for endocrine 
therapy resistance.   
A similar hormone-driven cancer akin to breast cancers is prostate cancer.  These tumors are driven 
by androgen receptor signaling, and CDK4/6 has also been found to be a bona fide target preclinically 
for advanced prostate cancer cell models3. Moreover, CDK4/6 inhibition can act as a radiation 
sensitizer through its effects on the DNA damage response and interactions with cell cycle pathway 
proteins4,5.  For example, it has been found that expression of DNA repair proteins can be regulated 

 
 
 
 
 
Page 5 of 86 
by E2F, a transcription factor necessary for the G1 to S phase transition6. Also, cyclin D1 has been 
found to exert a direct role on dna repair7-9.  Lastly, CDK4/6 inhibition has been found to modulate 
the DNA damage response10.  These data support the use of CDK4/6 inhibitors as a modulator of 
DNA damage to enhance sensitivity to radiation. 
 
Given the role of CDK4/6 in tumor resistance to endocrine therapy, in activation of the DNA damage 
response, and in promoting radiation resistance, we hypothesize that the targeting of CDK4/6 with 
abemaciclib will enhance the cytotoxicity in combination with blockade of the androgen receptor 
pathway.   
Objectives:  
Primary: 
 To assess clinical response rates using 
 Proportion of patients with PSA nadir of ≤ 0.5 ng/ml on treatment 
 
Secondary: 
 Proportion of patients with PSA declines prior to radiotherapy 
 Time to PSA failure 
 
To study the tolerability and feasibility of combining abemaciclib with androgen 
deprivation therapy (ADT) for localized high-risk or locally advanced prostate cancer. 
Exploratory: 
 MRI-US fusion imaging pre-treatment and at 6 months post RT with comparison 
with historical controls receiving RT + ADT 
 Baseline (mandatory) and 6 months (optional) post RT tumor tissue profiling 
(MRI-US fusion guided) to identify association of molecular profile with PSA 
decline at 1 year 
 Baseline, pre-radiotherapy, and 6 months post-RT blood collection and profiling 
for molecular analysis 
 
Methodology:  
Abemaciclib at 150 mg PO BID, ADT by administering LHRH analogues (goserelin, 
leuprolide, etc), and radiation therapy in conjunction with ADT 
 Overall design:  
A single institution (UAB) phase II trial is proposed to evaluate the clinical and radiologic response 
as well as safety and tolerability of  abemaciclib in combination with ADT neoadjuvantly and 
adjuvantly for patients with high-risk localized or locally advanced prostate cancer who will receive 

 
 
 
 
 
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definitive RT+ADT. Simon's optimal two-stage design (Simon, 1989) will be used for conducting the 
trial. The null hypothesis is that the proportion of patients with PSA <0.5 without any treatment is 
5%, and the alternative hypothesis is that the proportion of patient with PSA <0.5 at 6 weeks into 
treatment is 30% or higher. The trial is carried out in two stages. In stage I, a total number of 5 
patients is accrued. If there are 0 response (PSA< 0.5) among these 5 patients, the study will be early 
stopped. Otherwise, additional 18 patients will be accrued in stage II, resulting in a total number 
sample size of 23. If there are 4 or more responses (PSA< 0.5) among these 23 patients, we reject the 
null hypothesis and claim that the treatment is promising. The design controls the type I error rate at 
one-sided 0.025 and yields the power of 80%. If we reject the null hypothesis, seven additional 
patients will be enrolled to explore the association between biomarkers and clinical activities.  
Patients receive ADT x 2 years and will start 3 months before RT. Abemaciclib will start with 
initiation of ADT and pause 2 weeks prior to start of RT. Abemaciclib will resume with the first ADT 
administration post-radiation, which typically is at 1 month post radiation therapy. Abemaciclib and 
ADT will continue for a total ADT period of 24 months. Patients will have laboratory evaluation 
every 2 weeks for the first 2 months and monthly thereafter for the next 2 months.  Patients are also 
seen and evaluated every 4 weeks with laboratory evaluation. Labs may be drawn at outside 
laboratories at the PI’s discretion.  For toxicity or adverse event, patients will undergo labs, physical 
examination and grades of toxicities will be determined using NCI CTCAE version 4.03. Disease 
response and biochemical failure will be assessed by PSA prior to the start of radiation and every 3 
months following the end of radiotherapy and by the investigator (physical exam). The determination 
of disease progression for the study requires a confirmation of 3 consecutive rises of PSA 3 months 
apart in the setting of testosterone recovery. Patients will be withdrawn from study for following 
toxicities, 
 
Toxicity 
Category 
Drug-Related Toxicity/Grade 
Hematologic 
Grade 4 neutropenia for ≥5 days 
Febrile neutropenia:  ANC < 1000/mm3 with a single temperature of 
>38.3ºC (101 ºF) or a sustained temperature of > 38 ºC (100.4 ºF) for 
more than one hour. 
Neutropenic infection:  Grade ≥3 neutropenia with Grade ≥3 infection 
Grade ≥4 Anemia  
Grade ≥4 thrombocytopenia or Grade ≥3 thrombocytopenia with Grade 
≥3 hemorrhage 
Non-
hematologic 
Grade 2 (>3.0 x ULN) ALT/AST with total bilirubin >2 x ULN, in the 
absence of cholestasis 
Grade 3 or 4 non-hematologic toxicity with the following exceptions: 
 Asymptomatic electrolyte abnormality that resolve within 48 
hours. 

 
 
 
 
 
Page 7 of 86 
 
  
 Grade 3 headache lasting <48 hours 
Number of Patients (planned):  
30 patients with localized or locally advanced prostate cancer will be enrolled in the study. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria: 
1. Histologically confirmed (core biopsy proven) adenocarcinoma of prostate, localized 
high-risk or locally advanced. 
2. One of the below: 
• Gleason 7-8, any T-stage, and PSA > 20, 
• Gleason 8, ≥ T2, any PSA, 
• Gleason 9-10, any T-stage, any PSA 
• T3, any Gleason, any PSA 
• Positive pelvic lymph nodes are permitted. 
3. Available biopsy of primary tumor or resected tumor specimen with adequate 
samples.  
4. Prior treatment with systemic anti-cancer agents is not allowed. 
5. ECOG PS = 0 or 1 
6. Must have at least 1 target lesion 
7. Life expectancy > 6 months 
8. Adequate hematologic and end-organ function 
 ANC ≥ 1500/mm3 
 Platelet count ≥ 100,000/mm3 
 Hb ≥ 8g/dl 
 Creatinine ≤ ULN or Creatinine Clearance (CrCl) ≥ 60 ml/min 
 Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who can 
have total Bilirubin < 2.0 x ULN and direct bilirubin within normal limits are 
permitted) 
 AST and ALT ≤ 3.0 x ULN 
9. Agreement to remain abstinent or use appropriate contraception. 
10. Willingness and ability to consent for self to participate in study. 
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
Exclusion Criteria:   
1. Prior treatment with CDK 4/6 inhibitor.  
2. Prior treatment with systemic agents or radiation treatment for the primary cancer. 

 
 
 
 
 
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3. Major surgical procedure or significant traumatic injury within 4 weeks prior to study 
treatment, and must have fully recovered from any such procedure. 
4. Personal history of any of the following conditions: syncope of cardiovascular 
etiology, ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
5. Angina, myocardial infarction (MI), symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack TIA), arterial embolism, 
pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or 
coronary artery bypass grafting (CABG) within 6 months prior to study treatment.  
6. Known active viral or non-viral hepatitis or cirrhosis. 
7. Any active infection requiring systemic treatment, positive tests for Hepatitis B 
surface antigen or Hepatitis C ribonucleic acid (RNA). 
8. Known history of AIDS (acquired immunodeficiency syndrome)-defining illness. 
9. Patients must be surgically sterile or must agree to use effective contraception during 
the study treatment (including temporary breaks from treatment), and for at least 180 
days after stopping last dose of Abemaciclib  The definition of effective 
contraception is provided in Section 2.6.1 of this protocol.   
10. Other severe and/or uncontrolled acute or chronic medical or psychiatric condition or 
laboratory abnormality that, in the judgement of the investigator, may increase the 
risk associated with study participation or may interfere with the interpretation of 
study results and would make the patient inappropriate for 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], history of major 
surgical resection involving the stomach or small bowel,  or preexisting Crohn’s 
disease or ulcerative colitis or a preexisting chronic condition resulting in baseline 
Grade 2 or higher diarrhea). 
11. Secondary malignancy requiring active treatment. Past history of malignancy other 
than prostate cancer treated with curative intent and not requiring additional treatment 
may be eligible after discussion with PI.  
12. Patients with active autoimmune disease and history of inflammatory bowel disease. 
Brachytherapy boost will not be permitted.  
Abemaciclib Investigational Product Dose and Administration:  
All patients will receive 150 mg Abemaciclib PO BID for 28 days. Patients will receive 
treatment with Abemaciclib until there is (are) toxicity(ies) or disease progression on 
treatment or withdrawal from study for any reason. All patients will receive ADT using 
LHRH analogues every 3 months along with Abemaciclib. There will be no intra patient dose 
escalation in dosing of Abemaciclib. Patients will take Abemaciclib in clinic on Day 1 of 
each cycle. They can take the rest of the pills at home. Radiation Therapy will be scheduled 
at 3 months after C1D1 (Abemaciclib and ADT). Abemaciclib will be stopped 2 weeks 
before Radiation Therapy and resumed with first dose of ADT after Radiation therapy is 
completed (usually 1 month after completion of RT). Abemaciclib will continue along with 
ADT for 24 months (+/- 3 days). 

 
 
 
 
 
Page 9 of 86 
ADT Dose and Administration: 
ADT using LHRH analogues will be administered SC beginning on C1D1 and continue 
during radiation and after radiation for a total of 24 months (+/-3 days) in the absence of 
toxicity.  Dose modification of the ADT is not allowed.   
Duration of Treatment:  
Patients are eligible for abemaciclib treatment until unacceptable toxicity, or withdrawal of 
consent, or progression of disease on treatment or maximum of 24 months of ADT on the 
study.  A patient should be withdrawn from study treatment if, in the opinion of the 
Investigator, it is medically necessary, or if it is the wish of the patient.  In addition, patients 
will be withdrawn from treatment in the case of: 
1. A need for surgery, radiation, or for other anticancer therapy not permitted by this 
protocol 
2. Lost to follow-up or noncompliant with the protocol 
3. Any Abemaciclib dose delay > 7 days during the first cycle  
 
Parameters to be Assessed: 
Safety: 
Safety assessments will include physical examinations, vital signs, ECOG performance 
status, laboratory tests (complete blood counts [CBC] and serum chemistry), 12-lead 
electrocardiograms (ECGs), and additional studies as may be clinically indicated.   
Exploratory Biomarkers: 
Baseline archived tumor samples will be analyzed for mutations via the Strata Oncology platform 
(Oncomine), which includes analysis of genetic alteration of the CDK4/6 pathway. If sufficient 
sample is available, Nanostring analysis with the PanCancer pathways panel will be performed on 
pre-treatment and 6 month post treatment biopsy samples. Additionally, blood will be collected at 
baseline, 1 month, and q 3 month and analyzed for ctDNA. These will be used to correlate molecular 
profiling with responses. 
Efficacy: 
PSA values will be obtained to assess response and progression.  
  
 

 
 
 
 
 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................10 
2. 
BACKGROUND ........................................................................................................18 
2.1. 
High Risk Localized or Locally Advanced Prostate Cancer ......................................18 
2.2. 
ADT and Prostate Cancer ...........................................................................................18 
2.3. 
Abemaciclib Background ...........................................................................................19 
2.3.1. 
Cyclin D Kinase 4/6 inhibition in cancer ...................................................................19 
2.3.2. 
Abemaciclib Background Information .......................................................................19 
2.4. 
Study Rationale ...........................................................................................................20 
2.5. 
Population to be Studied .............................................................................................21 
2.6. 
Potential Risks and Benefits to Human Patients .........................................................21 
2.6.1. 
Potential Risks ............................................................................................................21 
2.7. 
Justification of the Dose, Schedule, and Route of Administration .............................22 
2.8. 
Study Conduct ............................................................................................................23 
3. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................24 
4. 
INVESTIGATIONAL PLAN .....................................................................................25 
4.1. 
Overall Study Design and Plan ...................................................................................25 
4.1.1. 
Overview .....................................................................................................................25 
4.1.2. 
Trial Procedures ..........................................................................................................26 
4.1.2.1. 
Screening ....................................................................................................................26 
4.1.2.2. 
Study Drug Treatment Period .....................................................................................27 
4.1.3. 
Follow-up ....................................................................................................................28 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................32 
5.1. 
Patient Inclusion Criteria ............................................................................................32 
5.2. 
Exclusion Criteria: ......................................................................................................32 
5.3. 
Patient Withdrawal Criteria ........................................................................................33 
5.4. 
General Guidelines .....................................................................................................34 
5.5. 
Registration Process ....................................................................................................34 
6. 
TREATMENT OF PATIENTS ..................................................................................35 

 
 
 
 
 
Page 11 of 86 
6.1. 
Description of Abemaciclib Study Drug ....................................................................35 
6.1.1. 
Abemaciclib Composition ..........................................................................................35 
6.1.2. 
Abemaciclib Dose Levels ...........................................................................................36 
6.1.3. 
Abemaciclib Packaging and Labeling ........................................................................36 
6.1.4. 
Abemaciclib Administration .......................................................................................36 
6.1.5. 
Abemaciclib Dose Modification/Dose Delays ...........................................................36 
6.1.5.1. 
Rationale for Dose modifications ...............................................................................36 
6.1.6. 
Abemaciclib Drug Accountability ..............................................................................36 
6.1.7. 
Abemaciclib Study Drug Handling and Disposal .......................................................37 
6.2. 
Description of Androgen Deprivation Therapy ..........................................................37 
6.3. 
Radiation Therapy ......................................................................................................39 
6.4. 
Dose modifications of Study drugs .............................................................................39 
6.4.1. 
Planned Dose modifications .......................................................................................39 
6.4.2. 
Criteria and Procedure for interruption .......................................................................40 
6.4.3. 
Procedures for management of Abemaciclib related adverse event(s) .......................40 
GENERAL GUIDANCE FOR INCREASES IN SERUM CREATININE AND 
ASSESSMENT OF RENAL INSUFFICIENCY .......................................................41 
GENERAL GUIDANCE FOR HEMATOLOGY TOXICITY AND DOSE 
MODIFICATION .......................................................................................................44 
6.4.3.1. 
Therapy for Febrile Neutropenia ................................................................................45 
6.4.3.2. 
Growth Factor Therapy ...............................................................................................45 
6.5. 
Criteria for permanent discontinuation of study drug(s) ............................................45 
6.6. 
Study Completion .......................................................................................................46 
6.6.1. 
Study completion criteria ............................................................................................46 
6.6.2. 
Withdrawal procedures ...............................................................................................46 
6.7. 
Concomitant Medications ...........................................................................................47 
6.8. 
Treatment Compliance ................................................................................................48 
6.9. 
Patient Enrollment ......................................................................................................48 
6.10. 
Beginning and End of the Study .................................................................................48 
7. 
ASSESSMENT OF EFFICACY ................................................................................49 
7.1. 
PSA serial measurements ...........................................................................................49 
8. 
ASSESSMENT OF SAFETY .....................................................................................50 

 
 
 
 
 
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8.1. 
Safety Parameters .......................................................................................................50 
8.1.1. 
Laboratory Safety Assessments ..................................................................................50 
8.1.1.1. 
Hematology, Serum Chemistry, and Coagulation Test ..............................................50 
8.1.1.2. 
Urinalysis ....................................................................................................................50 
8.1.2. 
Physical Examination .................................................................................................51 
8.1.3. 
Vital Signs ..................................................................................................................51 
8.1.4. 
Performance Status .....................................................................................................51 
8.1.5. 
Electrocardiogram (ECG) ...........................................................................................51 
8.2. 
Adverse Events ...........................................................................................................51 
8.2.1. 
Definition of Adverse Event .......................................................................................51 
8.2.2. 
Serious Adverse Events ..............................................................................................52 
8.2.2.1. 
Hospitalization ............................................................................................................53 
8.3. 
Reporting Adverse Events ..........................................................................................54 
8.3.1. 
Eliciting Adverse Event Information ..........................................................................54 
8.3.2. 
Adverse Event Reporting Period ................................................................................54 
8.3.3. 
Reporting Requirements .............................................................................................54 
8.3.4. 
Recording Adverse Events in the Case Report Forms ................................................55 
8.3.5. 
Grading of Adverse Event Severity ............................................................................55 
8.3.6. 
Relationship to Treatment Drugs (Abemaciclib) ........................................................55 
8.3.7. 
Expectedness ...............................................................................................................56 
8.3.8. 
Exposure in Utero .......................................................................................................56 
8.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................57 
8.4. 
Safety Monitoring .......................................................................................................57 
9. 
OTHER ASSESSMENTS ..........................................................................................58 
9.1. 
Other Laboratory Assessments ...................................................................................58 
9.1.1. 
Tumor Biopsies ...........................................................................................................58 
9.1.2. 
Biomarker analysis .....................................................................................................58 
10. 
STATISTICS ..............................................................................................................59 
10.1. 
Statistical Design/Sample Size ...................................................................................59 
10.1.1. 
Definition of Analyzed Study Populations .................................................................59 
10.2. 
Data Analysis ..............................................................................................................59 

