Clinical trial NCT03477396
Conditions: Estrogen Receptor and/or Progesterone Receptor Positive HER2/Neu Negative Stage IV Breast Cancer AJCC v6 and v7
Sponsor: City of Hope Medical Center
Start date: 2018-06-14; Completion date: 2023-06-05
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase IIA trial studies the side effects of ribociclib and aromatase inhibitor and how well they work in treating participants with hormone receptor positive breast cancer that has spread to other places in the body. Ribociclib and aromatase inhibitors may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the safety and tolerability of the combination of ribociclib and an aromatase inhibitor in adults age 70 or older with hormone receptor positive metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To describe the full toxicity profile including all grades. II. To estimate the rate of worst grades of myelosuppression (neutropenia, leukopenia, thrombocytopenia, and anemia), neutropenic fever, gastrointestinal (GI) side effects (nausea, diarrhea, decreased appetite, vomiting, stomatitis), fatigue, neuropathy, and thromboembolism.

III. To describe rates of dose reductions, dose holds, and hospitalizations. IV. To estimate objective response rate and clinical benefit rate as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) (1.1) criteria.

V. To estimate median progression-free and overall survival.

EXPLORATORY OBJECTIVES:

I. To estimate the rate of adherence to ribociclib. II. To explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-specific geriatric assessment.

III. To describe the results of the Was It Worth It (WIWI) and the results of the Overall Treatment Utility (OTU) Questionnaires.

OUTLINE:

Participants receive ribociclib orally (PO) once daily (QD) on days 1-21 and aromatase inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, then annually thereafter.

Arms: arm 1: Participants receive ribociclib orally PO QD on days 1-21 and aromatase inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Aromatase Inhibitor intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacokinetic Study intervention 4: Questionnaire Administration intervention 5: Ribociclib
Intervention descriptions: intervention 1: Aromatase inhibitor per treating investigator's discretion intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Ancillary studies intervention 5: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB #17471 
 
06/27/2018 
Packet: 08 
 
 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY                                                                            
 
TITLE:  A Phase IIA Trial Assessing the Tolerability of Ribociclib in Combination with an Aromatase Inhibitor in 
Patients aged 70 and Older with Hormone Receptor Positive Metastatic Breast Cancer 
 
CITY OF HOPE PROTOCOL NUMBER/PACKET: 
 
IRB #17471 
Protocol Date: 06/27/18 
 
COH Initial Approval 
COH Protocol dated 03/19/18 
Version: 00 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
COH Amendment 01 
COH Protocol dated 04/23/18 
Version: 01 
COH Amendment 02 
COH Protocol dated 05/17/18 
Version: 02 
COH Amendment 03 
COH Protocol dated 06/11/18 
Version: 03 
COH Amendment 04 
COH Protocol dated 06/27/18 
Version: 04 
COH Amendment 05 
Title Page dated 09/13/18 
Version:05 
COH Amendment 06 
 
   Title Page dated 11/08/2019  
 
         Version: 06 
COH Amendment 07at Continuation  Protocol Dated 06/27/2018  
 
          Packet: 07 
COH Amendment 08 At Continuation Protocol Dated 06/27/2018  
 
          Packet: 08 
 
SITE:  
 
 
 
 
Breast  
 
 
 
 
STAGE (If applicable):  
 
 
Metastatic 
 
 
 
MODALITY:   
 
 
 
 
 
 
 
TYPE:  
 
 
 
 
Phase 2 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:    
 
Mina Sedrak, M.D.  
 
CO INVESTIGATORS:   
 
 
Joanne Mortimer, M.D., Niki Patel, M.D.,  
  
 
 
 
 
 
Waisman, James, M.D., Yuan Yuan, M.D., Daphne Stewart, M.D. 
 
PARTICIPATING CLINICIAN 
 
 
Christina Yeon, M.D., Samuel Chung, M.D., Stephen Koehler, M.D., 
James Shen, M.D.,.,  Misagh Karimi, M.D., Mohammadbagher Ziari, 
M.D., George Hajjar, M.D., Swapnil Rajurkar, M.D., Naveen Gupta, M.D., 
Cary Presant, M.D., Shanmuga Subbiah, M.D., Naveed Khan, M.D. 
 
 
BIOSTATISTICIAN 
 
 
 
Kenneth Chin, M.S., Suzette Blanchard, Ph.D. 
 
PARTICIPATING SITES 
 
 
City of Hope, Duarte, CA 
 
 
City of Hope Community Practice Sites: 
City of Hope South Pasadena, CA 
City of Hope Antelope Valley, CA 
City of Hope Corona, CA 
City of Hope Mission Hills, CA 
City of Hope Rancho Cucamonga, CA 
City of Hope West Covina, CA  
City of Hope Santa Clarita, CA 
 
Roswell Park Comprehensive Cancer Center, Buffalo NY 
Wilmot Cancer Institute (University of Rochester), Rochester, NY 


CONFIDENTIAL 
 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
 
A Phase IIA Trial Assessing the Tolerability of Ribociclib in Combination with an 
Aromatase Inhibitor in Patients Aged 70 and Older with Hormone Receptor 
Positive Metastatic Breast Cancer 
 
Protocol Version Date:   
06-27-18 
 
Protocol Version No.: 
04 
 
COH Protocol No.: 
 
17471 
 
Sponsor: 
City of Hope 
 
Industry Partner: 
Novartis 
 
IND #: 
Exempt from IND 
 
Agents: 
Ribociclib (FDA approved; supplied by Novartis) 
Aromatase Inhibitors: Anastrozole; exemestane; letrozole 
(Commercial supply) 
 
 
Phase: 
IIA 
 
 
 
 
Study Principal Investigator  
Mina S. Sedrak, M.D., M.S. 
Dep. of Medical Oncology 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x89200 
E-mail: msedrak@coh.org 
Study Co-Principal Investigator  
Arti Hurria, M.D. 
Dep. of Medical Oncology 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x89200 
E-mail: ahurria@coh.org 
Study Statistician 
Kenneth Chin, M.S. 
Biostatistics Core 
City of Hope National Medical 
Center 
Phone: 626-256-4673 
E-mail: kechin@coh.org 


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Coordinating Center 
Data Coordinating Center 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x 83968 
E-mail: DCC@coh.org 
Study Manager 
Vani Katheria 
Dep. of Medical Oncology 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x61880 
E-mail: vkatheria@coh.org 
Senior Statistician 
Suzete Blanchard, Ph.D. 
Biostatistics Core 
City of Hope National Medical 
Center 
Phone: 626-256-4673 x64446 
E-mail: sblanchard@coh.org  
 
Collaborating Investigator 
Timothy Synold, Ph.D. 
Dep. of Cancer Biology  
City of Hope National Medical 
Center 
Phone: 626-256-4673 x 81110 
E-mail: tsynold@coh.org 
 
 
 


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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 


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IRB Protocol No.  17471 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase IIA Trial Assessing the Tolerability of Ribociclib in Combination with an Aromatase Inhibitor in Patients Aged 
70 and Older with Hormone Receptor Positive Metastatic Breast Cancer. 
Study Detail: 
Indication(s) 
Hormone Receptor Positive Metastatic Breast Cancer 
Phase 
IIA 
Number of subjects 
40 evaluable participants ≥ 70 yo (at least 20 participants ≥75 yo) 
Estimated Accrual Duration: 
24 months 
Estimated Study Duration: 
55 months 
Participating Sites: 
City of Hope, Duarte, CA 
 
City of Hope Community Practice Sites: 
x 
City of Hope South Pasadena 
x 
City of Hope Antelope Valley 
x 
City of Hope Corona 
x 
City of Hope Mission Hills 
x 
City of Hope Rancho Cucamonga 
x 
City of Hope West Covina  
Roswell Park Comprehensive Cancer Center, Buffalo NY 
Wilmot Cancer Institute (University of Rochester), Rochester, NY 
Study Agents: 
x 
Ribociclib (Supplied by Novartis) 
x 
Aromatase Inhibitors: Anastrozole; exemestane; letrozole (Commercial 
supply) 
Brief Protocol Title for the 
Lay Public: 
Ribociclib in combination with Aromatase Inhibitor in Older Adults 
Sponsor: 
City of Hope 
 