 
 
 
 
 
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10.2.1. 
Analysis of Primary Objective ....................................................................................60 
10.2.2. 
Analysis of Secondary Objective ................................................................................60 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................61 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
13. 
ETHICS ......................................................................................................................63 
13.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................63 
13.2. 
Ethical Conduct of the Study ......................................................................................63 
13.3. 
Written Informed Consent ..........................................................................................63 
13.4. 
Patient Compensation .................................................................................................63 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................64 
14.1. 
Inspection of Records .................................................................................................64 
14.2. 
Retention of Records ..................................................................................................64 
15. 
DEFINITION OF END OF TRIAL ...........................................................................65 
15.1. 
End of Trial .................................................................................................................65 
15.2. 
ELI LILLY Discontinuation Criteria ..........................................................................65 
16. 
PUBLICATION OF TRIAL RESULTS ....................................................................66 
17. 
FINANCING AND INSURANCE .............................................................................67 
18. 
REFERENCES ...........................................................................................................68 
19. 
APPENDICES ............................................................................................................70 
19.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) .......................................................................70 
19.2. 
Appendix 2:  ECOG Performance Status ...................................................................71 
19.3. 
UAB Department of Radiation Oncology Treatment Practice Guidelines .................72 
 
Table 2: Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term 
Explanation 
ADCC 
Antibody-dependent T-cell-mediated cytotoxicity 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AFP 
Alpha fetoprotein 

 
 
 
 
 
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AIDS 
Acquired immune deficiency syndrome 
ALK 
Activin receptor-like kinase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APA 
Anti-product antibody 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CABG 
Coronary Artery Bypass Graft 
CBC 
Complete blood count 
CD 
Cluster of differentiation antigen 
iCR 
Immune Complete response 
CRF 
Case report form 
iCPD 
Immune Confirmed progressive disease  
CT 
Computed tomography 
CTA 
Clinical Trials Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CxDx 
Cycle x Day x 
DEHP 
Diethylhexyl-phthalate 
dL 
Deciliter 
EBUS 
Endoscopic Bronchoscopic Ultrasound 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
EGD 
Esophagogastroduodenoscopy 
EGFR 
Epidermal growth factor receptor 
ELISA 
Enzyme-linked immunosorbent assay 

 
 
 
 
 
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EOS 
End of study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
Fe 
Iron studies 
FFPE 
Formalin fixed, paraffin-embedded 
g 
Gram 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRA 
Health Regulatory Authority 
IB 
Investigational Brochure 
ICH 
International Council on Harmonization 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
INR 
International normalized ratio 
IRB 
Institutional review board 
IUD 
Intra-uterine device 
IV 
Intravenous 
kDa 
KiloDalton 
kg 
Kilogram 
L 
Liter 
μL 
Microliter 
mg 
Milligram 
mL 
Milliliter 
MDSC 
Myeloid derived suppressor cell 

 
 
 
 
 
Page 16 of 86 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mm 
Millimeter 
mm Hg 
Millimeters of mercury 
MRI 
Magnetic resonance imaging 
ms 
Millisecond 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ng 
Nanogram 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PlGF 
Placental growth factor 
PD-1 
Programmed death receptor 1 
PD-L1,PD-L2 
Programmed death receptor ligands 
PK 
Pharmacokinetic 
pM 
Picomolar 
PR 
Partial response 
PT 
Preferred Term for adverse event in MedDRA 
PTCA 
Percutaneous transluminal coronary angioplasty 
PUD 
Peptic ulcer disease 
QA 
Quality assurance 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
ROS-1 
Proto-oncogene tyrosine-protein kinase 

 
 
 
 
 
Page 17 of 86 
RPTD 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
sCD105 
Soluble CD105/endoglin 
SC 
subcutaneous 
SCID 
Severe combined immunodeficient 
SCLC 
Small cell lung cancer 
iSD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
Systemic Organ Class in MedDRA 
SOP 
Standard operating procedure 
TGF 
Transforming growth factor 
TIA 
Transient ischemia attack 
TPS 
Tumor proportion score 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UPCR 
Urine protein-creatinine ratio 
iUPD 
Immune Unconfirmed progressive disease  
US 
United States of America 
VEGF 
Vascular endothelial growth factor 

 
 
 
 
 
Page 18 of 86 
2. 
BACKGROUND 
2.1. 
High Risk Localized or Locally Advanced Prostate Cancer 
 
Prostate cancer is the highest cause of incident cancer in men while it is 3rd highest cause of cancer deaths 
in US. In recent years, prostate cancer is increasingly being diagnosed at younger aged men and early in 
the disease stage. However, some men with newly diagnosed prostate cancer are detected at later stages 
with extensive primary tumors (T2b and above), presence of regional lymph node metastasis (N1) or 
other factors that are considered high risk for recurrence of tumor, such as PSA >= 20 or Gleason score of 
8 or above.  
For localized disease, multiple options exist – active surveillance (AS), radical prostatectomy 
and external beam radiotherapy / brachytherapy (NCCN, 2018). Interventional options, however, carry 
risks. Radical prostatectomy (open or robotic) has long term risks of erectile dysfunction and urinary 
incontinence. External beam radiation therapy (EBRT) and brachytherapy also carry risks, such as erectile 
dysfunction, urinary incontinence and bowel complications. While AS has emerged as one of the 
recommended options for low risk localized prostate cancer, a more aggressive approach is required for 
high risk disease.  
While radical prostatectomy with pelvic lymph node dissection is an option for selected high risk patients 
without tumor fixation to adjacent structures, adjuvant RT is often required especially for positive 
margins or lymph node involvement or PSA recurrence. Thus, ADT with definitive RT is often 
considered a standard approach in high risk disease, with the ability to radiate clinically occult lymph 
nodes which could harbor micrometastatic disease. ADT alone has proven to be inferior to combination 
therapy with definitive EBRT  11,12. ADT combined with definitive EBRT has consistently shown 
improvements in cancer specific and overall survival in multiple randomized trials 13,14. However, one in 
four patients will still have local recurrence and remain at risk of distant metastasis, with approximately 
10-20% risk of long term prostate cancer specific mortality15. Although ADT is often continued for 2 
years post-EBRT, recurrences can occur after completion of ADT, likely due to the presence of 
microscopic disease in the prostatic bed or in lymph nodes. Thus, we need strategies to improve the 
efficacy of combination ADT and EBRT.  
 
2.2. 
ADT and Prostate Cancer 
 
While prostate cancer is heavily androgen dependent, multiple studies have demonstrated that ADT alone 
is inferior compared to ADT plus RT for localized high risk prostate cancer 11,12,16,17.  However, even with 
combination ADT + EBRT, high risk patients remain at significant risk of developing distant metastasis, 
biochemical failure and prostate cancer-specific mortality 13,14,18.  

 
 
 
 
 
Page 19 of 86 
2.3. 
Abemaciclib Background 
2.3.1. Cyclin D Kinase 4/6 inhibition in cancer 
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division 19,20.  The cyclin-dependent kinases (CDKs), CDK4 and 
CDK6, participate in a complex with D-type cyclins to initiate the transition through the G1 
restriction point by phosphorylating and inactivating the retinoblastoma (Rb) tumor-suppressor 
protein. Alterations in this pathway occur frequently in human cancers and involve (1) loss of 
CDK inhibitors by mutation or epigenetic silencing, (2) mutation/overexpression of either CDK4 
and CDK6 or cyclin D, or (3) inactivation of Rb. These alterations render cells less dependent on 
mitogenic signaling for proliferation. With the possible exception of those tumors with complete 
inactivation of Rb, which functions downstream of the CDK4 and CDK6–cyclin D complex, all 
of these cancers are potentially sensitive to pharmacologic inhibition of CDK4 and CDK6. From 
a therapeutic standpoint, the goal of inhibiting CDK4 and CDK6 with a small-molecule inhibitor 
is to prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth. 
 
2.3.2. Abemaciclib Background Information 
Abemaciclib represents a selective and potent small-molecule CDK4 and CDK6 dual inhibitor 
with a broad antitumor activity in preclinical pharmacology models, acceptable physical and 
pharmacokinetic (PK) properties, and an acceptable toxicity profile in nonclinical species. 
This compound demonstrates significant inhibition of tumor growth as monotherapy in multiple 
human xenograft models including models for: breast cancer, colorectal cancer, glioblastoma 
multiforme, acute myeloid leukemia, melanoma, mantle cell lymphoma (MCL), and non–small-
cell lung cancer (NSCLC). Although characterized by a different constellation of genomic 
mutations, each of these human xenografts has an intact, functional Rb protein. Xenograft 
growth inhibition is generally dose dependent from 25 to 100 mg/kg following daily oral 
administration for 21 to 28 days. Additional nonclinical studies in xenograft models for human 
NSCLC and melanoma also show that abemaciclib may be used in combination with standard 
cytotoxic or targeted therapies to improve efficacy of these agents. 
 
In nonclinical species, abemaciclib distributes efficiently to the brain and potentially provides a 
unique opportunity to treat primary brain tumors as well as cancers that have metastasized to the 
brain. As a result of its brain exposure, treatment with abemaciclib in a rat orthotropic brain 
tumor model produces statistically significant and dose-dependent improvement in survival. 
Abemaciclib demonstrates moderate-to-high bioavailability in preclinical species. In repeat-dose 
toxicokinetic studies, abemaciclib showed generally dose-dependent exposure with no gender 
differences. Abemaciclib is highly metabolized, and hepatic elimination plays a major role in the 
clearance of abemaciclib and its metabolites in rats, dogs, and humans. In humans, the terminal 
elimination half-life (t1/2) in plasma ranges from approximately 17 to 38 hours across the 
doserange tested. At a single dose of 200 mg, the mean apparent oral clearance (CL/F) is 38.3 
L/hour with a high interindividual variability (105% coefficient of variation [CV]) and the 

 
 
 
 
 
Page 20 of 86 
apparent volume of distribution is large at 1300 L (96% CV). In the xenograft models and skin 
biopsies from patients, abemaciclib inhibited phosphorylated Rb (pRb) and topoisomerase II 
alpha (TopoIIα) at clinically relevant doses and exposures. 
In preclinical species, the primary target organs for toxicity (associated with up to 3 months of 
continuous daily dosing) are bone marrow (resulting in pancytopenia), gastrointestinal tract, 
lymphoid tissues, and male reproductive tract. All of these changes demonstrated complete or 
partial reversibility during the recovery period. In humans, the most common (≥10%) 
treatment-emergent adverse events (TEAEs) possibly related to the study drug for patients who 
received single-agent abemaciclib include diarrhea, nausea, fatigue, neutropenia, vomiting, 
decreased appetite, leukopenia, thrombocytopenia, anemia, abdominal pain, and blood creatinine 
increased. Increased rates of skeletal and cardiac variations and malformations, accompanied by 
decreased fetal weights, were observed in an embryo–fetal development study of abemaciclib in 
rats.  
After determining a recommended dose of 150 mg bid in a phase 1 study 21, abemaciclib 
monotherapy showed superior response rates in the MONARCH-1 study in a heavily pre-treated 
patient population 22. It has subsequently demonstrated impressive response rates and 
improvement in PFS in 2 randomized phase 3 studies 23,24. In the neoadjuvant breast cancer 
setting, the ongoing neoMONARCH Phase 2 open-label, randomized study (I3Y-MC-JPBY) 
showed an acceptable safety profile for abemaciclib (150 mg twice daily) as monotherapy and in 
combination with anastrozole, with reduction of breast cancer tumor cell proliferation marker 
(Ki67 index) to a significantly greater extent than anastrozole alone 25. Abemaciclib has been 
well studied in breast cancer, and common side effects encountered in clinical studies include 
diarrhea (86%), neutropenia (46%), nausea (45%) and fatigue (40%) 23. but the major grade 3 or 
higher side effect remains neutropenia in upto 20% of patients 23,24. Thus patients on CDK4/6 
inhibitors  require frequent lab checks to monitor development of neutropenia, though the 
clinical significance of  CKD4/6 inhibition – related neutropenia is debatable as the incidence of 
febrile neutropenia remains very low 23. More significantly, compared to the 2 other approved 
CDK4/6 inhibitors, abemaciclib has a significantly reduced incidence of grade 3 or higher 
neutropenia 26. Thus, abemaciclib represents a significant new option for CDK4/6 inhibition with 
impressive clinical efficacy and decreased incidence of significant neutropenia.  
2.4. 
Study Rationale 
 
Recently, CDK4/6 inhibition in combination with the anti-estrogen fulvestrant was found in a randomized 
phase III study to prolong the progression free survival of patients with advanced hormone receptor 
positive, HER2 negative breast cancer refractory to previous endocrine therapy compared to fulvestrant 
alone, irrespective of the menopausal status of patients enrolled in the study1. A prolonged progression 
free survival was also found in a randomized phase II study in combination with letrozole in the front-line 
setting compared to letrozole alone2.  Abemaciclib has demonstrated significant improvement in PFS in 
combination with fulvestrant and with letrozole in the MONARCH 2 and MONARCH 3 studies leading 
to its approval in the post endocrine therapy and also, frontline setting for hormone receptor positive, 
HER2 negative breast cancer 23,24. The basis of this synergy involves the dependence of estrogen receptor 

 
 
 
 
 
Page 21 of 86 
positive breast cancers to CDK4/6 for growth and proliferation.  Additionally, activation of growth factor 
receptor signaling is a hallmark for endocrine therapy resistance.   
A similar hormone-driven cancer akin to breast cancers is prostate cancer.  These tumors are driven by 
androgen receptor signaling, and CDK4/6 has also been found to be a bona fide target preclinically for 
advanced prostate cancer cell models3. Moreover, CDK4/6 inhibition can act as a radiation sensitizer 
through its effects on the DNA damage response and interactions with cell cycle pathway proteins4,5.  For 
example, it has been found that expression of DNA repair proteins can be regulated by E2F, a 
transcription factor necessary for the G1 to S phase transition6. Also, cyclin D1 has been found to exert a 
direct role on dna repair7-9.  Lastly, CDK4/6 inhibition has been found to modulate the DNA damage 
response10.  These data support the use of CDK4/6 inhibitors as a modulator of DNA damage to enhance 
sensitivity to radiation. 
Given the role of CDK4/6 in tumor resistance to endocrine therapy, in activation of the DNA damage 
response, and in promoting radiation resistance, we hypothesize that the targeting of CDK4/6 with 
abemaciclib will enhance the cytotoxicity in combination with blockade of the androgen receptor 
pathway.  Therefore, we propose a pilot phase II investigator initiated trial in patients with high-risk 
prostate cancer patients testing the tolerability and toxicity of abemaciclib in combination with ADT. 
2.5. 
Population to be Studied 
Patients with high risk localized or locally advanced prostate cancer who will be eligible for 
definitive treatment with Radiation therapy and ADT. 
2.6. 
Potential Risks and Benefits to Human Patients 
2.6.1. Potential Risks 
Abemaciclib 
Based on clinical experience with abemaciclib, the adverse events of special interest (AESIs) are 
neutropenia, infections, diarrhea, blood creatinine increased, hepatic events (increases in 
aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and embolism (mainly 
pulmonary embolism and deep vein thrombosis)); furthermore, interstitial lung 
disease/pneumonitis is considered an adverse event (AE) of note.  
Computed Tomography (CT) Scans 
Patients will be exposed to a relatively small amount of radiation as a result of the CT scans 
required in this study.  This degree of exposure has not been associated with harmful health 
effects.  In addition, the frequency of CT scans performed in this study is similar to the standard 
of care frequency.  Patients with a medical contraindication to CT scans or known iodinated 
contrast allergies may instead undergo magnetic resonance imaging (MRI).  There is minimal 
risk of MRI imaging in patients able to undergo this type of exam including very rare reports of 
gadolinium-induce nephrogenic systemic fibrosis in patients with poor renal function. 
 

 
 
 
 
 
Page 22 of 86 
MRI-US imaging.  
Patients will undergo MRI-US fusion imaging pre-treatment and at 6 months post RT with 
comparison with historical controls receiving RT + ADT. There is minimal risk of MRI imaging 
in patients able to undergo this type of exam including very rare reports of gadolinium-induce 
nephrogenic systemic fibrosis in patients with poor renal function. 
 Prostate biopsy 
Patients will have undergone MRI-US guided biopsy of the prostate at the time of diagnosis and 
archived tumor tissue will be used at screening for baseline analysis. An optional biopsy will be 
scheduled at 6 months post RT for tumor tissue profiling to identify association of molecular 
profile with PSA decline at 1 year. Risks include but are not limited to bleeding from biopsy site, 
increased risk of infection and complications related to anesthesia for the procedure.  
Venipuncture 
Patients could also experience side effects from venipuncture for tests that will be done as part of 
this study, including pain, tenderness, and bruising at the site of collection, and rarely infection 
may occur at the spot where the needle is inserted. 
Other Risks 
This study treatment may involve risks to unborn children and therefore patients should not 
father a baby while participating in this study.  
Men must agree to use 2 effective and highly reliable methods of contraception at the same time 
(i.e., vasectomy, male latex condom with or without spermicide, partner’s tubal sterilization, 
partner’s use of an IUD, partner’s use of diaphragm with spermicide, cervical cap with 
spermicide, or vaginal sponge that contains spermicide) during study treatment (including 
temporary breaks from treatment), and for at least 180 days after stopping Abemaciclib.  The 
long-term risk of infertility is unknown.  
Potential Benefits 
Abemaciclib is an investigational product and its efficacy in combination with ADT has not been 
established. ADT is approved for treatment of localized or locally advanced prostate cancer. It is 
expected that the administration of Abemaciclib and ADT may result in clinical benefit (i.e. 
Tumor response). 
2.7. 
Justification of the Dose, Schedule, and Route of Administration 
The dose, schedule, and route of administration of Abemaciclib (150 mg BID) was selected 
based on safety, pharmacokinetics, and evidence of activity in the Phase 1b study (JBIF).  Dose 
reduction is possible for treatment of adverse events, including anemia. Refer to section 6.3.1, 
Table 4 and section 6.3.3 

 
 
 
 
 
Page 23 of 86 
ADT with LHRH analogues will be admisitered at Standard of care doses.   
2.8. 
Study Conduct 
This clinical trial will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and the applicable regulatory requirements. 

 
 
 
 
 
Page 24 of 86 
3. 
TRIAL OBJECTIVES AND PURPOSE 
The purpose of this study is to evaluate the safety and tolerability of Abemaciclib in combination 
with ADT. 
Primary Objective: 
 To assess clinical response rates using 
 Proportion of patients with PSA nadir of ≤ 0.5 ng/ml on treatment 
Secondary Objectives: 
 Proportion of patients with PSA declines prior to radiotherapy 
 Time to PSA failure 
 To study the tolerability and feasibility of combining Abemaciclib with ADT for 
localized high risk or locally advanced prostate cancer. 
Exploratory Objective: 
1) MRI-US fusion imaging pre-treatment and at 6 months post RT with comparison with 
historical controls receiving RT + ADT. 
2) Baseline (mandatory) and 6 months (optional) post RT tumor tissue profiling (MRI-US 
fusion guided) to identify association of molecular profile with PSA decline at 1 year. 
3) Baseline, pre-radiotherapy and 6 months post-RT blood collection and profiling for 
molecular analysis. 

 
 
 
 
 
Page 25 of 86 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
4.1.1. Overview 
This is a single center, Phase II, single arm, open-label study of Abemaciclib in combination 
with ADT in patients with localized high-risk or locally advanced prostate cancer who are 
eligible for definitive RT and ADT.   
All patients must sign and date a consent form prior to undertaking any study-related procedures.  
Prospective patients will be screened to determine if they qualify for the study within 28 days of 
enrollment.  Patients will receive ADT with LHRH analogues every 3 months and will receive 
Abemaciclib starting on C1D1 at 150 mg PO BID for 28 day cycles Table 3 (see Abemaciclib 
Administration Section 6.1.4 and ADT Administration).   Patients receive ADT x 2 years and 
will start 3 months before RT. Abemaciclib will start with initiation of ADT and pause 2 weeks 
prior to start of RT. Abemaciclib will resume with the first ADT administration post-radiation, 
which typically is at 1 month post radiation therapy. Abemaciclib and ADT will continue for a 
total ADT period of 24 months (+/- 3 days to allow for holidays and weekends). Patients will 
have laboratory evaluation every 2 weeks for the first 2 months and monthly thereafter for the 
next 2 months.  Patients are also seen and evaluated every 4 weeks with laboratory evaluation. 
Labs may be drawn at outside laboratories at the PI’s discretion.   
Patients will receive study treatment until development of toxicity or disease progression on 
treatment or any reasons of withdrawal or a maximum of 24 months of therapy with ADT.  
Adverse events will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03.   
All patients will receive Abemaciclib at 150 mg BID PO dose. The trial is carried out in two 
stages. In stage I, a total number of 5 patients are accrued. If there are 0 response (PSA< 0.5) 
among these 5 patients, the study will be early stopped. Otherwise, additional 18 patients will be 
accrued in stage II, resulting in a total number sample size of 23. If there are 4 or more responses 
(PSA< 0.5) among these 23 patients, we reject the null hypothesis and claim that the treatment is 
promising. The design controls the type I error rate at one-sided 0.025 and yields the power of 
80%. If we reject the null hypothesis, seven additional patients will be enrolled to explore the 
association between biomarkers and clinical activities. To account for 10% screen failure, total 
of 33 patients will be recruited to the study.  

 
 
 
 
 
Page 26 of 86 
Table 1: 
Toxicities leading to withdrawal of subjects 
Toxicity 
Category 
Drug-Related Toxicity/Grade 
Hematologic 
Grade 4 neutropenia for ≥5 days 
Febrile neutropenia:  ANC < 1000/mm3 with a single temperature of 
>38.3ºC (101 ºF) or a sustained temperature of > 38 ºC (100.4 ºF) for more 
than one hour. 
Neutropenic infection:  Grade ≥3 neutropenia with Grade ≥3 infection 
Grade ≥4 Anemia 
Grade ≥4 thrombocytopenia or Grade ≥3 thrombocytopenia with Grade ≥3 
hemorrhage 
Non-
hematologic 
Grade 2 (>3.0 x ULN) ALT/AST with total bilirubin >2 x ULN, in the 
absence of cholestasis 
Grade 3 or 4 non-hematologic toxicity with the following exceptions: 
 Asymptomatic electrolyte abnormality that resolve within 48 
hours. 
 Grade 3 headache lasting <48 hours 
4.1.2. 
Trial Procedures 
All on-study procedures are permitted within the time window indicated in the Schedule of 
Assessments (Table 2).  
4.1.2.1. 
Screening 
The following screening procedures must be performed within 28 days prior to the first day of 
study therapy unless indicated.  Qualifying hematology, serum chemistry (including thyroid-
stimulating hormone [TSH] testing), coagulation, physical examination, ECG, and urinalysis 
collected within 7 days of Cycle 1 Day 1 (C1D1) do not need to be repeated.  The following will 
be performed according to the Schedule of Assessments (Table 2).  
 Patient signature and date on current Institutional Review Board (IRB)-approved 
informed consent form - Prior to undergoing any study-specific procedure, patients must 
read, sign, and date the current IRB)-approved informed consent form.  Patients may sign 
consent prior to the 28-day screening period. 
 Medical history, baseline signs and symptoms, drug allergies, primary diagnosis, and 
demographics 
 Physical examination, including examination of all major body systems, ECOG 
performance status, and vital signs - The patient’s height will be obtained only at this 
Screening visit. 

 
 
 
 
 
Page 27 of 86 
 Hematology, coagulation (prothrombin time and INR), and serum chemistry (including 
liver function tests and TSH) to be performed locally 
 Hepatitis B and C serology will be done for all patients. 
 Urinalysis to be performed locally - Microscopic analysis and/or urine protein-creatinine 
ratio (UPCR) should be performed as clinically indicated. 
 CT or MRI scans of abdomen and pelvis to rule out metastatic disease. (within 3 months) 
 Bone scans are to be performed if metastases to bone are suspected at screening (within 3 
months) and to rule out bone metastases.  
 Single tracing 12-Lead ECG (QT, PR, and QRS intervals and heart rate will be captured) 
 Assessment of concomitant medications and treatments from 28 days prior to the start of 
study treatment 
 Pre-operative baseline core tumor biopsy - Archival Tumor Tissue Specimens:  Archival 
specimens (formalin-fixed, paraffin-embedded) of the primary cancer specimen for each 
study participant.  It is preferable that the entire paraffin block be submitted, but if this is 
not feasible, then at least 20 unstained slides are requested for immunohistochemical and 
molecular analysis (sections of ~ 5 microns are preferred).   
4.1.2.2. 
Study Drug Treatment Period 
Qualifying hematology, blood chemistry (including TSH testing), coagulation, urinalysis, 
physical examination, and ECG test do not need to be repeated on C1D1 if acceptable screening 
assessments are performed within 7 days prior to the start of study therapy.  On days of dosing, 
all assessments should be performed prior to dosing with Abemaciclib unless otherwise indicated 
in the Schedule of Assessments (Table 2).  Patients will be eligible to receive Abemaciclib until 
unacceptable toxicity, withdrawal of consent, progression of disease or end of study.  Each cycle 
is 28 days in duration (+/- 3 days).  The following will be performed according to the Schedule 
of Assessments (Table 2). 
 Physical examination including examination of all major body systems, ECOG 
performance status, weight, and vital signs (heart rate, temperature, blood pressure, 
respiratory rate) 
 Hematology, coagulation (prothrombin time and INR) and serum chemistry (including 
liver function tests and TSH) to be performed locally 
 Urinalysis to be performed locally - Microscopic analysis and/or UPCR should be 
performed as clinically indicated. 
 Administration of Abemaciclib:  Abemaciclib will be administered at a dose of 150 mg 
twice daily and it is provided as 50-mg tablets. Abemaciclib should be taken twice daily 
(with at least 6-hour separating doses) at the same time each day with a glass of water. 
Patients should be instructed to swallow tablets whole and not open, chew, or crush. 
Intrasubject dose escalation of Abemaciclib is not permitted. Abemaciclib will be briefly 

 
 
 
 
 
Page 28 of 86 
stopped 2 weeks prior to radiation therapy and will be restarted a month after radiation 
therapy is completed. Abemaciclib may be given up to a maximum of 24 months. 
 Administration of ADT:  Administer ADT as given in standard of care dosing on C1D1 
along with Abemaciclib. ADT is given every 3 months. The maximum treatment duration 
with ADT is 24 months   
 Radiation Therapy: This is administered after 2 and half cycles of Abemaciclib and 
ADT regimen. RT will be given as administered standard of care at the institution – 
180 cGy x 28 fractions to the whole pelvis and boost to prostate with 250 cGy x 28 
fractions. After RT is completed, both ADT and Abemaciclib are resumed and can be 
continued up to 24 months. See Section 6.3 and Appendix 3: UAB Department of 
Radiation Oncology Treatment Practice Guidelines for further details of radiation 
therapy. 
 Assessment of adverse events (AEs) 
 Assessment of concomitant medications and concomitant treatments 
 
4.1.3. Follow-up 
  
 
Safety Follow-up 
All subjects will complete a safety follow-up visit approximately 30 (+7) days after 
the last dose of study treatment. Serious adverse events and any concomitant 
medications associated with serious adverse events observed by the investigators or 
reported by the subjects that occur through 90 (+7) days after the cessation of all 
study treatment or 30 (+7) days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, will be reported to Eli Lilly and 
recorded in the CRF. 
 
  
 
 Long-term Follow-up 
After the safety follow-up visit, all subjects will enter the long-term follow-up. 
Subjects will be followed for survival and subsequent anticancer therapies every 12 
weeks (± 28 days) from safety follow-up for approximately 12 months after the end 
of treatment. In addition, Abemaciclib related adverse events that occur through the 
end of the long-term follow-up will be reported.  
 
For subjects who discontinue study treatment without documented PD and have not 
initiated a new anticancer therapy, every effort should be made to continue 
monitoring tumor response status by clinical and radiographic tumor assessments.  
 

 
 
 
 
 
Page 29 of 86 
Table 2: 
Schedule of Assessments  
Protocol Activities 
Screening 
Cycle 1 (28 
days) 
Cycle 2-3 
(+/- 3 
days) 
Cycle 4 
onwardsh 
(+/-3days) 
EOT/Follow 
upa 
Day -28 
Day 1  
Day 1  
Day 1 
 
Baseline 
Documentation 
 
 
 
 
 
   Informed Consent  
X 
 
 
 
 
   Medical/Oncology 
History 
X 
 
 
 
X 
   Baseline Signs and 
Symptoms 
X 
 
 
 
 
   Physical 
Examination 
X 
X 
X 
X 
X 
   Vital Signs  
X 
X 
X 
X 
X 
Laboratory 
Studiesi 
 
 
 
 
 
PSA (at screening, 
prior to RT, and q 
month after RT)i 
X 
X 
X 
X 
X 
   Hematologyi 
X 
X 
X 
X 
X 
   Coagulationi 
X 
X 
 
 
 
   Blood Chemistry 
including LFTs i 
X 
X 
X 
X 
X 
Serology for 
Hepatitis B and C 
X 
 
 
 
 
   Urinalysis  
X 
X 
X 
X 
 
Testosterone level to 
confirm chemical 
castration 
X 
 
X 
X 
 
Treatment with 
Study Drug 
 
 
 
 
 
   Abemaciclib 
Dosingb  
 
X 
Xg 
X 
 

 
 
 
 
 
Page 30 of 86 
Protocol Activities 
Screening 
Cycle 1 (28 
days) 
Cycle 2-3 
(+/- 3 
days) 
Cycle 4 
onwardsh 
(+/-3days) 
EOT/Follow 
upa 
Day -28 
Day 1  
Day 1  
Day 1 
 
   LHRH analogues 
(SC)c 
 
X 
 
 
 
   RT 
 
 
Xe 
 
 
Tumor 
Assessments 
 
 
 
 
 
   CT or MRI Scans  
Xf 
 
 
 
Xf 
Other Clinical 
Assessments 
 
 
 
 
 
   12-Lead ECG  
X 
X 
 
 
X 
   Concomitant 
Medications/Treatm
ents 
X 
X 
X 
X 
X 
   Adverse Events  
 
X 
X 
X 
 
Special Laboratory 
Assessments 
 
 
 
 
 
   Optional Tumor 
Biopsyd  
 
 
Xd 
 
 
   Archival Tumor 
Tissue 
X 
 
 
 
 
 
a.           Refer Section 4.1.3 for frequency of follow-up (safety and long-term). 
b.          BID PO dosing Abemaciclib. Abemaciclib will be stopped 2 weeks before RT and 
will be resumed 1 month after RT. 
c.  
LHRH analogues will be administered on C1D1 and continued every 3 months for a 
maximum of 24 months. 
d. 
An optional MRI-TRUS guided biopsy will be performed at 6 months post 
radiotherapy, 
e.  
Radiotherapy will be started after 3 months of start of abemaciclib and ADT.  
f. 
CT scan or MRI scan will be done to rule out metastatic disease (within 3 months). It 
will be conducted again at the time of PSA rise (biochemical failure). 
g. 
Abemaciclib will be stopped 2 weeks before scheduled RT. It will be administered for 
half a cycle in cycle 3. 

 
 
 
 
 
Page 31 of 86 
h. 
Abemaciclib and ADT will be resumed after 1 month of completing RT. This will be 
counted as 4th cycle and future cycles will continue monthly for Abemaciclib. ADT 
will be given quarterly. Study treatment will continue until patient progresses, has 
toxicities or withdraws from study. 
i. 
Laboratory Studies: The first 2 cycles, labs will be drawn every 2 weeks and may be 
drawn at outside lab at the PI’s discretion.  

 
 
 
 
 
Page 32 of 86 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1. 
Patient Inclusion Criteria 
 
1. Histologically confirmed (core biopsy proven) adenocarcinoma of prostate, localized 
high-risk or locally advanced 
2. One of the below: 
• Gleason 7-8, any T-stage, and PSA > 20, 
• Gleason 8, ≥ T2, any PSA, 
• Gleason 9-10, any T-stage, any PSA. 
• T3, any Gleason, any PSA 
• Subjects with positive pelvic lymph node(s) are eligible 
3. Available biopsy of primary tumor or resected tumor specimen with adequate 
samples. 
4. Prior treatment with systemic anti-cancer agents is not allowed. 
5. ECOG PS = 0 or 1 
6.  Must have at least 1 target lesion 
7. Life expectancy > 6 months 
8. Adequate hematologic and end-organ function 
 ANC ≥ 1500/mm3 
 Platelet count ≥ 100,000/mm3 
 Hb ≥ 8g/dl 
 Creatinine ≤ ULN or Creatinine Clearance (CrCl) ≥ 60 ml/min 
 Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who can 
have total Bilirubin < 2.x ULN and direct bilirubin within normal limits are 
permitted) 
 AST and ALT ≤ 3.0 x ULN 
9. Agreement to remain abstinent or use appropriate contraception. 
10. Willingness and ability to consent for self to participate in study. 
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
5.2. 
Exclusion Criteria:   
1. Prior treatment with CDK 4/6 inhibitor. 
2. Prior treatment with systemic or radiation treatment for the primary cancer. 
3. Major surgical procedure or significant traumatic injury within 4 weeks prior to study 
treatment, and must have fully recovered from any such procedure. 
4. Personal history of any of the following conditions: syncope of cardiovascular 
etiology, ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
5. Angina, myocardial infarction (MI), symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack TIA), arterial embolism, 

 
 
 
 
 
Page 33 of 86 
pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or 
coronary artery bypass grafting (CABG) within 6 months prior to study treatment.  
6. Known active viral or non-viral hepatitis or cirrhosis. 
7. Any active infection requiring systemic treatment, positive tests for Hepatitis B 
surface antigen or Hepatitis C ribonucleic acid (RNA). 
8. Known history of AIDS (acquired immunodeficiency syndrome)- defining illness.   
9. Patients must be surgically sterile or must agree to use effective contraception during 
the study treatment (including temporary breaks from treatment), and at least 180 
days after stopping last dose of Abemaciclib.  The definition of effective 
contraception is provided in Section 2.6.1 of this protocol.   
10. Other severe and/or uncontrolled acute or chronic medical or psychiatric condition or 
laboratory abnormality that, in the judgement of the investigator, may increase the 
risk associated with study participation or may interfere with the interpretation of 
study results and would make the patient inappropriate for 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], history of major 
surgical resection involving the stomach or small bowel,  or preexisting Crohn’s 
disease or ulcerative colitis or a preexisting chronic condition resulting in baseline 
Grade 2 or higher diarrhea). 
11. Secondary malignancy requiring active treatment. Past history of malignancy other 
than prostate cancer treated with curative intent and not requiring additional treatment 
may be eligible after discussion with PI. 
12. Patients with active autoimmune disease and history of inflammatory bowel disease 
will be excluded. Brachytherapy boost will not be permitted.  
   