 


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Rationale for this Study: 
Older adults are underrepresented in clinical trials. Despite pronounced changes in drug metabolism, absorption, 
and distribution with increasing age, limited evidence exists to guide therapy with targeted agents in the older 
adult population. Evidence now suggests that targeting the CDK/RB pathway has the potential to control ER+ breast 
cancer progression. To date, clinical data from LEE011 (ribociclib) and PD0332991 (palbociclib) have demonstrated 
efficacy and tolerable adverse event safety profiles. As the MONALEESA-2 trial demonstrates, the combination of 
riblociclib and endocrine therapy is a novel targeted treatment approach for postmenopausal women with 
hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. 
The combination improves progression-free survival compared to endocrine therapy alone. However these studies 
primarily focused on women less than age 65. For example, the randomized phase II trial (MONALEESA-2) of 
riblociclib and letrozole compared to letrozole alone (mean age 62) included only 295 patients study wide aged 65 
and older and 373 patients aged less than 65 years study-wide with no published cohort data for enrolled patients 
over the age of 70. The phase III trial (PALOMA-3) of PD0332991 (mean age 57, respectively) included only 25% of 
participants age 65 and older, while not reporting on participants aged 75 and older (personal communication with 
Kellen Meadows, 21 August 2015).  
The most common adverse events of riblociclib in combination with endocrine therapy are neutropenia, 
leukopenia, and fatigue. In particular, MONALEESA-2 patients receiving the combination riblociclib and letrozole 
experienced grade 3 or 4 neutropenia (59.3%), leukopenia (21%), or fatigue (2.4%). In particular, there is a decrease 
in bone marrow reserve with aging, hence amplifying the potential risk of neutropenia and myelosuppresion. Older 
adults often have other co-morbid medical conditions which may predispose them to thromboembolism thereby 
increasing the risk. Because of this, a definitive study in the older adult population will diminish any reservations 
oncologists may have in prescribing ribociclib with an aromatase inhibitor, and can provide guidance regarding the 
dosing and toxicity management in older adults.  
Study Design: 
This study will be an open label, single arm, Phase IIA safety and tolerability study to describe the toxicity profile of 
ribociclib in combination with an aromatase inhibitor in patients age 70 and older with hormone receptor positive 
metastatic breast cancer. We plan to study 40 evaluable subjects, stratifying on age such that at least 20 evaluable 
participants are aged 75 years or older.  There will be one interim analysis after 20 evaluable participants have 
completed one cycle of the drug. 
All patients who begin study treatment will be included in the analysis of all clinical endpoints. 
Objectives: 
Primary objective: 
To estimate the safety and tolerability of ribociclib in combination with an aromatase inhibitor in adults aged 70 or 
older with hormone receptor positive metastatic breast cancer. 
Secondary objectives: 
1. To describe the full toxicity profile including all grades 
2. To estimate the rate of worst grades of myelosuppression (neutropenia, leukopenia,  
thrombocytopenia, and anemia), neutropenic fever, GI side effects (nausea, diarrhea, decreased appetite, 
vomiting, stomatitis), fatigue, neuropathy, and thromboembolism 
3. To describe rates of dose reductions, dose holds, and hospitalizations  
4. To estimate objective response rate and clinical benefit rate as defined by modified RECIST (1.1) criteria 
5. To estimate median progression-free and overall survival  


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6. To determine average plasma steady-state ribociclib Ctrough concentrations in patients over the age of 70 
years 
Exploratory objectives: 
1. To estimate the rate of adherence to ribociclib 
2. To explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-
specific geriatric assessment 
3. To describe the results of the Was It Worth It (WIWI) and Overall Treatment Utility (OTU) Questionnaires 
Endpoints: 
Primary: 
The primary endpoint is the incidence of grade 2 and above toxicities attributed to ribociclib. 
Secondary: 
1. All toxicities associated with the combinations as measured by NCI CTCAE v.4.03 
2. Dose reductions 
3. Dose holds 
4. Hospitalizations 
5. Response as determined by RECIST (1.1) criteria 
6. Progression free survival defined as the time from start of treatment to the first of the following disease 
events:  local/regional/distant recurrence, invasive contralateral breast disease, second primary or death 
due to any cause. 
7. Overall survival defined as the time from start of treatment to death due to any cause 
8. Average ribociclib Ctrough concentrations  
 
Exploratory Endpoints 
 
1. Adherence to ribociclib will be defined as taking 19/21 pills (90%) of their dose of ribociclib. 
 
2. Toxicity Risk Score 
 
3. WIWI response 
 
4. OTU response 
 
Statistical Considerations: 
Sample Size Justification:  
The sample size is 40 evaluable participants.  Participants that receive one dose of treatment will be considered 
evaluable, anyone that does not receive treatment will be replaced. 
Given a sample size of 40 subjects the half-width of the 95% confidence limits for the rate of grade 2 or higher 
toxicities will be less than or equal to 0.16. For example if we saw a toxicity rate of 0.5 (20 subjects/40) the 95% 
lower and upper confidence limits would be 0.34 and 0.66, respectively.  Further a sample size of 40 will allow us to 
see a toxicity with a true rate equal to 0.05 in 87 out of 100 trials. 
 Interim Analysis: 
After approximately 20 evaluable subjects have completed at least one full cycle of treatment, the study team will 
review the data (including the toxicity profile, rates of dose reduction, holds and hospitalizations) and assess if the 
dose being studied is too high, that it is requiring too many patients, in the opinion of the team, to experience a 
dose reduction. If so, a reduction of the dose will be considered, otherwise the study will continue to completion at 
the planned dose.  
Analysis Plan: 
Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for 1) grade 2 or 
higher other toxicities, and 2) dose reductions, dose holds and hospitalizations, and 3) objective response rate 
(CR+PR) and clinical benefit rate (CR+PR+SD) as determined by RECIST by age strata and overall.  Progression free 


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survival and overall survival will be estimated using the product limit method of Kaplan and Meier/Cox proportional 
hazards methods by age strata and overall.  
Tables will be created to summarize the toxicities and side effects by age strata, course, organ, severity and 
attribution for all patients.  Descriptive statistics will be provided for study participant demographics, number of 
drug cycles completed, responses from the WIWI Questionnaire and the OTU by age strata and overall.  General 
linear models and graphical methods will be used to explore factors as identified by a cancer-specific geriatric 
assessment that may be predictive of toxicity/dose reduction, dose holds or hospitalizations. 
The relationship between plasma trough and percent drop in neutrophil and platelet counts will be analyzed used 
linear models methods. 
Abbreviated Eligibility Criteria: 
Inclusion Criteria 
Ⴠ 
Hormone receptor positive metastatic breast cancer.  
Ⴠ 
First or second line endocrine therapy for metastatic disease. One prior line of chemotherapy for 
metastatic disease is allowed. 
Ⴠ 
Age: ≥ 70 years and life expectancy > 6 months 
Ⴠ 
Measurable disease per RECIST (1.1), or bone-only lytic or mixed lytic and blastic lesions that would be 
accurately assessed by means of computed tomography (CT) or magnetic resonance imaging (MRI). 
Ⴠ 
The ability to swallow and retain oral medication 
Ⴠ 
Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE Grade ≤ 1 (except 
alopecia)  
Exclusion Criteria 
Ⴠ 
Untreated brain metastases or symptomatic visceral spread at risk for life-threatening complications 
Ⴠ 
Concomitant CYP3A strong inhibitors or inducers  
Ⴠ 
Prior therapy with a CDK inhibitor 
Investigational Product Dosage and Administration: 
Ribociclib: Administered orally with food on Days 1-21 in each 28-day cycle. Starting dose: 600mg/day. 
Aromatase inhibitor: Administered per treating investigator’s discretion during each 28-day cycle; dosing should 
follow the package insert guidelines.   
Clinical Observations and Tests to be Performed: 
Clinical Observations/ Tests/ Questionnaires: medical history and demographics, physical exams, vital signs, 
performance status, routine laboratory tests, pill diary assessment, AE assessment, disease assessment, geriatric 
assessment, Was It Worth It Questionnaire assessment, Overall Treatment Utility assessment. Participants will be 
followed for survival.  
Correlative Biology Studies: From participants who consent to research blood sample collection, a baseline sample 
of blood will be collected for future studies. 
 