5.3. 
Patient Withdrawal Criteria 
A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is 
medically necessary, or if it is the wish of the patient.  If a patient does not return for a 
scheduled visit, every effort should be made to contact the patient.  In any circumstance, 
every effort should be made to document patient outcome.  Data to be collected at the end of 
study visit are described in the Schedule of Assessments (Table 2).  Patients will be followed 
for at least 28 days after the last dose of study drug (Abemaciclib or ADT) for AEs.  If the 
patient withdraws consent, no further evaluations should be performed, and no attempts 
should be made to collect additional data.  In addition, patients will be withdrawn from 
treatment in the case of: 
1. Lost to follow-up or noncompliant with the protocol 
2. Any Abemaciclib dose delay > 7 days during the first cycle 
3. Arterial thrombosis of any grade (including cerebrovascular ischemia, cardiac 
ischemia/infarction, or peripheral or visceral arterial ischemia) or Grade 3 or 4 venous 
thrombosis (including pulmonary embolism)   

 
 
 
 
 
Page 34 of 86 
5.4. 
General Guidelines 
Eligible patients will be entered on study at Kirklin clinic, UAB Hospital and Acton Road 
clinic.  Site clinical research coordinator (CRC) will ensure study agent availability before 
enrolling patients. Following enrollment and registration by site CRC, patients should begin 
protocol treatment within 28 days. Issues that would cause treatment delays should be 
discussed with the Principal Investigator. If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be cancelled. The Study 
Monitor should be notified of cancellations as soon as possible. 
 
5.5. 
Registration Process 
The Clinical Trials Network Monitoring Office (CTNMO) of the UAB Comprehensive 
Cancer Center (CCC) coordinates investigator-initiated clinical trials under Good Clinical 
Practice conditions at UAB to achieve timely study subject enrolment. Once a study subject 
has been screened and deemed eligible for study entry by the site CRC, a study-specific 
number is assigned to the study subject and a Registration Form is completed. Queries 
regarding data accuracy are forwarded from the CTNMO to the site CRC for clarification or 
correction. 
 

 
 
 
 
 
Page 35 of 86 
6. 
TREATMENT OF PATIENTS 
6.1. 
Description of Abemaciclib Study Drug 
Abemaciclib is an oral, selective, and potent ATP-competitive inhibitor of cyclin-dependent 
kinases 4 and 6 (CDK4 and CDK6, respectively). CDK4 and CDK6 promote cell growth by 
facilitate ing the progression of cells from the G1 to the S-phase of the mammalian cell cycle. 
This promotion of cell growth occurs primarily by counteracting the effects of a growth 
suppressor protein known as the retinoblastoma (Rb) protein, whereby the reversal of Rb  
mediated suppression is achieved by the phosphorylation of this protein by CDK4 and/or 
CDK6. 
 
The CDK4/CDK6-Rb pathway is commonly altered in cancer cells, whereby the activation of 
this pathway contributes to enhanced growth. Accordingly in cancer cells, abemaciclib 
inhibits CDK4/CDK6-dependent phosphorylation of Rb, which subsequently blocks 
proliferation by inhibiting the progression of these cells from the G1 phase into the S and 
G2/M phases of the cell cycle. 
 
Abemaciclib showed antitumor activity within multiple preclinical pharmacology models and 
an acceptable toxicity profile in nonclinical species. Abemaciclib has been shown to 
significantly inhibit tumor growth in multiple murine xenograft models for human cancer.   
6.1.1. Abemaciclib Composition 
The chemical name of Abemaciclib is ( 2-Pyrimidinamine, N-[5-[(4-ethyl-1-
piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-ethylethyl)-
1Hbenzimidazol-6-yl]-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-
fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine and the structural 
formula is presented in Figure 2. Abemaciclib has a molecular formula of C27H32F2N8 and a 
molecular weight of 506.60.  
 
 

 
 
 
 
 
Page 36 of 86 
6.1.2. Abemaciclib Dose Levels 
Subjects in this phase II study will receive 150 mg BID PO dose of Abemaciclib. There will be no 
intra-patient dose escalation of Abemaciclib 
6.1.3. Abemaciclib Packaging and Labelling 
Abemaciclib will be provided by Lilly. Clinical trial materials will be labeled according 
to the country’s regulatory requirements. 
 
6.1.4. Abemaciclib Administration 
Abemaciclib will be administered at a dose of 150 mg twice daily and it is provided as 50-mg tablets. 
Abemaciclib should be taken twice daily (with at least 6-hour separating doses) at the same time each 
day with a glass of water. Patients should be instructed to swallow tablets whole and not open, chew, 
or crush. 
Doses of Abemaciclib will be self-administered except on the days scheduled to be given at the study 
clinic. Abemaciclib will be given daily in combination with ADT as long as subjects do not have 
toxicity, disease progression, have not met any criteria for study withdrawal or up to a maximum of 
24 months. Intrasubject dose escalation of Abemaciclib is not permitted. 
 
Table 3: 
Ideal Dosing Schema for Study Drugs and Abemaciclib Premedications 
Sequence 
Drugs 
C1D1 and 
onwards 
1 
Abemaciclib PO (BID) 
150 mg  
6.1.5. Abemaciclib Dose Modification/Dose Delays 
6.1.5.1. 
Rationale for Dose modifications 
Modifications to Abemaciclib dose regimens are planned and independent of the determination of 
tolerability during the study, subjects may require modification of Abemaciclib if necessitated by 
drug-related or unrelated AEs. 
6.1.6. Abemaciclib Drug Accountability 
The Investigator must maintain an accurate accounting of Abemaciclib supplies.  During the 
study, the following information must be recorded: 
 Date of receipt, quantity, and lot number of the Abemaciclib study drug received. 
 Identification number of the patient to whom the product is dispensed. 
 The date(s) and quantity of the product dispensed. 
 Dates and quantity of product returned, lost, or accidentally or deliberately 
destroyed. 
Investigational Drug Accountability Logs should be maintained by the site and must be 
readily available for inspection. 

 
 
 
 
 
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6.1.7. Abemaciclib Study Drug Handling and Disposal 
The Investigator must maintain an accurate accounting of the Abemaciclib product that is 
used. During the study, the following information must be maintained: 
 Identification number of the patient to whom the product is dispensed. 
 Lot number dispensed. 
 The date(s) and quantity of the product dispensed. 
 
6.2. 
Description of Androgen Deprivation Therapy 
The commonly used preparations are listed below. However any of the other preparations 
with FDA approval, that result in androgen suppression are acceptable. 
 
Goserelin acetate implant (Zoladex®) / Leuprolide (Lupron) 
a. PHARMACOLOGY 
Mechanism of Action: Following initial administration in males, goserelin causes an initial 
increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels 
with subsequent increases in serum levels of testosterone. Chronic administration of goserelin 
leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone 
consequently fall into the range normally seen in surgically castrated men approximately 2-4 
weeks after initiation of therapy. 
b. PHARMACOKINETICS 
1. Absorption: Goserelin 3.6 mg is released slowly in first 8 days, and then rapid and 
continuous release for the remainder of the 28 day dosing period. Time to peak concentration 
for goserelin 3.6 mg is 12-15 days in males and 8-22 days in females. Goserelin 10.8 mg 
exhibits an initial rapid release resulting in a peak concentration at 2 hours after dosing. 
From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin 
produces a reasonably stable systemic exposure.  
2. Distribution: Apparent volumes of distribution determined after subcutaneous 
administration of 250 mcg aqueous solution of goserelin were 44.1 and 20.3 liters for males 
and females, respectively. Goserelin is approximately 27% protein bound. 
3. Metabolism: Metabolism of goserelin by hydrolysis of the C-terminal amino acids is the 
major clearance mechanism. The half-life elimination (t1/2)) is approximately 4 hours in 
males and 2 hours in females 
4. Elimination: Clearance of goserelin is very rapid and occurs primarily via urinary excretion 
(>90%; 20% as unchanged drug). 
c. ADVERSE EFFECTS 
1. Refer to the package insert or manufacturer website for the most 
complete and up to date information on contraindications, warnings and 
precautions, and adverse reactions. 
Side Effects 
Adverse events associated with the use of Leuprolide/Goserelin may include, but are not 
limited 
to, the following: 
 hot flashes 

 
 
 
 
 
Page 38 of 86 
 injection site reactions 
 weight gain 
 increase in liver enzymes 
 tiredness 
 hypertension 
 back and joint pain 
 chills 
 urinary tract infection 
 decreased sex drive and trouble with erectile function 
 
Adverse effects occurring in <1%, postmarketing, and/or case reports: 
1. ALT increased, anaphylaxis, AST increased, diabetes, glucose tolerance decreased, 
hypercalcemia, hypercholesterolemia, hyperlipidemia, hypersensitivity reactions, 
hypotension, ovarian cyst, pituitary apoplexy, psychotic disorders, urticaria. 
2. Pregnancy and Lactation: Not applicable as this study only enrolls male patients. 
Pregnancy category X in patients with endometriosis and endometrial thinning. Pregnancy 
category D in patients with advanced breast cancer. It is not known if goserelin is excreted in 
human milk, however goserelin is excreted in the milk of lactating rats. 
3. Drug Interactions: Luteinizing hormone-releasing hormone analogs may diminish the 
therapeutic effect of antidiabetic agents. No formal drug-drug interaction studies have been 
performed. Please refer to the current FDA-approved package insert for additional 
information. 
4. The FDA issued a safety communication in October 2010 based on their ongoing safety 
review of LHRH agonists. The safety communication discusses the potential for an increased 
risk of diabetes and cardiovascular disease (myocardial infarction, sudden cardiac death, 
stroke) associated with these agents. The risk is thought to be low in men receiving LHRH 
agonists for prostate cancer. In this trial, LHRH agonists are being administered for a short 
period of time. FDA recommendations include management of cardiovascular risk factors 
according to current standards of practice. 
d. DOSING & ADMINISTRATION 
1. Dosing – See Package Insert of preparation used. 
2. Goserelin is administered subcutaneously into the anterior abdominal wall below the navel 
line using aseptic technique. 
e. STORAGE & STABILITY 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
f. HOW SUPPLIED 
1. Goserelin acetate implant is available in a 10.8 mg disposable syringe device. The unit is 
sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate pouch 
containing a desiccant capsule. 
2. Goserelin is commercially available and will not be supplied. Refer to the current FDA-
approved package insert for additional information. 
Leuprolide (Eligard®, Lupron Depot®) (NSC-377526) 
a. PHARMACOLOGY 
Mechanism of Action: Leuprolide inhibits gonadotropin secretion by acting as an luteinizing 
hormone-releasing hormone (LHRH) agonist. Continuous administration results in 

 
 
 
 
 
Page 39 of 86 
suppression of ovarian and testicular steroidogenesis due to decreased levels of LH and FSH 
with subsequent decrease in testosterone (male) and estrogen (female) levels. In males, 
testosterone levels are reduced to below castrate levels. Leuprolide may also act directly on 
the testes as well as act by a different mechanism not directly related to reduction in serum 
testosterone. 
d. DOSING & ADMINISTRATION 
1. Dosing – Per package insert. Typically 22.5 mg every 3 months 
2. Leuprolide is administered intramuscular (Lupron Depot®) or subcutaneous (Eligard®) 
injection based on commercial depot formulation. Injection sites should be varied 
periodically. 
e. STORAGE & STABILITY 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
f. HOW SUPPLIED 
1. Leuprolide acetate is available in 3.75 mg, 7.5 mg, 11.25 mg, 22.5 mg, 30mg, or 45 mg 
depot formulation kit with accompanying diluent. The prefilled dual chamber syringe 
contains lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic 
acid polymer. 
2. Leuprolide/Goserelin is commercially available and will not be supplied. 
 
Other LHRH agents can be utilized per the FDA approved dose and schedule. GNRH 
antagonists cannot be used. 
6.3. 
Radiation Therapy 
Refer to Appendix 3 for UAB Department of Radiation Oncology Treatment 
Practice Guidelines for further details of radiation therapy.  
Brachytherapy boost will not be permitted.  
6.3.1 Target Volume 
Dose inhomogeneity ranges for PTV coverage will be 95% of PTV volume will 
receive 100% of prescribed dose; 100% of PTV volume will receive 95% of dose. 
Global hotspot <107%.  
Minor deviation that is acceptable: 90% of PTV receiving 100% of dose; 95% 
PTV receive 95% of dose; global hotspot 110%.  
6.3.2 Compliance 
Treatment plans will be peer-reviewed for compliance prior to starting radiation at the 
weekly treatment planning conference.  
6.4. 
Dose modifications of Study drugs 
6.4.1.  Planned Dose modifications 
Intrasubject dose escalations are not permitted. Table 4 describes Abemaciclib dose reductions that 
may occur due to any related AEs. There will be no dose reductions of LHRH analogues allowed for 
the management of toxicities of individual subjects. Doses of ADT may be delayed for toxicity 
management. 

 
 
 
 
 
Page 40 of 86 
 
 Table 4: 
Allowable Abemaciclib Dose Modifications for Toxicity Attributed to 
Abemaciclib  
Cohort 
Current Dose 
Dose Reduction 
1 
150 mg BID 
100 mg BID 
6.4.2. Criteria and Procedure for interruption 
In some circumstances, it may be necessary to temporarily interrupt study treatments as a result of 
AEs that may have an unclear relationship to the study drug(s). If an interruption is necessary, both 
study treatments should be interrupted. 
Any dose interruptions of > 2 weeks for LFT abnormalities must be discussed with the medical 
monitor before resuming treatment. Treatment with both study drugs should be withheld for drug-
related Grade 4 hematologic toxicities, non-hematological toxicity ≥ Grade 3 (including laboratory 
abnormalities), and severe or life-threatening AEs. 
Except in cases of emergency, it is recommended that the investigator consult with the sponsor's 
medical monitor (or other representative of the sponsor) before temporarily interrupting therapy for 
reasons other than Protocol-mandated medication hold. Additionally, the investigator must notify the 
sponsor's medical monitor and study project manager via email or during safety teleconferences 
before restarting study drug that was temporarily interrupted because of an AE. 
Dose modifications for hematologic and non-hematologic AEs related to chemotherapy may be 
managed per institutional guidelines.  
6.4.3. 
Procedures for management of Abemaciclib related adverse event(s) 
Guidelines for Diarrhea Management 
Clinical trial data indicates the majority of patients who receive abemaciclib will develop 
diarrhea. Our experience indicates early identification and intervention for the management 
of diarrhea has been helpful to patients.  
At enrollment, patients should receive instructions on the prompt management of 
diarrhea. In the event of diarrhea, supportive care measures should be initiated as early as 
possible.  These include the following: 
 
At the first sign of loose stools, the patient should initiate antidiarrheal therapy (e.g. 
loperamide) and notify the investigator for further instructions and appropriate follow-up. 
 
Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids per 
day). 
 
Site personnel should assess response within 24 hours.  
 
Refer to Table 5 for additional information for diarrhea management and dose modification. 
 
 
 

 
 
 
 
 
Page 41 of 86 
Table 5: Dose Modification and Management- Diarrhea 
At the first sign of loose stools, start treatment with antidiarrheal agents, such as loperamide. 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 
No dose modification is required.  
Grade 2  
If toxicity does not resolve within 24 hours to ≤Grade 1, 
suspend dose until resolution. Dose reduction is not 
required. 
Grade 2 that persists or recurs 
after resuming the same dose 
despite maximal supportive 
measures  
Suspend dose until toxicity resolves to ≤Grade 1. 
Resume at next lower dose. 
Grade 3 or 4 or requires 
hospitalization 
General Guidance for Increases in Serum Creatinine and Assessment of Renal 
Insufficiency 
Elevation of serum creatinine is observed with abemaciclib, and is due to a pharmacological 
inhibitory effect of abemaciclib on renal tubular transporters without affecting glomerular function. 
The rise in serum creatinine (mean increase, 0.2 mg/dL) occurs within the first 28-day cycle of 
abemaciclib, and remains elevated but stable throughout the treatment period, and were reversible 
upon treatment discontinuation. Alternative markers (such as BUN, cystatin C level, or cystatin C 
calculated GFR) which are not based on creatinine, may be considered to determine whether renal 
function is impaired.  
 
General Guidance for Interstitial lung disease (ILD)/Pneumonitis events 
Interstitial lung disease (ILD) /pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in clinical trials were Grade 1 or Grade 2 with serious 
cases and fatal events reported. Additional information is available in the IB.  
Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis and ask your 
patients to report any new or worsening pulmonary symptoms such as dyspnea, cough, and fever, and 
investigate and treat as per your local clinical practice (including corticosteroids as appropriate). If 
ILD/pneumonitis is suspected, investigations may include imaging, such as high resolution computed 
tomography, broncheoalveolar lavage, and biopsy as clinically indicated. Discontinue abemaciclib in 
cases of severe (Grade 3 or 4) ILD/pneumonitis.  
 
 
 
 

 
 
 
 
 
Page 42 of 86 
Table 6: 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 
Suspend dose until toxicity resolves to baseline or Grade 
1. 
Resume at next lower dose. 
Grade 3 or 4 
Discontinue abemaciclib. 
 