 
 


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TABLE OF CONTENTS 
SECTION                                                                                                                                                                     PAGE 
Experimental Design Schema ......................................................................................................................... 3 
Protocol Synopsis............................................................................................................................................ 4 
Table of Contents ........................................................................................................................................... 8 
List of Tables and Figures .............................................................................................................................. 10 
Abbreviations ................................................................................................................................................ 11 
1. 
Goals and Objectives (Scientific Aims) ................................................................................................ 12 
2. 
Background ......................................................................................................................................... 12 
2.1. Introduction/Rationale for Development ............................................................................ 12 
2.2. Rationale for Studying Cancer Therapy in Older Adults ....................................................... 12 
2.3. Factors Other than Chronological Age that Impact Drug Tolerance .................................... 13 
2.4. Ribociclib .............................................................................................................................. 14 
2.5. Overview and Rationale of Study Design ............................................................................. 15 
3. 
Participant Eligibility Criteria .............................................................................................................. 17 
3.1. Inclusion Criteria ................................................................................................................ 157 
3.2. Exclusion Criteria .................................................................................................................. 18 
3.3. Participation of Special Populations .................................................................................... 20 
4. 
Participant Enrollment  ....................................................................................................................... 20 
4.1. Pre-Enrollment Informed Consent and Screening Procedures ............................................ 20 
4.2. Participant Enrollment ......................................................................................................... 20 
4.3. Screen Failures and Registered Participants Who Do Not begin Study Treatment ............. 21 
4.4. Stratification ......................................................................................................................... 21 
5. 
Treatment Program ............................................................................................................................ 22 
5.1. Treatment Overview ............................................................................................................ 22 
5.2. Treatment Cycle Definition and Day Count ......................................................................... 22 
5.3. Treatment Plan and Agent Administration .......................................................................... 22 
5.4. Duration of Protocol Therapy - Criteria for Ending Protocol Therapy ................................. 23 
5.5. Long-Term Follow-Up  .......................................................................................................... 23 
5.6. Criteria for Completion of Study Participation ..................................................................... 23 
5.7. Supportive Care, Other Concomitant Therapy, Prohibited Medications ............................. 24 
5.8. Assessments ......................................................................................................................... 25 
6. 
Anticipated Toxicities and Dose Delay/Modification .......................................................................... 25 
6.1. Anticipated Toxicities ........................................................................................................... 25 
6.2. Dose Modifications/ Delays ................................................................................................. 27 
7. 
Adverse Event Reporting  ................................................................................................................... 30 
7.1. Definitions ............................................................................................................................ 30 
7.2. Protocol Deviations and Single Subject Exceptions ............................................................. 35 
7.3. Study Oversight, Quality Assurance, and Data & Safety Monitoring ................................... 37 
7.4. Novartis Adverse Event Reporting Guidelines  .................................................................... 40 
8. 
Agent Information .............................................................................................................................. 41 
8.1. Ribociclib  ............................................................................................................................. 41 


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8.2. Letrozole .............................................................................................................................. 43 
8.3      Exemestane .......................................................................................................................... 44 
8.4      Anastrozole .......................................................................................................................... 46 
9. 
Correlative/Special Studies ................................................................................................................. 47 
9.1. Blood Banking (Optional) ..................................................................................................... 47 
10. 
Ribociclib Pharmacokinetics ............................................................................................................... 48 
10.1. Clinical Pharmacology Objectives …………………………………………………………………………………… 48 
10.2. Blood Sample Collection ………………………………………………………………………………………………… 48 
10.3. Sample Processing …………………………………………………………………………………………………………. 48 
10.4. Analytical Method …………………………………………………………………………………………………………. 48 
10.5. Pharmacokinetic Data Analysis Methods ………………………………………………………………………. 48 
11. 
Study Calendar ……………………………………………………………………………………………………………………………… 49 
12. 
Endpoint Evaluation Criteria/Measurement of Effect ........................................................................ 53 
12.1. Definitions ............................................................................................................................ 53 
12.2. Disease Parameters .............................................................................................................. 53 
12.3. Methods for Evaluation of Measurable Disease .................................................................. 54 
12.4. Response Criteria ................................................................................................................. 55 
12.5. Duration of Response …………………………………………………………………………………………………….. 57 
13. 
 Statistical Considerations ................................................................................................................... 57 
13.1    Study Design ........................................................................................................................ 57 
13.2. Sample Size and Accrual Rate  ............................................................................................. 58 
13.3. Interim Analyses  .................................................................................................................. 58 
13.4. Analysis Plan......................................................................................................................... 58 
14.       Data Handling, Data Management, Record Keeping ......................................................................... 59 
14.1.   Source Documents ............................................................................................................... 59 
14.2.   Data Capture Methods and Management ........................................................................... 59 
14.3.   Case Report Forms/Data Submission Schedule ................................................................... 59 
14.4.   Regulatory Records .............................................................................................................. 60 
 
15.      Ethical and Regulatory Considerations .............................................................................................. 60 
15.1. Ethical Standard .................................................................................................................... 60 
15.2. Regulatory Compliance ......................................................................................................... 60 
15.3. Institutional Review Board .................................................................................................... 61 
15.4. Informed Consent .................................................................................................................. 61 
15.5. Participant Withdrawal ......................................................................................................... 62 
15.6. Special and Vulnerable Populations  ..................................................................................... 62 
15.7. Participant Confidentiality ..................................................................................................... 62 
15.8. Conflict of Interest ................................................................................................................. 63 
15.9. Financial Obligations, Compensation, and Reimbursement of Participants ......................... 63 
15.10. Publication/Data Sharing  .................................................................................................... 64 
16.       References ......................................................................................................................................... 65 
Appendix A: Karnofsky Performance Status ................................................................................................. 67 


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Appendix B: Prohibited Medications ............................................................................................................ 68 
Appendix C: Registration Coversheet ........................................................................................................... 72 
Appendix D-1: Blood Banking Collection Form (Optional)............................................................................ 73 
Appendix D-2: Blood Banking Shipping Details- Non-COH Sites ................................................................... 74 
Appendix E: Ribociclib Pill Diary ................................................................................................................... 75 
Appendix F-1: Geriatric Assessment: Survey  ............................................................................................... 79 
Appendix F-2: Geriatric Assessment: Healthcare Professional Questionnaire ………………………………………… 89 
Appendix G: Was It Worth It (WIWI) Questionnaire  ................................................................................... 93 
Appendix H: Overall Treatment Utility (For Clinician Only) .......................................................................... 94 
Appendix I: List of Supplemental Materials ……………………………………………………………………………………………. 95 
Appendix J: SAE/UP Reporting Coversheet .................................................................................................. 96 
 
LIST OF TABLES AND FIGURES 
Table 2.4.1a: Common Adverse Reactions in Patients in MONALEESA-2 Study[3] ...................................... 15 
Table 5.3: Treatment regimen ........................................................................................................................ 2 
Table 6.2.1: Ribociclib dose levels ................................................................................................................ 27 
Table 6.2.2a: Ribociclib Dose Modification and Management - Hematologic Toxicities .............................. 28 
Table 6.2.2b: Ribociclib Dose Modification and Management- Non-Hematologic Toxicities ...................... 29 
Table 6.2.2c: Ribociclib Dose Modification and Management - Hepatobiliary Toxicity …………………………... 29 
Table 6.2.2d: Ribociclib Dose Modification and Management - QT Prolongation …………………………………… 30 
Table 10.2: Pharmacokinetic Blood Sample Calendar …………………………………………………………………………….. 48 
Table 11.0 Study Activity Calendar  .............................................................................................................. 49 
Table 12.4.3: Assessment of Best Overall Response Using Target and Non-Target Lesions ........................ 56 
Table 14.3: Data Submission Schedule ......................................................................................................... 59 
 


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ABBREVIATIONS 
 
 
 
 
Abbreviation 
Meaning 
AE 
CFR 
CICSL 
COH 
CR 
CRA 
CRF 
CTCAE 
CTEP 
DCC 
DSMC 
EMR 
EOT 
FDA 
GCP 
HIV 
IDS 
IND 
IRB 
NCI 
OIDRA 
PD 
PI 
PMT 
PR 
RECIST  
SAE 
SD 
SOC 
Tx 
WIWI 
Adverse Event 
Code of Federal Regulations 
Clinical Immunobiology Correlative Studies Laboratory 
City of Hope 
Complete Response 
Clinical Research Associate 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
Data Coordinating Center 
Data & Safety Monitoring Committee 
Electronic Medical Record 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Human Immunodeficiency Virus 
Investigational Drug Services 
Investigational New Drug 
Institutional Review Board 
National Cancer Institute 
Office of IND Development and Regulatory Affairs 
Progressive Disease 
Principal Investigator 
Protocol Management Team 
Partial Response 
Response Evaluation Criteria In Solid Tumors 
Serious Adverse Event 
Stable Disease 
Standard of Care 
Treatment 
Was It Worth It 


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1. 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1. Primary Objective 
o To estimate the safety and tolerability of the combination of ribociclib and an aromatase 
inhibitor in adults age 70 or older with hormone receptor positive metastatic breast cancer. 
1.2. Secondary Objectives 
o To describe the full toxicity profile including all grades 
o To estimate the rate of worst grades of  myelosuppression (neutropenia, leukopenia, 
thrombocytopenia, and anemia), neutropenic  fever, GI side effects (nausea, diarrhea, 
decreased appetite, vomiting, stomatitis), fatigue, neuropathy, and thromboembolism 
o To describe rates of dose reductions, dose holds, and hospitalizations 
o To estimate objective response rate and clinical benefit rate as defined by modified RECIST 
(1.1) criteria 
o To estimate median progression-free and overall survival  
1.3.  Exploratory Objectives 
o To estimate the rate of adherence to ribociclib 
o To explore factors other than chronologic age that can affect toxicity rates as identified 
using a cancer-specific geriatric assessment 
o To describe the results of the Was It Worth It (WIWI) and the results of the Overall 
Treatment Utility (OTU) Questionnaires 
2. 
BACKGROUND 
2.1. Introduction/Rationale for Development 
This proposal addresses a key research priority of the Cancer and Aging Research Group, National 
Cancer Institute, National Institute on Aging, and the Institute of Medicine: the assessment of the 
pharmacology of cancer therapy in older adults. [1, 2] Ribociclib is a novel drug with the potential to 
change the treatment of metastatic breast cancer- a disease primarily affecting older adults. The 
combination of ribociclib and endocrine therapy (aromatase inhibitor) is associated with an 
improvement in progression-free survival (PFS) compared to endocrine therapy alone. [3] The goal of 
this study is to fill this gap in knowledge by utilizing a phase II design to examine the tolerability of 
ribociclib and endocrine therapy among older adults aged 70 and older with hormone receptor positive 
breast tumors.  A comprehensive cancer-specific geriatric assessment that includes an evaluation of 
functional status, other medical conditions, cognitive function, nutritional status, social support, 
psychological state, and a review of medications will be included, as well as an assessment of 
adherence. 
2.2. Rationale for Studying Cancer Therapy in Older Adults 
Aging brings about a progressive decrease in physiologic reserve that affects each individual at a unique 
pace.[4, 5] The age-related physiological decline in organ systems typically begins in the 3rd decade of 
life and is not evident at times of rest, but becomes most apparent when the body is stressed.[6]  Both 
cancer and cancer treatment can be considered a physiological stressor, and age-related decreases in 
physiologic reserve may affect tolerance to cancer treatment. 


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A number of age-related changes in drug absorption, distribution, metabolism, and excretion may 
contribute to differences in treatment tolerance between older and younger patients.  The absorption of 
drugs can be affected by decreased gastrointestinal motility, decreased splanchnic blood flow, 
decreased secretion of digestive enzymes, and mucosal atrophy.[7, 8]  With the increased use of oral 
therapy, medication compliance is an important issue as well.[9]  As a person ages, body composition 
changes, with an increase in body fat and decrease in lean body mass and total body water.  The 
increase in body fat leads to a rise in the volume of distribution for hydrophilic drugs. In the population 
of older adults with cancer, malnutrition and hypoalbuminemia may result in an increased concentration 
of drugs that are albumin-bound.[10] 
Hepatic mass and blood flow also decrease with age.[4]  The impact of the decline in hepatic mass and 
blood flow on hepatic enzyme function is controversial.[11]  In a study of 226 patients, the cytochrome 
P-450 content in liver biopsy samples decreased by approximately 30% in patients over the age of 
70.[12] Renal function also declines with age, and renal insufficiency is common in older adults.[13, 14] 
A progressive reduction in the functional reserve of various organ systems may alter the 
pharmacokinetics of anti-cancer therapies[7, 15] and increase the susceptibility of older individuals to 
complications of treatment.[12, 14, 18, 19]Normal tissues may be less able to repair the molecular 
damage caused by antineoplastic agents due to cellular senescence, resulting in greater potential 
cardiotoxicity, neurotoxicity, mucositis, and hematologic toxicities.[16]  
2.3. Factors Other than Chronological Age that Impact Drug Tolerance 
Aging is a heterogeneous process.  While certain declines in organ function are universal as the human 
body ages, the rate of this decline and the consequences of this decline on everyday function proceeds 
at a unique pace in each individual.  Therefore, chronologic age tells us relatively little about the specific 
individual.  A more detailed evaluation of an older adult patient is needed in order to capture factors 
other than chronological age that predict for morbidity and mortality.  A comprehensive geriatric 
assessment may serve this purpose.  The comprehensive geriatric assessment includes an evaluation of 
functional status, co-morbid medical conditions, cognitive function, nutritional status, social support and 
psychological state, and a review of medications.  Conclusions from several studies are emerging 
regarding the benefits of performing a comprehensive geriatric assessment for older patients with 
cancer. 
1. Factors evaluated in a comprehensive geriatric assessment predict survival;[17] 
2. Factors evaluated in a comprehensive geriatric assessment predict toxicity to 
chemotherapy;[18] 
3. A comprehensive geriatric assessment uncovers problems not detected by routine history 
and physical in initial consultation and follow-up care;[19] 
4. Patients undergoing a comprehensive geriatric assessment and intervention based on the 
results had improved pain control;[20] 
5. A comprehensive geriatric assessment and intervention improves an older patient’s mental 
health and well-being.[20] 
Consensus guidelines recognize the benefits and recommend the inclusion of a geriatric assessment as 
part of the evaluation of an older patient.[21] 
 
 


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2.4. Ribociclib 
Ribociclib is a cyclin dependent kinase (CDK) 4 and 6 inhibitor which causes cell cycle arrest as the cell 
travels from G1 phase to S phase [3]. In the absence of ribociclib, these kinases will phosphorylate the 
retinoblastoma protein (Rb). This phosphorylation causes a release of transcription factors which allows 
the cell to move through the cell cycle, thus allowing the growth of cancerous cells[3]. When ribociclib 
inhibits CDK4 and CDK6, the retinoblastoma protein is arrested at the G1 phase, prohibiting “S-phase 
entry and cell growth” of the cancerous cells [22]. Estrogen-induced proliferation of breast epithelium is 
further associated with an increased expression of cyclin D1 mRNA and protein. This is consistent with a 
model of ER+ breast cancer in which receptor activation induces increased cyclin D1 expression, CDK4/6i 
activation and cell cycle progression. Therefore, targeting the CDK/Rb has great potential to control ER+ 
breast cancer progression.  
2.4.1. Rationale for Combining Ribociclib and Endocrine Therapy     
Ribociclib in combination with endocrine therapy compared to endocrine therapy alone improves 
progression-free survival.  Data from the MONALEESA-2 trial demonstrates the efficacy of ribociclib with 
letrozole in the first line treatment of hormone receptor positive metastatic breast cancer.[23] In this 
randomized open-label phase III study, 668 women ranging from ages 23-91 had advanced estrogen 
receptor positive and HER-2 negative breast cancer. The median age of women enrolled was 62 years; 
all patients had hormone positive disease, and all but 1 patient in each group had HER2-negative 
disease.[3] These cohorts received either letrozole orally (2.5 mg/day) or received letrozole with 
ribociclib (600 mg/day for three weeks on and one week off). This dosage and treatment schedule has 
an acceptable safety profile, lower risk for QT interval prolongation (defined as QTcF), adequate 
exposures, and preliminary evidence of clinical activity. Three hundred thirty-four patients were 
assigned to both the ribociclib-letrozole group and to letrozole alone.[3] The median duration of 
progression-free survival was not reached for the ribociclib and letrozole arm (95% CI, 19.3 to not 
reached), compared to 14.7 months (95% CI 13.0 to 16.5) for letrozole alone.[3] The rate of locally 
assessed progression-free survival was significantly higher in the ribociclib group than in the letrozole 
alone group. After 12 months, the progression free survival rate was 72.8% (95% CI, 67.3 to 77.6) in the 
ribociclib group compared to 60.9% (95%CI, 55.1 to 66.2) in the letrozole alone group. Common side 
effects for ribociclib with letrozole were: Grade 3-4 neutropenia (59.3% vs 0.9% in letrozole alone), 
leukopenia (21% vs 0.6% in letrozole alone), and fatigue (2.4% vs 1% with letrozole). Patients receiving 
ribociclib with letrozole experienced a pulmonary embolism at a rate of 0.6%. Among patients in the 
ribociclib and letrozole group, 7.5% discontinued due to adverse events whereas only 2.1% of the 
letrozole group discontinued the study.   
 