General Guidance for Hepatic Monitoring 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation are considered as 
ADR with the use of abemaciclib. The following information in Table 7 on hepatic monitoring: 
Table 7: Dose Modification and Management — Increased ALT/AST 
Monitor ALT/AST prior to the start of abemaciclib therapy, every 2 weeks for the first 2 
months, monthly for the next 2 months, and as clinically indicated. 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 (>ULN-3.0 x ULN) 
Grade 2 (>3.0-5.0 x ULN) 
No dose modification is required. 
Persistent or Recurrent Grade 
2, or Grade 3 (>5.0-20.0 x 
ULN) that does not resolve 
with maximal 
supportivemeasures within 7 
days to baseline or Grade 1: 
suspend dose until toxicity 
resolves to baseline 
or Grade 1. 
Suspend dose until toxicity resolves to baseline or Grade 
1. 
Resume at next lower dose. 
Grade 2 (˃3.0 x ULN)  
with total bilirubin >2 x 
ULN, in the absence of 
cholestasis 
Discontinue abemaciclib 
Grade 4 (>20.0 x ULN) 
Discontinue abemaciclib. 
 
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities are shown below in Table 7.  
 
 

 
 
 
 
 
Page 43 of 86 
Table 8: Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality. 
 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs ‐ red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs ‐ white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma‐glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT‐INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti‐HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti‐HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti‐nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti‐smooth muscle antibody (ASMA) a 
    HBV DNA c 
Anti‐actin antibody b 
Hepatis C virus (HCV) testing: 
Epstein‐Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA c 
    EBV DNA c 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNA c 

 
 
 
 
 
Page 44 of 86 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA c 
    HSV (Type 1 and 2) DNA c 
Microbiology  
Liver kidney microsomal type 1 (LKM‐1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
 
a 
Not required if anti‐actin antibody is tested. 
b 
Not required if anti‐smooth muscle antibody (ASMA) is tested. 
c 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
General Guidance for Hematology Toxicity and Dose Modification 
Hematologic toxicities including neutropenia, leukopenia, anemia, and thrombocytopenia have been 
observed in patients treated with abemaciclib, and causality has been established.  Severe (Grade 3 
and 4) neutropenia was observed in patients receiving abemaciclib.  Patients should be monitored 
closely for signs of infection, anemia, and bleeding. Table 9 provides guidance on dose 
modification and management of hematologic toxicities. 
 
 Table 9: Dose Modification and Management — Hematologic Toxicities 
Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 weeks for the 
first 2 months, monthly for the next 2 months, and as clinically indicated. 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required. 
Grade 3 
Suspend dose until toxicity resolves to ≤Grade 2. 
Dose reduction is not required. 
Grade 3, recurrent, or Grade 4 
Suspend dose until toxicity resolves to ≤Grade 2. 
Resume at next lower dose. 
Patient requires administration 
of a blood cell growth factor 
Suspend abemaciclib dose for at least 48 hours after the 
last dose of blood cell growth factor and until toxicity 
resolves to ≤Grade 2. 
Resume abemaciclib at next lower dose unless the dose 
was already reduced for the toxicity that led to the use of 
the growth factor. 
 

 
 
 
 
 
Page 45 of 86 
General Guidance for Non-hematologic Toxicities (excluding diarrhea, ILD/Pneumonitis and 
increased ALT/AST) Monitoring 
 
Table 10: Dose Modification and Management — Non-hematologic Toxicities Excluding 
Diarrhea and ALT Increased 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required. 
Persistent or recurrent Grade 
2 toxicity that does not 
resolve with maximal 
supportive measures within 7 
days to baseline or Grade 1 
Suspend dose until toxicity resolves to baseline or Grade 
1. 
Resume at next lower dose. 
Grade 3 or 4 
  
6.4.3.1. 
Therapy for Febrile Neutropenia 
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
IV antibiotic therapy. Events that require a patient to be hospitalized are considered SAEs 
 
6.4.3.2. 
Growth Factor Therapy 
Growth factors should not be administered to a patient to satisfy study inclusion criteria. 
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 
2015). Dosing of abemaciclib must be suspended if the administration of growth factors is 
required and must not be recommenced within 48 hours of the last dose of growth factors 
having been administered. Following the administration of growth factors, the dose of 
abemaciclib must be reduced to the previous dosing level on recommencement, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred. 
 
6.5. 
Criteria for permanent discontinuation of study drug(s) 
Subjects may withdraw consent at any time for any reason or be withdrawn from the study at 
the discretion of the investigator should any untoward effect occur. In addition, a subject may 
be withdrawn by the investigator or the sponsor if enrollment into the study is inappropriate, 
the study plan is violated, or for administrative and/or other safety reasons.  
Subjects must be withdrawn from the study treatment for the following reasons: 
・ In the investigator's medical judgment, further participation would be injurious to the subject's 
health or well-being. 
・ Consent is withdrawn by the subject or legal representative (such as parent or legal guardian). 

 
 
 
 
 
Page 46 of 86 
・ The study is terminated by the sponsor. 
・ The study is terminated by the local health authority or IRB/IEC. 
・ The subject has experienced an unacceptable toxicity or a toxicity that does not recover in 2 weeks. 
Investigators who wish to continue treatment after a treatment delay of 2 weeks should consult 
with the sponsor's medical monitor for approval. 
・ Noncompliance with study treatment or procedure requirements. 
・ The subject is lost to follow-up. 
 
6.6. 
Study Completion 
6.6.1. Study completion criteria 
Subjects will be considered completing the study if they met any of the following criteria: 
・ Subject dies and a date of death is available. 
・ Subject is known to have died; however, the date of death cannot be obtained. 
(NOTE: every effort must be made to obtain the date of death.) 
・ Consent is withdrawn for any further contact related to this study. 
・ Subjects may choose to withdraw from the study at any time without penalty of jeopardizing their 
health care or loss of benefits to which the subject is otherwise entitled. Every reasonable effort 
should be made to determine the reason a subject withdraws prematurely, and this information 
should be recorded in the eCRF. 
・ The study is terminated by the sponsor. 
・ The study is terminated by the local health authority or IRB or IEC. 
6.6.2. Withdrawal procedures 
In the event that any subject discontinues study drug and, subsequently, withdraws from the 
study before completion, regardless of reason, reasonable efforts should be made to have the 
subject return for the EOT procedures to be completed. The date the subject was withdrawn 
from the study and the specific reason for withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from the study: 
・ The study monitor or sponsor must be notified. 
・ The reason(s) for withdrawal must be documented in the subject's medical record and in the eCRF. 
・ The EOT or early termination visit should be performed. 

 
 
 
 
 
Page 47 of 86 
・ Subjects must be followed for safety until the time of the follow-up visit or until study drug–related 
toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer. 
6.7. 
Concomitant Medications 
No other approved or investigational anticancer treatment will be permitted during the study 
period.  No other investigational drug may be used during treatment on this protocol, and 
concurrent participation in another clinical trial is not allowed. 
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 concomitant use cannot be avoided, abemaciclib dose adjustments may be required:  
 
Patients who must take CYP3A inhibitors such as clarithromycin, diltiazem, or verapamil should 
reduce the abemaciclib dose to 100 mg twice daily.  
 
Patients who must take itraconazole should reduce the abemaciclib dose to 50 mg twice daily.  
 
Patients who must take ketoconazole should reduce the abemaciclib dose to 50 mg once daily.  
 
Patients should avoid grapefruit or grapefruit juice. 
Strong CYP3A inhibitors and/or inducers should not be used until the completion of the dose-
limiting evaluation period. 
 
Patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) on study should also 
receive peptic ulcer disease (PUD) prophylaxis with a histamine-2 (H2) blocker or proton 
pump inhibitor. 
Narcotic analgesics, NSAIDs, ketorolac and triptans (e.g., sumatriptan) may be offered as 
needed for relief of pain or headaches.  Antihistamines and decongestants may be offered for 
the treatment of sinus congestion. 
Antibiotic prophylaxis should be used for invasive dental procedures. 
Packed red blood cells, colony stimulating factors, and platelet transfusions should be 
administered as clinically indicated.  

 
 
 
 
 
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6.8. 
Treatment Compliance 
All infusions (ADT) and oral intake of Abemaciclib will occur at the investigational site 
under the direct supervision of the Investigator or his or her designee.  
6.9. 
Patient Enrollment 
Patients will be manually enrolled by site research coordinator in Oncore database and 
assigned an 8-digit patient number.  This 8-digit number will be used to identify patients 
throughout their participation in the trial.  A regulatory binder will be provided and will 
include detailed instructions for the manual enrollment process.  
6.10. 
Beginning and End of the Study 
The study begins when the first subject signs the informed consent. The end of the study may be 
designated as the timepoint when all subjects have discontinued the study. At this point a database 
lock of the study may occur to allow the analysis of the study data.  
 

 
 
 
 
 
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7. 
ASSESSMENT OF EFFICACY 
7.1. 
PSA serial measurements 
Serum samples for assessment of PSA levels will be collected at all study visits and analyzed 
by the central laboratory. Additional assessments of PSA levels during the subject’s 
participation in the study, either done for-cause or per standard of care, should be 
done through the central laboratory as well.  Before the start of the study, sampling and 
storing procedures will be provided in a laboratory manual.  
 
   

 
 
 
 
 
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8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
Safety will be characterized in terms of the incidence, timing, severity graded by the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03), seriousness, and drug-relatedness of adverse events (AEs) and laboratory 
abnormalities.  In addition, physical examination, vital signs, and ECOG performance status 
will be serially monitored.  Laboratory safety analyses will be based on the data from which 
labs are collected, and will include hematology (including iron studies at baseline), serum 
chemistry (including liver and kidney function, and TSH), urinalysis, and coagulation profile 
(baseline only).  Serum will also be assessed for immunogenicity to Abemaciclib (including 
anti-product antibody titers).  In addition, single tracing 12-lead ECGs will be performed at 
the time points indicated in the Schedule of Assessments (Table 2).  QT, PR and QRS 
intervals and heart rate will be captured.  ECGs will also be collected as clinically indicated 
throughout the study.   
8.1.1. Laboratory Safety Assessments 
Abnormal and clinically significant laboratory tests should be recorded as adverse events.  To 
meet the definition of clinically significant, the test result generally requires a change in 
medical management (e.g., new medication, unplanned treatment, additional tests, etc.). 
8.1.1.1. 
Hematology, Serum Chemistry, and Coagulation Test  
Assessments will be performed at the time points indicated in the Schedule of Assessments 
(Table ) and analyzed at laboratories where collected.  Investigators may have additional 
blood tests performed for the purpose of planning treatment administration, or for following 
AEs, as clinically indicated.  
 Hematology: Complete blood count (CBC) with differential and platelet count.   
 Coagulation: Prothrombin time and International Normalized Ratio (INR). 
 Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate transaminase 
(AST), alkaline phosphatase, lipase, amylase, sodium, potassium, bicarbonate, 
chloride, calcium, phosphorus, blood urea nitrogen, creatinine, magnesium, thyroid 
stimulating hormone (TSH), and glucose. 
 Patients must agree to use effective contraception during the study and for ≥ 180 days 
following last dose of study drug (Abemaciclib).  The definition of effective 
contraception is provided in Section 2.6.1 of this protocol. 
8.1.1.2. 
Urinalysis  
Urinalysis (without microscopic analysis, unless indicated) will be performed at time points 
indicated in the Schedule of Assessments (Table 2) and analyzed by local laboratories.  
Microscopic analysis, urine protein-creatinine ratio (UPCR), and 24-hour urine collection for 
protein should be performed as clinically indicated. 

 
 
 
 
 
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8.1.2. Physical Examination 
A physical examination including, but not limited to, general appearance, head, eyes, ears, 
nose, throat, neck, heart, chest, abdomen, musculoskeletal, extremities, skin, lymph nodes, 
neurological, genitourinary (as appropriate), and rectal (as appropriate) will be assessed at 
time points indicated within the Schedule of Assessments ( 2).  The physical examination will 
include examination of known and suspected sites of disease.   
8.1.3. Vital Signs 
Heart rate, temperature, blood pressure, respiratory rate, and weight will be assessed at time 
points indicated within the Schedule of Assessments (Table 2).  Height will be assessed only 
at the Screening visit.  Heart rate, temperature, blood pressure, and respiratory rate will also 
be assessed during Abemaciclib as described in Section 4.1.2.2 and the footnotes of the 
Schedule of Assessments (Table 2).  
8.1.4. Performance Status 
The ECOG scale will be used to assess performance status at Screening and at time points 
indicated within the Schedule of Assessments (Table 2).   
8.1.5. Electrocardiogram (ECG) 
A single tracing 12-lead tracing will be used for all ECGs.  It is preferable that the machine 
used has a capacity to calculate standard intervals automatically.  ECG will be performed at 
the time points indicated in the Schedule of Assessments (Table 2) and as clinically indicated 
throughout the study.  
8.2. 
Adverse Events 
All observed or volunteered AEs regardless of suspected causal relationship to study drug 
(Abemaciclib) will be reported as described below.  
8.2.1. Definition of Adverse Event 
An AE is any untoward medical occurrence in a trial patient who is administered a drug or 
biologic (medicinal product); the event may or may not have a causal relationship with the 
medicinal product.  Examples of AEs include, but are not limited to the following: 
 Clinically significant symptoms and signs including:  
 Worsening of signs and symptoms of the malignancy under study drug 
treatment  (Note:  Disease progression with or without worsening of signs and 
symptoms assessed by measurement of malignant lesions on radiographs or 
other methods should not be reported as AEs unless the outcome is fatal 
during the study or within the safety reporting period for the study.) 
 Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction, or toxicity   
 All treatment-emergent possibly related and unrelated illnesses, including the 
worsening of a preexisting illness 
 Injury or accidents - Note that if a medical condition is known to have caused 
the injury or accident (e.g., hip fracture from a fall secondary to dizziness), the 

 
 
 
 
 
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medical condition (dizziness) and the outcome of the accident (hip fracture 
from a fall) should be reported as 2 separate AEs.   
 Symptoms or signs resulting from exposure in utero 
 Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat confirmatory 
test) 
 Laboratory abnormalities that meet any of the following criteria  (Note:  Merely 
repeating an abnormal test, in the absence of any of the below conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE.) 
 Test result that is associated with accompanying symptoms 
 Test result that requires additional diagnostic testing or medical/surgical 
intervention 
 Test result that leads to a change in study drug (Abemaciclib) dosing other 
than protocol-stipulated dose adjustments or discontinuation from the trial, 
significant additional concomitant drug treatment, or other therapy 
 Test result that is considered to be an AE by the Investigator or ELI LILLY 
8.2.2. Serious Adverse Events 
An AE that meets one or more of the following criteria/outcomes is classified as a serious /ae 
(SAE): 
 Results in death 
 Is life-threatening (i.e., at immediate risk of death) 
 Requires in patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity 
 Results in congenital anomaly/birth defect 
 Other Important Medical Events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events 
are intensive treatment in an emergency room for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or the development of 
drug dependence or drug abuse.  
Serious also includes any other AE that the Investigator or sponsor judges to be serious, or 
which is defined as serious by the Health Regulatory Authority (HRA) in the country in 
which the event occurred.   
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal during the study or within the 
safety reporting period for the study.  Hospitalizations due to signs and symptoms of disease 
progression should not be reported as SAEs.  However, if the malignancy has a fatal outcome 

 
 
 
 
 
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during the study or within the safety reporting period for the study, then the AE leading to 
death must be recorded as an SAE with CTCAE Grade 5.  
The onset date of an SAE is defined as the date on which the event initially met serious 
criteria (e.g., the date of admission to a hospital).  The end date is the date on which the event 
no longer met serious criteria (e.g., the date the patient was discharged from a hospital).  
8.2.2.1. 
Hospitalization 
AEs associated with in-patient hospitalization, or prolongation of an existing hospitalization, 
are considered serious.  Any initial admission, even if the duration is less than 24 hours, is 
considered serious.  In addition, any transfer within the hospital to an acute/intensive care 
unit is considered serious (e.g., transfer from the psychiatric wing to a medical floor or 
transfer from a medical floor to a coronary care unit).  However, the following 
hospitalizations should not per se constitute a serious AE:  
 Rehabilitation facility admission 
 Hospice facility admission 
 Respite care 
 Skilled nursing facility admission 
 Nursing home admission 
 Emergency room visit, including observation unit visit 
 Outpatient same day surgery/procedure 
 Hospitalization or prolongation of hospitalization in the absence of precipitating 
clinical adverse events as follows: 
 Admission for treatment of preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition  
 Social admission 
 Administrative admission (e.g., for yearly physical exam) 
 Protocol-specified admission during a clinical trial 
 Optional admission not associated with a precipitating clinical adverse event 
(e.g., for elective cosmetic surgery) 
 Preplanned treatments or surgical procedures that are not related to an SAE 
 Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs.  The medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE (e.g., acute 
appendicitis that begins during the AE reporting period should be reported as an AE 
and the appendectomy should be recorded as a concomitant treatment). 