 


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Table 2.4.1a: Common Adverse Reactions in Patients who Received Ribociclib plus Letrozole or 
Letrozole Alone in MONALEESA-2 Study[3] 
 
Ribociclib plus Letrozole (N=334) 
Letrozole (N=330) 
Grade 3 
Grade 4 
Grade 3 
Grade 4 
Any adverse event 
221 (66%) 
50 (15%) 
105 (32%) 
3 (1%) 
Neutropenia 
166 (50%) 
32 (10%) 
3 (1%) 
0 
Leukopenia 
66 (20%) 
4 (1%) 
2 (0.6%) 
0 
Anemia 
3 (1%) 
1 (0.3%) 
4 (1.2%) 
0 
*Data are in n (%) unless otherwise specified 
2.4.2. Age Specific Data from MONALEESA-2 and Other CDK4/6 Inhibitor Trials 
Limited evidence exists to guide therapy with ribociclib and endocrine therapy in older adults.  In 
MONALEESA-2, the mean age of patients was 62 with a range from 23-91. In other CDK4/6 inhibitor 
trials for PD0332991, (PALOMA-3) only 25% of the participants were aged 65 and over. Review of the 
data obtained from 165 patients in the PALOMA-1 trial, as well as the 521 patients in the PALOMA-3 
trial, did not show any apparent differences in systemic exposure related to age. [19] 
A subgroup analysis of the efficacy and safety of first-line PD0332991 plus letrozole compared with 
letrozole alone in patients in the PALOMA-1 study evaluated 165 postmenopausal women. Of the 76 
patients aged 65 and older, 37 were treated with PD0332991 and letrozole, and the remainder received 
letrozole alone. Among patients receiving PD0332991 and letrozole the median PFS for patients aged 65 
and over was 26.6 months (95% CI 12.6-NR) in comparison to 7.7 months (95% CI 3.7-10.9) for patients 
who received letrozole alone. Grade 3-4 neutropenia occurred in 56.8% of patients receiving PD0332991 
and letrozole (compared to 2.7% in patients with letrozole alone). In addition, grade 3-4 leucopenia 
occurred in 29.7% of the patients receiving ribociclib and letrozole, and grade 3-4 fatigue was reported 
in 10.8% of patients receiving ribociclib and letrozole.  Neither of these adverse events occurred in any 
patients taking letrozole alone.[23] 
2.5. Overview and Rationale of Study Design 
Ribociclib and endocrine therapy is emerging as a novel treatment for hormone receptor positive 
metastatic breast cancer. A gap in knowledge specifically exists with regard to the tolerability of this 
combination in adults aged 70 and over. This is an important research area, since cancer is a disease 
associated with aging. This Phase II study will evaluate the safety and tolerability of the combination of 
ribociclib and an aromatase inhibitor in patients aged 70 and over, as well as describe the full toxicity 
profile, and estimate the objective response rate and clinical benefit, as well as survival. A geriatric 
assessment and measures of adherence will be included within the study.  Overall, our goal is to close 
this gap in knowledge in older adults with metastatic breast cancer who may derive significant benefit 
from this novel treatment option.   
To further assess treatment efficacy we will ask our participants to answer a short questionnaire that 
asks, “Was it worth it?” to undergo treatment. Because we know that this question will be largely 
influenced by the tolerability of this treatment in older adults, it is immensely important for us to 
determine whether the toxicity of this treatment is deemed “worth it” to extend the lives of older 


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adults. This is a unique assessment of the benefits and side effects associated with an improvement in 
progression free survival that could potentially allow patients to make a more informed decision 
regarding the treatment.  
The Was It Worth It (WIWI) questionnaire simply asks three questions “Was it worthwhile to undergo 
treatment in this research study?”, “If you had to do it over, would you undergo this treatment?”, 
“Would you recommend this treatment to others?” WIWI also asks the participant to indicate whether 
their quality of life was affected (improved, stayed the same, or got worse), and what could have been 
done to improve their treatment experience in this research study. In addition to these standard 
questions, we are planning to incorporate the question “What made it worth it to undergo this 
treatment?” in order to determine whether participants have a reason to want to endure potential 
toxicity for the benefit of progression free survival.  
We will also be including a measure of Overall Treatment Utility (OTU) to assess the “objective and 
subjective measures of anticancer efficacy, tolerability and acceptability.” This is determined using an 
analysis of clinical benefits in conjunction with an analysis of whether toxicity and serious adverse 
events affect one’s daily functions. This provides a way to quantify advantages and disadvantages of 
receiving treatment in this study, as well as an understanding of how a patient aged 70 and older may 
respond to treatment. OTU is useful in answering the following hypothetical question from the patient’s 
perspective: “With the benefit of hindsight, are you glad you received treatment?” By including the OTU 
in this study, researchers and oncologists will be able to better understand the patient’s perspectives 
regarding the benefits and side effects of treatment, in combination with an assessment of treatment 
efficacy and toxicity. 
 
 


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3. 
PARTICIPANT ELIGIBILITY CRITERIA 
3.1. Inclusion Criteria 
Participants must meet the following criteria upon screening examination to be eligible to participate in 
the study: 
1. Patient has signed the Informed Consent (ICF) prior to any study procedures being performed 
and is able to comply with protocol requirements. 
2. Must be able to swallow ribociclib. 
Age Criteria, Life Expectancy and Language Skill  
3. Age: ≥ 70  years at time of enrollment     
    ≥ 70 to < 74 years OR ≥ 75 years  
o NOTE: A minimum of 20 participants must be ≥ 75 years. The remaining 20 
participants may be ≥ 70 to < 74 years OR ≥ 75 years. 
4. Subjects must be able to communicate with the investigator and comply with the requirements 
of the study procedures. 
Nature of Illness and Treatment History 
5. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor 
positive and/or progesterone receptor positive breast cancer, HER2-negative breast cancer 
defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+, and metastatic 
breast cancer.  
6. First or second line endocrine therapy for metastatic disease. One prior line of chemotherapy 
for metastatic disease is allowed.  
Laboratory Information 
7. Patient has adequate bone marrow and organ function as defined by the following laboratory 
values at screening: 
a. Absolute neutrophil count ≥1.5 × 109 /L 
b. Platelets ≥100 × 109 /L 
c. Hemoglobin ≥9.0 g/dL 
d. Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplement before the first dose of study medication:  
x Sodium 
x Potassium 
x Magnesium 
x Total Calcium (corrected for serum albumin) 
x Phosphorous  
e. Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min 
f. In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and AST <5 x 
ULN 
g. Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in 
patients with well-documented Gilbert’s Syndrome. 
Cardiac Information 