 
 
 
 
 
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8.3. 
Reporting Adverse Events 
8.3.1. Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs reported by the study 
patient using concise medical terminology.  In addition, each study patient will be questioned 
about AEs at each clinic visit following initiation of treatment.  The question asked will be, or 
words to the effect, “Since your last clinic visit have you had any health problems?” 
8.3.2. Adverse Event Reporting Period 
Safety information for each patient will be collected from the date of informed consent.  AEs 
occurring prior to the initiation of the study treatment with Abemaciclib study drug will be 
considered " baseline-emergent adverse events,” will be recorded on corresponding CRFS 
and will not be retained for patients who fail screening.  The AE reporting period for this 
study begins when the patient has received even a portion of the first dose of Abemaciclib 
study drug and ends 28 days after the last dose of the latest study treatment (i.e., Abemaciclib 
study drug) is administered.  
All AEs that occur in study patients during the AE reporting period specified in the protocol 
must be reported to ELI LILLY, whether or not the event is considered study treatment-
related.  In addition, any known untoward event that occurs beyond the AE reporting period 
that the Investigator assesses as possibly related to either investigational medication/product 
should also be reported as an AE. 
8.3.3. Reporting Requirements 
 
To comply with applicable laws, regulations and standards regarding Investigator’s and 
Institution’s obligations, as the sponsor of the Study, to collect and report adverse events to 
regulatory authorities, IRBs, Ethics Committees or other third parties.  In addition to the 
obligations set forth below, Investigator and Institution agree to provide Lilly with a copy of 
all information Investigator and/or Institution submit to regulators related to any adverse 
events for the Study Drug that occur during the Study that Investigator and/or Institution have 
not otherwise provided Lilly; 
 
To notify Lilly, sub-investigators, and the IRB of any problems involving risk to Study 
patients and report new safety information to IRBs in accordance with applicable 
requirements; 
 
to notify Lilly within twenty-four (24) hours 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 CIOMS Form or other form acceptable to Lilly.  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. 

 
 
 
 
 
Page 55 of 86 
 
For SAEs which are fatal or life-threatening, unexpected, and associated with use of the study 
drug (Abemaciclib), a 7-Day Alert Report will be submitted to the FDA within 7 calendar 
days of receipt of the SAE information.  For all other SAES that are unexpected and 
associated with use of the study drug (Abemaciclib), a written report will be made no more 
than 15 calendar days from the date Eli Lilly learns of the event.  Participating clinical sites 
will be notified of these events in parallel with FDA notification. 
All AEs, including SAEs, are to be reported on the AE CRFs.  
8.3.4. Recording Adverse Events in the Case Report Forms 
The Investigator is to report all directly observed AES and all AEs reported by the study 
patient.  In addition, each study patient will be questioned about AEs.  All AEs that meet the 
criteria specified in Section 8.2.1 are to be recorded on patient source documents and on the 
CRFs.  AEs should be reported using concise medical terminology on the CRFs.  
8.3.5. Grading of Adverse Event Severity 
To report AEs on the CRFs, the Investigator will use the severity grading as described in NCI 
CTCAE (Version 4.03).  Every effort should be made by the Investigator to assess the AE 
according to CTCAE criteria.  If the Investigator is unable to assess severity because the term 
is not described in NCI CTCAE (Version 4.03), then severity of MILD, MODERATE, 
SEVERE, LIFE-THREATENING, or FATAL may be used to describe the maximum 
intensity of the AE, as guided by Table 10  Note that the selection of the most appropriate 
verbatim term for AEs is not restricted to only those toxicities represented in NCI CTCAE.  
For purposes of consistency, these intensity grades are defined as follows:  
Table 10: 
Adverse Event Grading 
Grade 
Non-CTCAE Severity 
Definition 
1 
Mild  
Does not interfere with patient’s usual function 
2 
Moderate 
Interferes to some extent with patient’s usual 
function 
3 
Severe 
Interferes significantly with patient’s usual 
function 
4 
Life-Threatening 
Results in immediate risk of patient’s death 
5 
Fatal 
Results in patient’s death 
Note the distinction between the severity and the seriousness of an AE.  A severe AE is not 
necessarily a serious AE.  For example, a headache may be severe (interferes significantly 
with patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for serious events.   
8.3.6. Relationship to Treatment Drugs (Abemaciclib) 
In this study, there are 2 study drugs; the investigational drug Abemaciclib is given in 
combination with ADT.  The relationship of each AE to each study drug will be made and 

 
 
 
 
 
Page 56 of 86 
should be guided in part by the known safety profile of each drug, including the Abemaciclib 
IB.  The relatedness should be classified by the Investigator using the following guidelines: 
 Suspected Adverse Reaction: There is a reasonable possibility that study drug caused 
the AE (i.e., there is evidence to suggest a causal relationship between study drug and 
the AE). 
 Not Related: There is no reasonable possibility that the AE is associated with study 
drug.  
AEs related to study drug are considered Adverse Drug Reactions (ADR). 
8.3.7. Expectedness  
All AEs and ADRs are considered “unexpected” if not listed in the Abemaciclib IB.  For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents.  "Unexpected," as used in this 
definition, also refers to AEs or suspected ADRs that are mentioned in the IB as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation. 
8.3.8. Exposure in Utero 
If the partner of a study patient becomes or is found to be pregnant during the study or within 
90 days of discontinuing the investigational medication/product, the Investigator must report 
the information to ELI LILLY, or designee via the Pregnancy Notification Report Form 
within 24 hours of awareness of the pregnancy.  This must be done irrespective of whether an 
AE has occurred.  The information submitted should include the anticipated date of delivery.   
The Investigator will follow the pregnant partner of a study patient until completion of the 
pregnancy or until pregnancy termination (i.e., induced abortion) and then notify ELI LILLY, 
or its designee, of the outcome within 5 days or as specified below.  The Investigator will 
provide this information as a follow-up to the initial report.  The reason(s) for an induced 
abortion must be specified. 
The Investigator should follow procedures for reporting an SAE if pregnancy outcome meets 
criteria for an SAE (e.g., spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly [including that in an aborted fetus]). 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
and the Pregnancy Outcome Report Form should be completed (i.e., no minimum follow-up 
period of a presumably normal infant must pass before a Pregnancy Outcome Report Form 
can be completed).  The “normality” of an aborted fetus can be assessed by gross visual 
inspection unless pre-abortion laboratory findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
 “Spontaneous abortion” includes miscarriage and missed abortion. 
 All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 1 month that the 

 
 
 
 
 
Page 57 of 86 
Investigator assesses as possibly related to the in utero exposure to the study drug 
should also be reported. 
8.3.9. Follow-up of Unresolved Adverse Events  
All AEs should be followed until resolved, improved to the patient’s pre-treatment baseline 
severity or better, or the patient’s participation in the study is completed, whichever occurs 
first.  All serious adverse events and those non-serious events assessed by the Investigator as 
suspected reactions (i.e., at least possibly related) to a Abemaciclib must be followed, even 
after the patient’s withdrawal from study, until the event is either resolved, improved to the 
patient’s pre-treatment baseline or better, stable without anticipated future change, or the 
patient is lost to follow-up, or, in the case of a suspected adverse reaction, later determined to 
be not related to the ELI LILLY investigational medicinal product.  Any increase or decrease 
in AE grade should be recorded as a new adverse event.  All AEs should also be documented 
on the AE CRF.  
8.4. 
Safety Monitoring 
   
Data and Safety Monitoring Plan 
Dr. Eddy Yang will function as the sponsor of the trial at UAB. The UAB Comprehensive Cancer 
Center Data and Safety Monitoring Plan (DSMP) instituted by the CTNMO will monitor subjects 
treated at UAB in the trial.  The Clinical Trials Monitoring Committee (CTMC) on a weekly basis 
will closely monitor adverse reactions observed during treatment.  The CTMC is responsible for data 
and safety monitoring of the trial and adherence to the DSMP. The independent Quality Assurance 
Committee (QAC) is responsible for oversight of the operation of CTMC, including adherence to the 
DSMP.  Reports from the CTMC are reviewed annually by the QAC.  
These committees will monitor safety throughout this study and all studies of Abemaciclib 
via the following activities:  
 Surveillance for SAEs according to regulatory guidelines 
 Routine monitoring of non-serious AES as they are recorded in the CRFs and the 
source documents at study sites 
Toxicity information that may affect the treatment of patients on this study will be promptly 
communicated in writing to all participating Abemaciclib clinical sites, as well as institutions 
participating in this clinical trial.   

 
 
 
 
 
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9. 
OTHER ASSESSMENTS 
9.1. 
Other Laboratory Assessments  
9.1.1. Tumor Biopsies 
Tumor biopsies will be fixed in formalin and embedded in paraffin, and immune cell markers 
will be assessed by immunohistochemistry and immunofluorescence, focusing on CD8+ 
T-cells, T regulatory cells, and MDSCs. 
9.1.2. Biomarker analysis 
The current standard extended-sextant 12 core prostate biopsy technique is essentially a 
random but systematic sampling in various regions of the prostate gland, serving as a 
surrogate sampling technique. However, the natural course of most clinically-significant 
prostate cancer appears to be driven by dominant intra-prostatic lesions (IPL). Advances in 
multi-parametric prostate MRI (mpMRI) have allowed for identification and radiographic 
risk stratification of these IPLs, and real-time fusion of mpMRI with trans-rectal ultrasound 
(TRUS) now allows urologists to perform targeted biopsies of IPLs with optimized detection 
of clinical significant prostate cancer foci. At UAB, we have analyzed specimens obtained 
from targeted biopsies from high risk (Gleason score 8 and above) and low risk (Gleason 
score 6). Using the Nanostring nCounter platform, we were able to find deregulation of 
various cancer driver pathways (DNA repair, Wnt, Notch, cell cycle, PI3K, and ras) in high 
risk vs. low risk cancers14. Furthermore, imaging metrics such as DCE and PiRADS scores 
also correlated with pathway deregulation. Given these findings, we also propose to use 
archived tumor tissue from diagnostic biopsy as well as imaging with MRI-US fusion and 
conducting an optional biopsy at 6 months post-RT. Tumor samples will be assessed for 
mutations using the Strata Oncology panel and for gene expression analysis using the 
Nanostring nCounter platform and the PanCancer Pathways panel. Imaging characteristics, 
such as DCE and PiRADs scores, will be correlated with PSA response and outcomes. Given 
the emergence of blood-based analysis of biomarkers, we will also collect blood at baseline, 
pre-radiotherapy (2-3 months of ADT+abemaciclib), 1 and 6 months post-RT to perform 
molecular analysis to correlate with PSA responses  
 

 
 
 
 
 
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10. 
STATISTICS 
10.1. 
Statistical Design/Sample Size 
Simon's optimal two-stage design (Simon, 1989) will be used for conducting the trial. The null 
hypothesis is that the proportion of patients with PSA <0.5 without treatment is 5%, and the 
alternative hypothesis is that the proportion of patients with PSA <0.5 at 6 weeks into treatment is 
30% or higher. The trial is carried out in two stages. In stage I, a total number of 5 patients is accrued. 
If there are 0 response (PSA< 0.5) among these 5 patients, the study will be early stopped. Otherwise, 
additional 18 patients will be accrued in stage II, resulting in a total number sample size of 23. If there 
are 4 or more responses (PSA< 0.5) among these 23 patients, we reject the null hypothesis and claim 
that the treatment is promising. The design controls the type I error rate at one-sided 0.025 and yields 
the power of 80%. If we reject the null hypothesis, seven additional patients will be enrolled to 
explore the association between biomarkers and clinical activities. To account for 10% screen failure, 
total 33 patients will be recruited to the study. 
10.1.1. 
Definition of Analyzed Study Populations 
The following study populations will be considered when reporting study results: 
 The study population for safety includes all patients receiving at least a portion of 
1 dose of study drug (Abemaciclib).   
 The study population for efficacy will include all safety population patients who 
have baseline and follow-up tumor measurements as required for assessment by 
iRECIST. 
Only those patients who are deemed ineligible (e.g., do not satisfy eligibility criteria) or who 
receive no study drug (i.e., no Abemaciclib) will be eliminated from the analysis.  Ineligible 
patients who receive therapy will not be included in the assessment of efficacy endpoints, but 
their data will be included in the assessment of all AE reporting.  
10.2. 
Data Analysis 
 Simon's optimal two-stage design (Simon, 1989) will be used for conducting the trial. The 
null hypothesis is that the proportion of patient with PSA <0.5 without treatment is 5%, and 
the alternative hypothesis is that the proportion of patient with PSA <0.5 at 6 weeks into 
treatment is 30% or higher. The trial is carried out in two stages. In stage I, a total number of 
5 patients is accrued. If there are 0 response (PSA< 0.5) among these 5 patients, the study 
will be early stopped. Otherwise, additional 18 patients will be accrued in stage II, resulting 
in a total number sample size of 23. If there are 4 or more responses (PSA< 0.5) among these 
23 patients, we reject the null hypothesis and claim that the treatment is promising. The 
design controls the type I error rate at one-sided 0.025 and yields the power of 80%. This 
response rate will be summarized using both a point estimate and its 2-sided 95% confidence 
limits. If we reject the null hypothesis, seven additional patients will be enrolled to explore 
the association between biomarkers and clinical activities. Descriptive statistics will be used 
to summarize patient demographics, baseline characteristics, treatment 
administration/compliance, efficacy, biomarkers, and archival tumor tissue, safety, and 
efficacy parameters. Time to PSA failure will be analyzed using the Kaplan-Meier method. 
The assessment of safety data will be based on the summarization of treatment related AEs, 
SAEs, AEs leading to discontinuation from study treatment or efficacy follow-up, and 
clinical laboratory tests. Data will also be displayed graphically, where appropriate. 

 
 
 
 
 
Page 60 of 86 
 
10.2.1. Analysis of Primary Objective  
For each patient, PSA will be measured on systemic treatment with Abemaciclib and ADT after 
radiotherapy. The primary endpoint is percentage of patients who achieve the PSA nadir levels of ≤ 
0.5 ng/ml during their treatment. Simon's optimal two-stage design (Simon, 1989) will be used for 
conducting the trial. The null hypothesis is that the proportion of patient with PSA <0.5 is 5%, and the 
alternative hypothesis is that the proportion of patient with PSA <0.5 is 30% or higher. The trial is 
carried out in two stages. In stage I, a total number of 5 patients is accrued. If there are 0 response 
(PSA< 0.5) among these 5 patients, the study will be early stopped. Otherwise, additional 18 patients 
will be accrued in stage II, resulting in a total number sample size of 23. If there are 4 or more 
responses (PSA< 0.5) among these 23 patients, we reject the null hypothesis and claim that the 
treatment is promising. The design controls the type I error rate at one-sided 0.025 and yields the 
power of 80%. This response rate will be summarized using both a point estimate and its 2-sided 95% 
confidence limits.  
 
10.2.2. Analysis of Secondary Objective 
For each patient, PSA declines prior to radiotherapy- calculated from nadir level prior to 
initiation of radiation therapy compared from pre-treatment baseline - will be listed. The 
secondary endpoint will be reported as percentage of patients who achieve a PSA decline 
prior to radiotherapy with combination treatment of ADT and Abemaciclib compared to their 
baseline PSA levels. This response rate will be summarized using both a point estimate and 
its 2-sided 95% confidence limits.   
Another secondary endpoint will be time to PSA failure. Time to PSA failure will be 
analyzed using the Kaplan-Meier method. SAEs (including deaths) will be tabulated. Subject 
listings of all AEs, SAEs (including deaths), and their attribution will be provided. 
All AEs with an onset after initiation of treatment will be considered as treatment-emergent 
AEs.  A preexisting condition that worsens after study drug treatment will also be considered 
as a treatment-emergent AE.  All AEs will be coded by MedDRA SOC and PT. 
The number and percentage of patients with the following types of treatment-emergent AEs will be 
summarized: all AEs, all SAEs, AEs related to study drug ((Abemaciclib), AEs resulting in study drug 
discontinuation, and clinically significant laboratory abnormalities.  Non-treatment-emergent serious 
AEs will be presented separately from treatment-emergent AEs.  Deaths will be reported with 
demographic information. Laboratory results will be summarized descriptively by dose level. 
Additional exploratory statistical analysis will be performed as it deemed necessary. 
 
 

 
 
 
 
 
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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
All data entered on CRFs/electronic CRFs (eCRFs) must be verifiable within the patients’ 
source documents (written or electronic record).  UAB PI, CTNMO, QAC,  and appropriate 
regulatory authorities direct access to the original source records for the duration of the 
agreed study record retention period.  Printouts of source records that are electronically 
obtained and stored will not be acceptable for audit/inspection unless provided as certified 
exact copies and the data remains as meaningful and useful as in its original electronic state. 
Legally protected patient identification and other personal health information must be 
securely stored with limited access by the participating institutions.  Unless secure provisions 
are established by the institution to allow ELI LILLY (or designee) to perform remote 
monitoring of electronic source records, ELI LILLY (or designee) will review source 
records/data on site and will not remove any such protected health information. 

 
 
 
 
 
Page 62 of 86 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
CTNMO and QAC committee at UAB will conduct monitoring periodically during the trial 
to ensure that GCPs and all aspects of the protocol are being followed.   
The trial site will also be subject to possible inspection by the institutional review board 
(IRB) or independent ethics committee (IEC) or other appropriate regulatory authority.  The 
trial site is also subject to quality assurance audits performed by UAB CTNMO and QAC. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits, audits, and inspections and that sufficient attention, time, and support is 
devoted to the process.  
UAB CTNMO and QAC will be governed by applicable regulations, GCP standards, and 
internal standard operating procedures (SOPs) for the conduct of monitoring visits and 
quality assurance (QA) audits. 

 
 
 
 
 
Page 63 of 86 
13. 
ETHICS 
13.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the Investigator to have approval of the study protocol, protocol 
amendments, informed consent forms, advertisements from the IRB/IEC, and any other 
patient-distributed materials before potential patients are consented for participation on the 
trial.  All correspondence and other evidence of appropriate and timely communications with 
the IRB/IEC should be retained in the Investigator/site files.  Copies of all IRB/IEC approvals 
should also be forwarded to ELI LILLY. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the Investigator must notify the IRB/IEC and ELI LILLY in writing within 5 
business days after the implementation. 
13.2. 
Ethical Conduct of the Study 
The trial will be performed in accordance with the protocol, applicable local regulatory 
requirements and laws, and the International Council on Harmonization (ICH) Guideline on 
Good Clinical Practice (GCP), which supports the application of ethical principles that have 
their origin in the Declaration of Helsinki (see ICH E6, § 2.1).  
13.3. 
Written Informed Consent 
The informed consent form language must be agreed upon by UAB PI and the IRB/IEC and 
must be in compliance with ICH GCP, local regulatory requirements, and legal requirements.  
The informed consent information must not be changed without prior approval by UAB PI 
and the IRB/IEC.  The informed consent form used in this trial, and any changes made during 
the course of the study, must be approved by both the IRB/IEC and UAB PI, before use.  
It is the responsibility of the Investigator to give each patient full and adequate verbal and 
written information regarding the objective and procedures of the trial and the possible risks 
involved.  This information must be provided to the patient prior to undertaking any protocol-
specified procedure.  Patients must be informed about their right to withdraw from the trial at 
any time.  Furthermore, it is the responsibility of the Investigator to ensure all patients are 
appropriately informed before obtaining their signed and dated consent.  Signatures from the 
Investigator conducting the informed consent discussion should also be obtained, prior to 
undertaking any trial-related procedure.  Consent by a legally authorized representative is not 
permitted.  Should an impartial witness be needed, ICH E6 requirements for impartial 
witnesses will apply.  
The Investigator will retain the original of each patient’s signed consent form in the 
Investigator/site files. 
13.4. 
Patient Compensation 
Patients will not be compensated for participation in this study; this will be outlined in the 
patient informed consent form. 

 
 
 
 
 
Page 64 of 86 
14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Inspection of Records 
CRFs/eCRFs are required and should be completed for each patient who receives treatment 
with Abemaciclib.  Screen failure CRF’s will not be collected.  Nevertheless, records of 
potential patients identified and screened shall be retained on site screening logs.  The 
completed original CRFs/eCRFs are the sole property of UAB Comprehensive Cancer Center 
and should not be made available in any form to third parties without written permission from 
UAB PI (except for authorized representatives of the HRA and in accordance with Health 
Insurance Portability and Accountability Act [HIPAA] regulations). 
It is the Investigator’s responsibility to ensure completion and to review and approve all CRF 
data.  The investigator will sign off on his/her data per patient.  These signatures serve to 
attest that the Investigator has reviewed and approved the information contained on the CRFs 
and that the information is complete, accurate, and true.  At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory 
data entered on the CRFs.    
The use of electronic CRFs (eCRFs) to capture study data using automated computerized data 
capture systems does not change the principles and requirements for collecting study data.  
The Investigator still retains final personal responsibility for eCRF data and any associated 
data pertaining to it (e.g., metadata including any record of change to the originally recorded 
data).  The Investigator’s signed approval of the eCRF data serves to attest that the electronic 
data and all of its associated metadata (including changes) has been reviewed and accepted as 
complete, accurate, and true for each patient in the study. 
14.2. 
Retention of Records 
To allow for appropriate evaluations and/or audits by regulatory authorities UAB PI agrees to 
keep records, including the identity of all participating patients (sufficient information to link 
records, CRFs and hospital records), all original signed informed consent forms, copies of all 
CRFs, source documents, and detailed records of treatment disposition.  The Investigator 
should retain these records according to local regulations or as specified in the Clinical Trial 
Agreement, whichever is longer.   
If the Investigator relocates, retires, or for any reason withdraws from the study, then ELI 
LILLY should be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another Investigator, another institution.  The Investigator must 
inform ELI LILLY of any such transfer of responsibilities and properly identify the person or 
institution assuming the responsibility.  The responsible institution must obtain UAB PI’s 
written permission before disposing of any records.  

 
 
 
 
 
Page 65 of 86 
15. 
DEFINITION OF END OF TRIAL 
15.1. 
End of Trial  
End of trial is defined as the time at which all patients enrolled in the study have completed 
the treatment follow-up period. 
.  
15.2. 
ELI LILLY Discontinuation Criteria 
Premature termination of this trial may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of ELI LILLY.  
In addition, ELI LILLY retains the right to discontinue development of Abemaciclib at any 
time.  
ELI LILLY reserves the right to discontinue the trial prior to inclusion of the intended 
number of patients, but intends only to exercise this right for valid scientific or administrative 
reasons.  If a trial is prematurely terminated or discontinued, ELI LILLY will promptly notify 
the Investigator.  After notification, the Investigator must contact all participating patients 
within a 28-day time period.  As directed by UAB PI, all trial materials must be collected and 
all CRF data must be completed to the greatest extent possible.  

 
 
 
 
 
Page 66 of 86 
16. 
PUBLICATION OF TRIAL RESULTS 
Publication of trial results is discussed in the Clinical Trial Agreement.  

 
 
 
 
 
Page 67 of 86 
17. 
FINANCING AND INSURANCE 
Financing and Insurance are discussed in the Clinical Trial Agreement.  

 
 
 
 
 
Page 68 of 86 
18. 
REFERENCES 
 
1. Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast 
Cancer. The New England journal of medicine 2015. 
2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-
positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 
study. The Lancet Oncology 2015;16:25-35. 
3. Comstock CE, Augello MA, Goodwin JF, et al. Targeting cell cycle and hormone receptor 
pathways in cancer. Oncogene 2013;32:5481-91. 
4. Whiteway SL, Harris PS, Venkataraman S, et al. Inhibition of cyclin-dependent kinase 6 
suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. Journal of 
neuro-oncology 2013;111:113-21. 
5. Hagen KR, Zeng X, Lee MY, et al. Silencing CDK4 radiosensitizes breast cancer cells by 
promoting apoptosis. Cell division 2013;8:10. 
6. Zhussupova A, Hayashida T, Takahashi M, et al. An E2F1-HOXB9 transcriptional circuit is 
associated with breast cancer progression. PloS one 2014;9:e105285. 
7. Jirawatnotai S, Hu Y, Livingston DM, Sicinski P. Proteomic identification of a direct role for 
cyclin d1 in DNA damage repair. Cancer research 2012;72:4289-93. 
8. Shimura T, Kakuda S, Ochiai Y, et al. Acquired radioresistance of human tumor cells by DNA-
PK/AKT/GSK3beta-mediated cyclin D1 overexpression. Oncogene 2010;29:4826-37. 
9. Dok R, Kalev P, Van Limbergen EJ, et al. p16INK4a impairs homologous recombination-
mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer research 
2014;74:1739-51. 
10. Dean JL, McClendon AK, Knudsen ES. Modification of the DNA damage response by 
therapeutic CDK4/6 inhibition. The Journal of biological chemistry 2012;287:29075-87. 
11. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy 
for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011;378:2104-11. 
12. Mason MD, Parulekar WR, Sydes MR, et al. Final Report of the Intergroup Randomized Study of 
Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy 
Alone in Locally Advanced Prostate Cancer. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2015;33:2143-50. 
13. Roach M, 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and 
external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2008;26:585-91. 
14. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term 
androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC 
randomised study. The Lancet Oncology 2010;11:1066-73. 

 
 
 
 
 
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15. Lawton CA, Winter K, Grignon D, Pilepich MV. Androgen suppression plus radiation versus 
radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: 
updated results based on national prospective randomized trial Radiation Therapy Oncology Group 
85-31. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2005;23:800-7. 
16. Fossa SD, Wiklund F, Klepp O, et al. Ten- and 15-yr Prostate Cancer-specific Mortality in 
Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, 
Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results 
of The Scandinavian Prostate Cancer Group-7. European urology 2016;70:684-91. 
17. Brundage M, Sydes MR, Parulekar WR, et al. Impact of Radiotherapy When Added to Androgen-
Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes 
From the NCIC CTG PR3/MRC PR07 Randomized Trial. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2015;33:2151-7. 
18. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive 
radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. International journal 
of radiation oncology, biology, physics 2005;61:1285-90. 
19. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. 
Biochim Biophys Acta 2002;1602:73-87. 
20. Sherr CJ. Cancer cell cycles. Science 1996;274:1672-7. 
21. Fujiwara Y, Tamura K, Kondo S, et al. Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 
6, as a single agent for Japanese patients with advanced cancer. Cancer Chemother Pharmacol 
2016;78:281-8. 
22. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A Phase II Study of Abemaciclib, a 
CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR(+)/HER2(-) Metastatic 
Breast Cancer. Clin Cancer Res 2017;23:5218-24. 
23. Sledge GW, Jr., Toi M, Neven P, et al. MONARCH 2: Abemaciclib in Combination With 
Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While 
Receiving Endocrine Therapy. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2017;35:2875-84. 
24. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for 
Advanced Breast Cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2017;35:3638-46. 
25. Hurvitz S, Abad MF, Rostorfer R, et al. breast cancer, early stageInterim results from 
neoMONARCH: A neoadjuvant phase II study of abemaciclib in postmenopausal women with HR + 
/HER2- breast cancer (BC). Annals of Oncology 2016;27:LBA13-LBA. 
26. Iwata H. Clinical development of CDK4/6 inhibitor for breast cancer. Breast Cancer 2018. 

 
 
 
 
 
Page 70 of 86 
19. 
 APPENDICES 
19.1. 
Appendix 1:  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) 
The NCI CTCAE (Version 4.03) should be used to assess adverse events and may be 
reviewed on-line at the following NCI website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 

 
 
 
 
 
Page 71 of 86 
19.2. 
Appendix 2:  ECOG Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
Page 72 of 86 
19.3. 
Appendix 3: UAB Department of Radiation Oncology Treatment 
Practice Guidelines 
 
 
 

 
 
 
 
 
Page 73 of 86 
Indications/Work Up 
 
The initial diagnosis of localized prostate cancer is generally made by a urologist who has 
performed a prostate biopsy. The initial risk stratification of men with prostate cancer 
requires 
o Tissue sampling 
 
Specimens obtained at outside institutions should be re‐reviewed by the 
UAB Department of Pathology for consensus as to the grade 
o Prostate specific antigen (PSA) testing 
o Digital rectal examination (DRE) 
 
The need for further clinical staging is determined by the risk stratification as defined by the 
NCCN: 
Low Risk (all of the following) 
- 
T1c or T2a 
- 
PSA ≤ 10 ng/mL 
- 
Gleason ≤ 6 
- 
No additional imaging needed. 
- 
May consider prostate MRI to aid in treatment planning 
- 
Pelvic MRI indicated if SBRT is considered 
- 
 
Intermediate Risk (any of the 
following) 
- 
T2b or T2c 
- 
PSA 10‐20 ng/mL 
- 
Gleason 7 
- 
For patients with nomogram assessed probability of LN 
involvement exceeding 10% pelvic imaging (CT or MRI 
[preferred]) is indicated 
- 
Pelvic MRI indicated if SBRT is considered 
- 
Pelvic MRI may also be indicated if considering omission 
of seminal vesicles in CTV 
High Risk (any of the following) 
- 
T3 or T4 
- 
PSA > 20 ng/mL 
- 
Gleason ≥ 8 
- 
Pelvic imaging (MRI [preferred] or CT) 
- 
Nuclear medicine bone scan or NaF PET/CT 
- 
The role of other PET agents such as fluciclovine can be 
considered in select cases. 
 
 
 

 
 
 
 
 
Page 74 of 86 
 
Radiotherapy Options for Primary Therapy 
 
As with global treatment options, appropriate radiotherapy techniques and choice of the use 
of androgen suppression is also based on disease and patient characteristics. For men who 
choose to proceed with a definitive radiotherapy modality a table of recommendations is 
presented below: 
Low Risk 
Life expectancy >20 years: 
‐ 
Fractionated external beam radiotherapy 
‐ 
Stereotactic body radiotherapy (SBRT) 
Life expectancy <20 years: 
‐ 
Active surveillance 
Intermediate 
Risk 
Life expectancy >10 years: 
‐ 
External beam radiotherapy +/‐ short term androgen suppression 
‐ 
SBRT +/‐ short term androgen suppression (see Appendix B) 
Life expectancy <10 years: 
‐ 
Active surveillance 
High Risk 
Life expectancy >5 years: 
‐ 
External beam radiotherapy + long term androgen suppression 
(preferred) (see Appendix B) 
Life expectancy <5 years: 
‐ 
Consider androgen suppression therapy (See Appendix B) 
‐ 
Observation 
 
Choice of Fractionation Schedule 
 
We recommend moderate hypofractionation as the default dosing schedule for men 
undergoing definitive EBRT 
o See Appendix A for discussion 
 
Consider protracted fractionation schedule for patients with high IPSS score (>15), inability 
to meet standard dosimetric constraints, and inflammatory bowel disease  
 
 

 
 
 
 
 
Page 75 of 86 
 
Simulation 
 
CT simulation is recommended for all men for whom EBRT or SBRT is planned 
 
Supine position is preferred 
o Foot fix or other immobilization device at the discretion of the treatment team 
 
Men will be asked to have a full bladder and empty rectum at the time of simulation 
o With respect to bladder fullness, care should be taken that the volume is 
reproducible. 
 
Instruct patients to drink 24‐32 oz of fluid 1 hour prior to simulation and 
treatments  
o A retrograde urethrogram is suggested to aid in the visualization of the apex of the 
prostate 
o Oral contrast to improve visualization of the small bowel is optional 
o IV contrast is rarely indicated  
o Consider IV contrast in the setting of malignant lymphadenopathy  
 
The scan should include L2 through the upper femur with 2‐2.5mm slices. 
 
MRI fusion with axial T2 sequence for any patient with an MRI data set 
 
 

 
 
 
 
 
Page 76 of 86 
 
Sample Conventionally Fractionated Simulation Order 
 
 
 
Sample Prostate (non‐SBRT) Simulation Order 
 
 
Target Volumes 
 
Moderate hypofractionation and conventional fractionation 
o The Gross Tumor Volume (GTV) within the prostate is not routinely defined 
o The Clinical Target Volume (CTV) 
 
CTV1 will always include entire prostate and any gross disease beyond the 
prostate 
 
For men with high risk disease CTV1 should be expanded to include 
at least the proximal 1‐2cm of the seminal vesicles (SV) 
o Inclusion of the entire seminal vesicles should be considered 
based on clinical judgment  
 
For men with intermediate risk disease CTV1 may be expanded 
beyond the prostate to include the proximal 1‐2cm of the SV 
o Alternatively the proximal seminal vesicles may be omitted 
from CTV1 if an MRI has been obtained and no SV invasion 

 
 
 
 
 
Page 77 of 86 
identified or the nomogram assessed risk of SV invasion is 
felt to be very low 
 
CTV2 is defined for men with high risk prostate cancer 
 
CTV2 consists of at‐risk lymphatics. Lymph node regions included 
are: 
o Obturator 
o Internal and external iliac 
o Common iliac 
o Pre‐sacral 
o Reference: RTOG Pelvic Node Contouring Atlas (Link) 
 
The cranial extent of CTV2 may be variable but should not routinely 
extend above the superior aspect of the L4 vertebral body 
o The Planning Target Volume (PTV) 
 
PTV1 will be a geometric expansion around CTV1.  Size of the expansion will 
be 7mm in all directions except posteriorly, where 4mm will be used. 
 
PTV2 will be a geometric expansion around CTV2.  Size of the expansion will 
be at least 8mm in all directions 
Dose Prescription 
 
Moderate Hypofractionation 
o PTV1 prescribed 70 Gy in 28 fractions 
o PTV2 prescribed 50.4 Gy in 28 fractions, simultaneously 
 
Conventional fractionation 
o PTV1 prescribed 75‐80 Gy in fractions of 1.8‐2.0 Gy 
o PTV2 prescribed 45‐50.4 Gy in fractions of 1.8 Gy, with sequential cone down to 
boost PTV1 
 
Dose‐Volume Analysis 
 
Treatment planning goals for moderately hypofractionated and conventionally fractionated 
regimens are available in the UAB Department of Radiation Oncology Treatment Planning 
Guide (See Appendix D) 
 
Daily Image Guidance 
 
The use of daily image guidance (IGRT) is recommended for all men undergoing EBRT 
 
For fixed field IMRT, images should be triggered by MU, at an interval of approximately 3% 
of the total MU of the plan. Fractionated EBRT (conventional or hypofractionated) 
o Daily CBCT without implanting fiducial markers is felt to be adequate image 
guidance for men undergoing fractionated EBRT 
 
CBCT allows for assessment of bladder, rectal, and prostate anatomy 

 
 
 
 
 
Page 78 of 86 
 
For men with intact prostate cancer the focus of alignment will be at the 
prostate‐rectum interface 
 
Where possible, the visible portion of the nodal PTV should also be 
assessed to ensure that the associated vessels fall within the target 
volumes. Note that field‐of‐view limitations may impair ability to 
visualize upper aspect of the pelvis with CBCT, depending on 
isocenter placement 
 
For men receiving post‐prostatectomy RT the focus of alignment will be at 
the anterior rectal wall at the level of the VUA (vesicoureteral anastomosis) 
o Alignment to implanted fiducial markers may be used instead of daily CBCT 
 
Weekly CBCT is strongly recommended to assess soft tissue anatomy and 
bladder and rectal filling. 
 