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8. Patient with available standard 12-lead ECG with the following parameters at screening (defined 
as the mean of the triplicate ECGs): 
a. QTcF interval at screening <450msec (using Fridericia’s correction) 
b. Resting heart rate 50-90bpm 
3.2. Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient received prior treatment with any CDK4/6 inhibitor 
2. Patient has a known hypersensitivity to any of the excipients of ribociclib. 
3. Patients with a prior malignancy  diagnosed within 2 years AND with evidence of disease (except 
adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or 
curatively resected cervical cancer) 
4. Patient with concurrent malignancy that is not clinically stable AND needs tumor-directed 
therapy. 
5. Patients with central nervous system (CNS) involvement unless they meet ALL the following 
criteria:  
a. Untreated brain metastases (e.g., lesions < 1cm) not needing immediate local therapy. 
b. Previously treated brain metastases not needing immediate local therapy. 
x 
At least 4 weeks from prior therapy completion (including radiation and/or surgery) 
to starting the study treatment.  
x 
Clinically stable CNS tumor at the time of screening and not receiving steroids 
and/or enzyme-inducing anti-epileptic medications for brain metastases.  
6. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, 
including any of the following:  
a. History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic 
pericarditis within 6 months prior to screening. 
b. Documented cardiomyopathy. 
c. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and 
third-degree AV block). 
d. Long QT syndrome or family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
x Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia. 
x Concomitant use of medication(s) with a known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe that cannot be discontinued (within 
5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative 
medication. 
x Inability to determine the QT interval on screening (QTcF, using Fridericia’s 
correction). 
e. Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening. 
7. Patient is currently receiving any of the following medications and cannot be discontinued 7 
days prior to starting study drug (see Table 1 for details):  
a. Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges. 


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b. That have a narrow therapeutic window and are predominantly metabolized through 
CYP3A4/5. 
c. Herbal preparations/medications, dietary supplements. 
d. Warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or 
otherwise. Therapy with heparin, low molecular weight heparin (LMWH), newer anti-
coagulation agents such as direct factor Xa inhibitors, or fondaparinux is allowed 
8. Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting 
study drug, or who have not fully recovered from side effects of such treatment. 
a. The following uses of corticosteroids are permitted: single doses, topical applications 
(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular). 
9. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection).  
10. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in 
the investigator’s judgment, cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol (e.g. chronic 
pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral 
infections, etc.). 
11. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-
lives of the investigational product, whichever is longer 
12. Patient has had major surgery and/or radiotherapy within 14 days prior to receiving study drug or 
has not recovered from major side effects (tumor biopsy is not considered as major surgery). 
13. Patient with a Child-Pugh score B or C. 
14. Patient has not recovered from the acute effects of prior systemic therapy (until the toxicity 
resolves to either baseline or at least Grade 1) except for residual alopecia or peripheral 
neuropathy. 
15. Patient has a history of non-compliance to medical regimen or inability to grant consent. 
16. Sexually active males unless they use a condom during intercourse while taking the drug and for 
21 days after stopping treatment and should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid. 
 
 


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3.3. Participation of Special Populations 
A discussion of the inclusion, exclusion, representation and participation of women, minorities, children, 
HIV positive individuals and vulnerable populations is provided in Section 17.6.  
4. 
PARTICIPANT ENROLLMENT  
NOTE: Sites must meet activation requirements prior to enrolling participants (See the COH Data 
Coordinating Center (DCC) Supplement). 
4.1. Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented (see Section 17.4), and the prospective participant must receive a 
copy of the signed informed consent document.   
4.2. Participant Enrollment 
4.2.1. COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the DCC at City of Hope.  DCC staff are 
available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday through Friday (except holidays).   
DCC contact information is as follows: 
 phone: (626) 256-4673 ext. 83968 
 e-mail: DCC@coh.org 
4.2.2. Slot verification and reservation 
Eligible participants are stratified based on age. Designated study staff should call the DCC to verify 
current slot availability, and to reserve a slot for a specific prospective subject.  Slots can only be held for 
a limited time by an institution.   
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.2.3. Registration Process 
To register a participant, the subsequent procedure is to be followed. 
1. 
The participating site’s data manager/coordinator/research nurse should contact the DCC via 
telephone or email to provide notification regarding the pending registration and communicate 
desired timeline of the registration, especially if it must be completed promptly to meet the 
registration window. 
2. 
The data manager/coordinator/research nurse should then e-mail copies to DCC@coh.org  of 
the following documents to the DCC:  
o Registration Cover Sheet (Appendix C) 
o Completed Eligibility Criteria List (printed from Section 3.0 of the protocol) 


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o Source documentation to support eligibility criteria**  
o Signed informed consent document 
o Signed HIPAA authorization form (if separate from the informed consent document) 
o Signed subject’s Bill of Rights (COH only)  
**For COH participants, provide copies of source documentation only if not readily 
available as a finalized record in the COH Electronic Medical Record (EMR).  
3. 
After having received all transferred documentation, the DCC will complete and review the 
documents to verify eligibility, working with the participating site as needed to resolve any 
missing required source elements. A subject failing to meet all protocol eligibility requirements 
will not be registered.  
4. 
Once eligibility has been confirmed, DCC staff will register the participant by: assigning a subject 
accession number, register the subject on study centrally into MIDAS for non-COH participants 
(the COH CRC will directly accession into MIDAS), and enter the subject into the eCRF system, 
Medidata RAVE. 
5. 
Once registration has been completed, DCC staff will send a Confirmation of Registration Form, 
including the participant study number to:  
o the site study team: site PI, treating physician, protocol nurse, CRC and pharmacy 
o the COH sponsor team designees 
4.3. Screen Failures and Registered Participants Who Do Not begin Study Treatment 
All sites should maintain a screening log of potential participants meeting age criteria who were 
considered for the study but did not meet eligibility criteria. The log should detail the reason for screen 
failure. 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria or do not 
initiate study treatment.  For non-COH sites, the reason for screen failure will be documented in 
registration coversheet (see Appendix C) and submitted to the DCC.  
4.4. Stratification 
Participants will be stratified based on age. A minimum of 20 evaluable participants ≥ 75 years must be 
enrolled. The remaining 20 evaluable participants may be ≥ 70 to < 74 years OR ≥ 75 years. 
 
 
 
 


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5. 
TREATMENT PROGRAM 
5.1. Treatment Overview 
Participants will be administered protocol therapy consisting of ribociclib in combination with aromatase 
inhibitor in the outpatient setting.  
Participants who end protocol therapy will undergo long-term follow-up (Section 5.1).  Windows for all 
assessments and treatments are detailed in Section 11.0. 
5.2. Treatment Cycle Definition and Day Count 
A cycle will be a fixed 28 (±2) days in duration (Note: exceptions under certain circumstances are 
permitted; see Section 6.2.1 (8)).  
The cycle day count and cycle count continue despite a hold in ribociclib administration due to toxicities 
(See Section 6.2.1) - i.e. a cycle may initiate even if ribociclib is being held.  
Day 1 safety assessments must be reviewed prior to initiation of ribociclib during a new cycle. 
Cycle 1 Day 1 is defined as the first day the participant initiates combined ribociclib and endocrine 
therapy regimen (See Table 5.3). 
5.3. Treatment Plan and Agent Administration 
Table 5.3: Treatment regimen 
Agent 
Starting Dose Frequency of Administration 
Route of 
Administration 
Ribociclib 
600 mg/ day 
Once daily on Days 1-21 of each 28-day 
cycle 
Orally 
Aromatase inhibitor  Per package 
insert 
Per treating investigator’s discretion 
during each 28-day cycle 
Per package insert 
 
5.3.1. Ribociclib 
Ribociclib should be taken at approximately the same time each day with food. Ribociclib tablets should 
be swallowed whole.  
If applicable, ribociclib may be taken at the same time as endocrine therapy.  
If a patient vomits or misses a dose, an additional dose should not be taken that day. The next 
prescribed dose should be taken at the usual time.  
Management and dose modification associated with ribociclib adverse events are outlined in Section 
6.2. ribociclib doses missed for toxicity will not be made up during a cycle. 
Participants will be supplied with a Pill Diary (Appendix E) to assess ribociclib compliance.  


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Ribociclib has been shown to prolong the QT interval in a concentration dependent manner, with mean 
increase in QTc interval being 22.9 ms (90% CI: 21.6-24.1). Therefore, ECG will be assessed prior to 
initiation of treatment and patients will only be eligible if QTcF values under <450 msec.  
5.3.2. Aromatase inhibitor:  
Participants will receive an aromatase inhibitor, according to the package insert and investigator 
discretion.  
Modification in the dose of endocrine therapy due to unacceptable toxicity will occur per treating 
investigator’s discretion.   
The type of aromatase inhibitor may be switched at the treating investigator’s discretion. Types of 
aromatase inhibitor includes letrozole, exemestane and anastrozole.  
5.4. Duration of Protocol Therapy - Criteria for Ending Protocol Therapy 
Participants will receive protocol therapy until one of the below criteria are met: 
o Disease progression  
o Participant is deemed intolerant to ribociclib because of toxicity, despite dose 
modification/ delay  
o General or specific changes in the patient's condition which render the patient 
unacceptable for further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy by the participant (See Section 17.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to End of Treatment and 30-Day-Post Last-Dose visits.  
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the change in 
participant status. 
5.5. Long-Term Follow-Up  
All participants whose disease had not progressed at the time of end of protocol therapy will undergo 
medical chart review for disease progression/response information until disease progression or the 
initiation of a new therapy. Medical chart review should occur at least twice annually or as requested by 
the lead study team.  
All participants will be followed for survival information by the site and/or by the lead study team 
designee. If performed by the lead study team, the following information will need to be transferred to 
the designee in a secure manner: the participant's first and last name, middle initial, social security 
number, date of birth, and gender. Methods for capturing survival status may include the Social Security 
Death Index and the National Death Index.  Survival analysis will be conducted at least annually or as 
requested by the lead study team. 
5.6. Criteria for Completion of Study Participation 
Study participation may conclude when any of the following occur:  
o Participant withdrawal (see Section 17.5). 


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o Participant is lost to follow-up. All attempts to contact the participant must be 
documented. 
o At the discretion of the investigator for safety, behavioral or administrative reasons 
Documentation of the reason for discontinuing study participation and the date effective should be 
made in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the 
change in participant status.   
5.7. Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Patients should receive full supportive care during the study, including treatment with antibiotics, 
antiemetics, blood transfusions, antidiarrheals, and analgesics as appropriate, with the exception of 
prohibited drugs listed below per institutional policies.  
5.7.1. Prohibited until end of protocol therapy 
End of protocol therapy is when treatment with ribociclib will no longer continue. 
o No other investigational therapy should be given to participants 
 
o No anticancer agents other than the study medications administered as part of this study 
protocol should be given to participants. If such agents are required for a participant then 
the participant must first be withdrawn from the study. 
 
o Co-medication that may interfere with study results; e.g. immuno-suppressive agents other 
than corticosteroids, such as systemic cyclosporine and tacrolimus are prohibited during the 
treatment phase of the study, unless discussed with principal investigator felt to be of low 
clinical risk to the participant. 
 
o Use of herbal medications may have unknown interactions with the metabolism of the study 
agents, and therefore are prohibited from use during the treatment phase of the trial. 
 
o Strong CYP3A inhibitors/inducers including St. John’s Wort and Grapefruit. Refer to 
Appendix B for an extensive list. 
 
o Drugs known to cause QT interval prolongation. Refer to Appendix B for an extensive list. 
 
o Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (eg, raloxifene). 
 
5.7.2. Use with caution 
o Medications that are substrates of CYP3A4 with narrow therapeutic indices may need to be 
reduced when given concurrently with ribociclib. 
 
o Steroids given for physiological replacement, as anti-emetics or inhaled as well as short 
course of oral/topical steroids given for allergic reactions or asthma flares. 
 
o Prophylactic use of white blood cell growth factors with ribociclib is not recommended 


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5.8. Assessments 
Refer to the Study Calendar in Section 11.0. 
6. 
ANTICIPATED TOXICITIES AND DOSE DELAY/MODIFICATION 
6.1. Anticipated Toxicities 
6.1.1. Ribociclib 
A list of the adverse events and potential risks associated with ribociclib, as determined by the Package 
Insert follows (* signifies occurs in ≤ 10%): 
Gastrointestinal: Nausea, stomatitis, diarrhea, decreased appetite, vomiting 
General disorders and administration site conditions: Fatigue 
Hematologic investigations: Abnormal absolute lymphocyte count; decreased lymphocytes, 
neutropenia, leukopenia, anemia, thrombocytopenia 
Infections and infestations: Infection, upper respiratory tract infection* 
Musculoskeletal and connective tissue: Weakness  
Nervous system: Peripheral neuropathy 
Respiratory, thoracic and mediastinal: Epistaxis  
Skin and subcutaneous tissue: Alopecia  
Vascular: Pulmonary embolism * 
6.1.2. Letrozole 
A list of the adverse events and potential risks associated with letrozole, as determined by the Package 
Insert follows (* signifies occurs in > 10%; ** signifies occurs in < 1%): 
Cardiac: Myocardial infarction**, chest pain-cardiac** 
Gastrointestinal: Nausea, vomiting, constipation*, diarrhea 
General disorders and administration site conditions: Fatigue, edema* 
Infections and infestations: Urinary tract infection  
Injury, poisoning and procedural complications:  Fracture 
Investigations: Weight gain*, cholesterol high*, weight loss 
Metabolism and nutrition: Anorexia 
Musculoskeletal and connective tissue: Arthralgia*, myalgia, osteoporosis, weakness*, back pain, 
chest wall pain 
Neoplasms benign, malignant and unspecified (including cysts and polyps): Treatment related 
secondary malignancy 
Nervous system:  Headache*, dizziness*, transient ischemic attack** 
Psychiatric: Insomnia 


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Reproductive system and breast: Night sweats*, vaginal hemorrhage, vaginal irritation/ dryness, 
breast pain 
Respiratory, thoracic and mediastinal: Dyspnea*, cough* 
Vascular: Hot flashes*, thromboembolic event** 
6.1.3. Exemestane  
A list of the adverse events and potential risks associated with exemestane, as determined by the 
Package Insert follows (* signifies occurs in > 10%; ** signifies occurs in < 1%): 
Cardiac: Myocardial infarction, angina, myocardial ischemia** 
Eye: Visual disturbances 
Gastrointestinal: Nausea*, diarrhea, constipation 
General disorders and administration site conditions: Fatigue*, edema, increased sweating*, 
abdominal pain* 
Immune system disorders: Allergy 
Investigations: Weight gain*  
Infections and infestations: Hepatitis  
Injury, poisoning and procedural complications:  Fractures 
Metabolism and nutrition: Increased appetite, anorexia 
Musculoskeletal and connective tissue: Arthralgia*, back pain, pain in limb, osteoarthritis, 
osteoporosis, myalgia 
Nervous system:  Headache*, dizziness, peripheral neuropathy**, paresthesia 
Psychiatric: Insomnia*, depression*, anxiety* 
Skin and subcutaneous tissue: Alopecia* 
Vascular: Hot flashes*, hypertension*  
6.1.4. Anastrozole 
A list of the adverse events and potential risks associated with anastrozole, as determined by the 
Package Insert follows (* signifies occurs in > 10%): 
Blood and lymphatic system: Anemia 
Cardiac: chest pain-cardiac, myocardial ischemia 
Eye: Cataract 
Gastrointestinal: Nausea*, vomiting, dyspepsia  
General disorders and administration site conditions: Edema limbs* 
Infections and infestations: Pharyngitis*, infection, sinusitis, bronchitis, vaginal infection, urinary 
tract infection, hepatitis, rhinitis 
Injury, poisoning and procedural complications:  fractures* 