Follow up 
 
Disease monitoring 
PSA every 3 months for first year and then every 6‐12 months 
thereafter. 
First follow‐up PSA should not be drawn sooner than 3 months post‐
radiation 
DRE if PSA is detectable and not actively declining 
Androgen suppression 
monitoring (if 
applicable) 
Bone density monitoring 
Consider repeating testosterone profile 6‐12 months after initiating 
androgen suppression for men receiving long term therapy 
Late toxicity 
evaluation 
IPSS at each visit 
SHIM at each visit 
CTCAE assessed lower GI toxicity 
CTCAE assessed GU toxicity 
Imaging 
Not routinely indicated 
 
Contributing authors 
 
Eddy Yang, MD, PhD (Site Leader) 
 
Andrew McDonald, MD (First Author) 
 
M. Chris Dobelbower, MD, PhD 
 
D. Hunter Boggs, MD 
 
John Fiveash, MD 
 
Richard Popple, PhD 
 
Christina Blalock, CMD 
 
Leesa Cordell, RT(R,T) 
 
Allen Jamerson, RT(R,T,CT) 
 
 

 
 
 
 
 
Page 79 of 86 
 
 
 
 
References 
1. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1.2016. Journal of the 
National Comprehensive Cancer Network : JNCCN 2016;14:19‐30. 
2. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy 
in Recurrent Prostate Cancer. The New England journal of medicine 2017;376:417‐28. 
3. Carrie C, Hasbini A, de Laroche G, et al. Salvage radiotherapy with or without short‐term 
hormone therapy for rising prostate‐specific antigen concentration after radical 
prostatectomy (GETUG‐AFU 16): a randomised, multicentre, open‐label phase 3 trial. The 
Lancet Oncology 2016;17:747‐56. 
4. Dulaney CR, Osula DO, Yang ES, Rais‐Bahrami S. Prostate Radiotherapy in the Era of 
Advanced Imaging and Precision Medicine. Prostate cancer 2016;2016:4897515. 
5. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external‐beam 
radiotherapy for prostate cancer. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2013;31:3860‐8. 
6. Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III Noninferiority Study Comparing 
Two Radiotherapy Fractionation Schedules in Patients With Low‐Risk Prostate Cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2016;34:2325‐32. 
7. McDonald AM, Baker CB, Popple RA, Cardan RA, Fiveash JB. Increased radiation dose 
heterogeneity within the prostate predisposes to urethral strictures in patients receiving 
moderately hypofractionated prostate radiation therapy. Practical radiation oncology 
2015;5:338‐42. 
8. Pisansky TM, Hunt D, Gomella LG, et al. Duration of androgen suppression before 
radiotherapy for localized prostate cancer: radiation therapy oncology group randomized 
clinical trial 9910. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2015;33:332‐9. 
9. Nabid A, Carrier N, Martin A‐G, et al. High‐risk prostate cancer treated with pelvic 
radiotherapy and 36 versus 18 months of androgen blockade: Results of a phase III 
randomized study. American Society of Clinical Oncology; 2013. 
10. Zapatero A, Guerrero A, Maldonado X, et al. High‐dose radiotherapy with short‐term or long‐
term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, 
controlled, phase 3 trial. The Lancet Oncology 2015;16:320‐7. 

 
 
 
 
 
Page 80 of 86 
11. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and 
strategies to mitigate them. European urology 2015;67:825‐36. 
12. Saad F, Adachi JD, Brown JP, et al. Cancer treatment‐induced bone loss in breast and 
prostate cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2008;26:5465‐76. 
13. Berruti A, Dogliotti L, Terrone C, et al. Changes in bone mineral density, lean body mass and 
fat content as measured by dual energy x‐ray absorptiometry in patients with prostate 
cancer without apparent bone metastases given androgen deprivation therapy. The Journal 
of urology 2002;167:2361‐7; discussion 7. 
14. Smith MR, Saad F, Egerdie B, et al. Sarcopenia during androgen‐deprivation therapy for 
prostate cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2012;30:3271‐6. 
15. Loprinzi CL, Dueck AC, Khoyratty BS, et al. A phase III randomized, double‐blind, placebo‐
controlled trial of gabapentin in the management of hot flashes in men (N00CB). Annals of 
oncology : official journal of the European Society for Medical Oncology 2009;20:542‐9. 
16. Irani J, Salomon L, Oba R, Bouchard P, Mottet N. Efficacy of venlafaxine, 
medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot 
flushes in men taking gonadotropin‐releasing hormone analogues for prostate cancer: a 
double‐blind, randomised trial. The Lancet Oncology 2010;11:147‐54. 
17. Vitolins MZ, Griffin L, Tomlinson WV, et al. Randomized trial to assess the impact of 
venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2013;31:4092‐8. 
 
Appendix A: Fractionation Schedules 
 
Moderately hypofractionated dose schedules have been compared to conventionally 
fractionated dosing schedules in multiple large randomized trials 
o Dulaney et al. published a review of the recent literature that readers are referred to 
for additional reading4. 
 
Given this large body of evidence we recommend moderate hypofractionation as the default 
dosing schedule for men undergoing definitive EBRT 
o Despite this recommendation we recognize that some authors have noted slightly 
worse late grade 2 GU morbidity with moderate hypofractionation5,6 
o In the Fox Chase randomized trial by Pollack et al. the slightly worse GU morbidity 
with hypofractionation was limited to those patients with initial IPSS scores of 
greater than 12, thus for this group of patients conventional fractionation is 
considered an acceptable alternative5.  

 
 
 
 
 
Page 81 of 86 
o The committee has also expressed concerns about moderate hypofractionation in 
men who have a history of prior TURP, thus for this group of patients conventional 
fractionation is also considered an acceptable alternative though we do note that in 
our institutional series reporting late GU morbidity no patient with prior TURP 
developed a late urethral stricture7 
o Consider protracted fractionation schedule for patients with high IPSS score (>15), 
inability to meet standard dosimetric constraints, and inflammatory bowel disease  
 
Appendix B: Androgen Deprivation Therapy 
 
Patient selection 
o High risk localized prostate cancer 
 
We recommend long‐term androgen suppression for all men with high risk 
prostate cancer in the absence of significant contraindications 
 
For men with high risk disease the use of androgen suppression has 
been associated with an overall survival advantage in multiple 
randomized trials 
o Intermediate risk localized prostate cancer 
 
For men with intermediate risk prostate cancer we recommend at least 
discussing the risks and benefits of androgen suppression 
 
For men with intermediate risk disease whether a survival 
advantage accompanies short term androgen suppression is 
controversial 
 
Trials that have reported improved overall survival with androgen 
suppression for intermediate risk disease have not utilized the 
escalated doses of radiation that are now considered standard 
 
The decision to proceed with androgen suppression for men with 
intermediate risk prostate cancer is highly individualized.  Some key factors 
include: 
 
Life expectancy 
 
Comorbidities 
 
Baseline sexual function 
 
Goals of care 
 
One reasonable strategy is to reserve androgen suppression for men with 
Gleason 4+3=7 disease or multiple intermediate risk factors (e.g. T2c and 
PSA > 10ng/mL) 
 
Androgen suppression regimens 
o Androgen deprivation vs. total androgen blockade 
 
For men with clinically localized prostate cancer, total androgen blockade 
for at least 4 months is a historical standard 
 
ADT vs. TAB have not been compared head‐to‐head in localized prostate 
cancer 

 
 
 
 
 
Page 82 of 86 
 
Among men with metastatic castrate sensitive prostate cancer TAB 
has not consistently shown an advantage over ADT alone, but one 
large non‐inferiority trial failed to confirm non‐inferiority 
o Our recommendation is that an anti‐androgen be combined with ADT for at least 2 
weeks to prevent testosterone flare associated with GnRH agonists 
 
Strong consideration should be given to completing a 4 month course of oral 
anti‐androgen medication for men with high risk disease 
o We endorse the following regimens 
 
Leuprolide +/‐ 2 weeks or 4 months of bicalutmide 50mg 
 
Goserelin +/‐ 2 weeks or 4 months of bicalutamide 50mg 
 
Degarelix without bicalutamide 
o The use of second generation anti‐androgen medication such as enzalutamide is 
considered investigational 
o We do not recommend routine use of bicalutamide monotherapy (150mg QD) or 
orchiectomy 
 
 
Length of androgen suppression 
o The ideal length of androgen suppression is controversial 
o For intermediate risk prostate cancer 6 months of androgen suppression has been a 
historical standard 
 
A recent clinical trial by the RTOG/NRG found equivalent outcomes among 
patients who received either 4 or 9 months of androgen suppression8, thus 
we also consider 4 months of androgen suppression acceptable 
o For men with high risk prostate cancer the historical standard is 28 (RTOG) or 36 
(EORTC) months 
 
Recently, a Canadian trial, reported in abstract, found that 18 months of 
androgen suppression resulted in equivalent outcomes to 36 months9. One 
study has compared short term androgen suppression with long term 
androgen suppression in the dose‐escalated RT era and prostate cancer 
mortality outcomes were improved with long‐term androgen suppression10. 
 
Thus, we recognize an ideal duration of 18‐28 months, depending on patient 
tolerance 
 
Monitoring of men during androgen suppression 
o We strongly recommend assessing testosterone and PSA response at approximately 
8 weeks following the initiation of androgen suppression 
 
Goal testosterone levels are <50 
 
Supportive care of men receiving androgen suppression 

 
 
 
 
 
Page 83 of 86 
o Androgen suppression therapy has been associated with a variety of adverse effects 
that can be associated with significant bother and morbidity 
o The most common manifestations and supportive strategies are outlined here. For 
more information please refer to the excellent review article by Nguyen et al.11 
o Bone effects: Decreases in bone mineral density (BMD) typically occur within 1 year 
of beginning androgen suppression therapy12,13.  This decline in BMD has been 
associated with an increased risk of hip and vertebral compression fractures. To 
mitigate these effects we recommend the following: 
 
Fracture risk assessment should be performed for all patients using the 
FRAX clinical fracture risk estimator. For these purposes androgen 
suppression therapy is considered secondary osteoporosis. 
 
Men with a 10‐year hip fracture risk ≥3% or major osteoporotic fracture risk 
≥20% should be referred to an osteoporosis specialist. 
 
Dual energy x‐ray absorptiometry (DXA) should be considered for men at 
elevated risk but who do not meet the above threshold. 
 
Consider DXA measurement at 1 year following the initiation of androgen 
suppression. 
 
All men who receive androgen suppression should be counseled on calcium 
and vitamin D supplementation in accordance with the NOF guidelines.  A 
minimum of 1,200 mg/day calcium and 800‐1,000 IU vitamin D are 
recommended.   
 
Weight bearing exercise should be encouraged in order to improve bone 
health. 
o Cardiac effects: The pathogenesis of cardiac morbidity among men who receive 
androgen suppression is controversial. Recent reviews and meta‐analyses have 
generally concluded that androgen suppression increases the risks of cardiovascular 
events but not mortality.  
 
In terms of managing cardiovascular risks we recommend close 
communication with patients’ other physicians such as primary care 
providers and cardiologists.  
 
The decision to use androgen suppressing agents in men with pre‐existing 
cardiac morbidity should be undertaken on an individual basis as evidence is 
conflicting on the risks and benefits. 
o Muscle mass: Significant changes in body composition can manifest within months 
of initiation of androgen suppression14.  
 
To combat these changes weight bearing exercise, cardiovascular exercise, 
and maintenance of a healthy diet should be encouraged. 
 
 For patients with unfavorable body composition at baseline we recommend 
consideration of consultation with a registered dietician. 
o Hot flashes: Hot flashes develop in a majority of men with castrate levels of 
testosterone.  
 
The pathophysiology of hot flashes in men receiving androgen suppression 
therapy appears to differ somewhat compared to the pathophysiology of 
hot flashes in menopausal women  
 
Thus the agents that have shown efficacy at reducing the severity of 
hot flashes differ between the populations.  

 
 
 
 
 
Page 84 of 86 
 
Prior to initiating any pharmacologic therapy clinicians and patients should 
be aware of the natural history of hot flashes following the initiation of 
androgen suppression  
 
Generally the severity of hot flashes will begin to decrease after 1‐2 
months.  
 
A number of small randomized trials have been conducted to assess the 
efficacy of different agents and, to date, the most effective therapies appear 
to be gabapentin 300mg TID and medroxyprogesterone 20mg QD15,16.  
 
Venlafaxine and soy products have not been shown in randomized 
trials to be superior to placebo17.  
 
A few single arm studies have suggested that acupuncture may be 
effective at reducing the severity of hot flashes for select patients 
with interest in alternative therapies.  
o Gynecomastia: Androgen suppression therapy, particularly when an anti‐androgen is 
used, can lead to gynecomastia.  
 
For men who are scheduled to receive long‐term anti‐androgen therapy 
prophylactic measures against gynecomastia should be considered.  
 
Traditionally external beam RT (1‐5 fractions) to the breast have 
resulted in acceptable prevention of gynecomastia.  
 
Tamoxifen at a dose of 10‐20mg QD is also an effective prophylactic 
regimen and was significantly more effective at preventing 
gynecomastia in one moderately sized randomized trial18, 19.  
o Decreased libido: Decreased libido occurs in the vast majority of men with castrate 
levels of testosterone. 
 
We emphasize the distinction between decreased libido and mechanical 
erectile dysfunction.  
 
 Androgen suppression does not generally lead to mechanical erectile 
dysfunction, thus response rates to PDE‐5 inhibitors are substantially less 
than 20%20.  
 
The most effective strategies to preserve sexual activity during androgen 
suppression are appropriate counseling of the patient/partner and 
cardiovascular exercise.  
o Emotional support: Men with castrate levels of testosterone are at increased risk for 
depression.  
 
Members of the treatment team should screen patients for depression and 
have a low threshold for referral to a supportive care specialist. 
 
Appendix C: Documentation 
• 
We believe that prostate cancer is conducive to synoptic style documentation 
o Appropriate documentation is considered a quality measure by many accrediting 
bodies 
o In addition to standard documentation that accompanies any patient encounter, we 
strongly recommend documentation of all of the following parameters at the time of 
initial consultation: 
 
Disease characteristics   

 
 
 
 
 
Page 85 of 86 
 
Intact prostate: 
o T‐stage (and modality by which T stage was determined) 
o Biopsy Gleason score 
o Most recent PSA 
 
Post‐prostatectomy: 
o Surgical stage 
o Most recent PSA 
o PSA doubling time 
 
Patient characteristics ‐ Baseline IPSS 
 
Baseline SHIM 
 
Life expectancy 
 
FRAX estimated 10 year fracture risk 
 
Charlson comorbidity index 
 
Staging studies ‐ Pelvic imaging: 
 
Results vs. planned vs. not indicated (why?) 
 
Bone scan: 
 
Results vs. planned vs. not indicated (why?) 
o Treatment recommendations ‐ radiotherapy recommendation 
 
Androgen suppression recommendation 
 
Yes (planned duration) vs. No (why?) 
• 
The committee has created a PowerChart template that is available for all practitioners to 
guide proper documentation at the time of consultation of men with intact localized 
prostate cancer. 
• 
We are actively working to create templates for men seen after prior prostatectomy and for 
follow‐up visits. 
 
Appendix D: Dose Volume Analysis 
 
 
‐Dose inhomogeneity ranges and coverage parameters 95% of PTV volume should receive 
100% of the prescribed dose. 
‐Due to potential OARs, it is acceptable to have 90% of PTV receive 100%; 100% of PTV 
volume should receive 95% of the prescribed dose. 
 
‐Due to potential OARs, it is acceptable that 100% of PTV receive 90%. 
 
Global hotspot should be <107%; it may be acceptable that hotspot could be <110% 
 
 
Conventional Fractionation 
Organ 
Constraint 
Priority* 
Rectum 
 
V75 Gy < 15% 
V70 Gy < 25%  or V70 Gy < 20%  
V65 Gy < 35%  
2 
2 
2 

 
 
 
 
 
Page 86 of 86 
V60 Gy < 50%  
V50 Gy < 50%  
2 
2 
Bladder 
V80 Gy < 15% 
V75 Gy <25%  
V70 Gy <30%  
V65 Gy < 50% 
V55 Gy < 50% 
2 
2 
2 
2 
2 
Small Bowel 
Max Dose 52Gy 
2 
  Femoral Heads           V50<10%  
 
                     2 
* 1 = Do not violate. Achieving constraint is more important than target coverage. 
   2 = Planning goal, but less important than target coverage. 
 
 
 
UAB Hypofractionation 
Organ 
Constraint 
Priority* 
Rectum 
 
V70 Gy < 3cc  
V60 Gy < 10 cc 
V50 Gy < 17%  
V40 Gy < 35%   
V35 Gy < 60% if ENI used 
2 
2 
2 
2 
2 
Bladder 
V60 < 10% 
V50 < 25 %  
V31< 50% 
2 
2 
2 
Small Bowel 
Max dose 54Gy 
V54<20cc 
2 
1 
  Femoral Heads           V50<10%  
 
 
         2 
* 1 = Do not violate. Achieving constraint is more important than target coverage. 
   2 = Planning goal, but less important than target coverage.