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Investigations: Weight gain, cholesterol high, Alkaline phosphatase increased, AST increased, 
ALT increased, bilirubin increased, GGT increased, hypercalcemia, lymphocyte count decreased, 
weight loss 
Immune system disorders: Allergy, anaphylaxis 
Musculoskeletal and connective tissue: Weakness*, arthritis*, arthralgia*, pain*, osteoporosis*, 
back pain*, bone pain*, arthrosis, myalgia 
Neoplasms benign, malignant and unspecified (including cysts and polyps): Treatment related 
secondary malignancy, breast neoplasm 
Nervous system:  Headache*, dizziness, Ischemia cerebrovascular 
Psychiatric: Depression*, insomnia*, anxiety, paresthesia  
Reproductive system and breast: Vaginal discharge, breast pain, vaginal hemorrhage 
Respiratory, thoracic and mediastinal: Cough*, dyspnea* 
Skin and subcutaneous tissue: Rash*, Stevens-Johnson syndrome, erythema multiforme, 
urticaria, alopecia, pruritus 
Vascular: Hot flashes*, hypertension*, lymphedema*, hypotension*, thromboembolic event 
6.2. Dose Modifications/ Delays 
6.2.1. General Information: 
1. The cycle length will remain 28 days (± 2 days) despite a delay in initiating ribociclib on Day 
1; endocrine therapy may continue to be administered per the preplanned schedule. 
2. Dose holds/reductions of endocrine therapy will occur per treating investigator’s discretion. 
3. See Table 6.2.1 for criteria to dose modify ribociclib. Dose reductions are as follows: 
Table 6.2.1: Ribociclib dose levels 
Dose Level 
Dose 
Starting dose 
600 mg/day 
First dose reduction 
400 mg/day 
Second dose reduction 
200 mg/day 
Third dose reduction 
discontinue protocol therapy 


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Table 6.2.2a: Ribociclib Dose Modification and Management - Hematologic Toxicities 
CTCAE v 4.0 Grade 
Ribociclib Dose Modifications For Hematologic Toxicities 
Grade ≤ 2 
Maintain treatment. 
Grade 3
 
(Except febrile neutropenia OR 
lymphopenia associated with 
clinical events) 
Hold ribociclib until recovery to Grade ≤2. Consider repeating complete blood 
count monitoring one week later. 
Ⴠ Upon recovery Grade ≤2 within 28 days resume therapy at the pre-hold 
dose.  
Ⴠ Permanently discontinue protocol therapy if the toxicity persists for > 28 
days. 
Grade 3 ANC (<1000 to 
500/mm3) + Fever (≥38.5oC)  
OR  
Grade 3 ANC + infection 
Hold ribociclib until recovery to Grade ≤2 (≥ 1000/mm3).  
Ⴠ Upon recovery Grade ≤2 within 28 days resume therapy at the next lower 
dose.  
Ⴠ Permanently discontinue protocol therapy if the toxicity persists for > 28 
days. 
Grade 4 ANC <500/mm3 
(Except lymphopenia 
associated with clinical events)
 
Hold ribociclib until recovery to Grade ≤2.  
Ⴠ Upon recovery Grade ≤2 within 28 days resume therapy at the next lower 
dose.  
Ⴠ Permanently discontinue protocol therapy if the toxicity persists for > 28 
days. 
 
 


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Table 6.2.2b: Ribociclib Dose Modification and Management- Non-Hematologic Toxicities 
 
CTCAE v 4.0 
Grade 
Dose Modifications For Non-Hematologic Toxicities 
RELATED  
to Ribociclib 
Grade ≤ 2  
Maintain treatment.  
Grade ≥3  
Hold ribociclib until recovery to Grade ≤1 or baseline.  
Ⴠ Upon recovery to Grade ≤1 or baseline within 28 days resume therapy at 
the next lower dose if medically appropriate at the discretion of the 
treating physician.   
Ⴠ Permanently discontinue protocol therapy if the toxicity persists for > 28 
days 
NOT-RELATED 
to Ribociclib 
Grade ≥3  
Treating investigator may hold ribociclib per his/her discretion. 
Permanently discontinue protocol therapy if the hold is for > 28 days 
 
Table 6.2.2c: Ribociclib Dose Modification and Management- Hepatobiliary Toxicity 
 
Grade 1 
(> ULN-3 x ULN) 
Grade 2  
(>3-5 x ULN) 
Grade 3 
(>5-20 x ULN) 
Grade 4 
(>20 x ULN) 
AST and/or ALT 
Elevations from 
baseline, 
WITHOUT 
increase in total 
bilirubin above 
2 x ULN 
No dose adjustment 
required 
Baseline at < grade 
2: Dose interruption 
until recovery to ≤ 
baseline grade, then 
resume ribociclib at 
the same dose level. 
If grade 2 recurs, 
resume ribociclib at 
the next dose level.  
Baseline at grade 2:  
No dose interruption 
Dose interruption 
until recovery to ≤ 
baseline grade then 
resume at the next 
lower dose level. If 
grade 3 recurs, 
discontinue 
ribociclib.  
Discontinue 
ribociclib 
Combined 
elevations in 
AST and/or ALT 
WITH total 
bilirubin 
increase, in the 
absence of 
cholestasis 
If patient develops ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN 
irrespective of baseline grade, discontinue ribociclib 
Table 6.2.2d: Ribociclib Dose Modification and Management- QT Prolongation 


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Grade 
Dose Modification 
For All Grades  
1. 
Check the quality of the ECG and the QT value and repeat if needed.  
2. 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If outside of 
the normal range, interrupt ribociclib administration, correct with 
supplements or appropriate therapy as soon as possible, and repeat 
electrolytes until documented as normal.  
3. 
Review concomitant medication usage for the potential to inhibit CYP3A4 
and/or to prolong the QT interval. 
4. 
Check compliance with correct dose and administration of ribociclib. 
Consider collecting a time matched PK sample; record date and time of last 
study drug intake  
1* 
QTcF 450-480 ms 
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment required. 
2* 
QTcF 481-500 ms 
Interrupt ribociclib. Perform steps 1-4 as directed in “For all Grades.” 
Perform a repeated ECG within one hour of the first QTcF of ≥ 481 ms.  
Repeat ECG as clinically indicated until the QTcF returns to < 481 ms, restart 
ribociclib with dose reduced by 1 dose level. Refer to Table 6.2.1. for dosing 
schedule.   
If QTcF ≥ 481 ms recurs, ribociclib should be reduced again by 1 dose level. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patients who had therapy interrupted due to QTcF ≥ 481 ms.  
3* 
QTcF ≥ 501 ms on at least 
two separate ECGs  
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and 
repeat cardiac monitoring as indicated until the QTcF returns to < 481 ms. 
x 
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level. 
(Refer to Table 6.2.1 for dosing schedule.) 
x 
If QTcF returns to ≥ 481 ms after performing steps 1-4 as directed in 
“For All Grades,” discontinue ribociclib. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patients who had therapy interrupted due to QTcF ≥ 501 ms. 
If QTcF of ≥ 501 recurs, discontinue ribociclib.  
 
4* 
[QT/QTcF ≥ 501 or > 60 ms 
change from baseline] 
and 
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or 
signs/symptoms of serious 
arrhythmia]  
Discontinue ribociclib. Perform steps 1-4 as directed in “For All Grades.” 
x 
Obtain local cardiologist (or qualified specialist) consultation and repeat 
cardiac monitoring as indicated until the QTcF returns to <481 ms.  


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*All values refer to the average of the triplicate measurements. 
Dose Modification for Use with Strong CYP3A Inhibitors:  
 
Avoid concomitant use of ribociclib with strong CYp3A inhibitors and consider an alternative 
concomitant medication with less potential for CYP3A inhbitiion, 
 
If a strong CYP3A inhibitor must be coadministered, reduce the ribociclib dose to 400 mg once 
daily.  
 
If strong inhibitor is discontinued, change the ribociclib dose (after at least 5 half-lives of the 
strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.  
Dose Modification for Hepatic Impairment 
 
No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). 
7. 
SAFETY MONITORING AND REPORTING 
7.1 Definitions  
7.1.1. Adverse Event (AE) 
An adverse event is any untoward medical experience or change of an existing condition that occurs 
during or after treatment, whether or not it is considered to be related to the protocol intervention. 
 
 
7.1.1.1 Serious Adverse Event (SAE) 
A serious adverse event is any expected or unexpected adverse events that result in any of the following 
outcomes: 
x 
Death 
x 
Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
x 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
x 
A persistent or significant disability/incapacity 
x 
A congenital anomaly/birth defect 
x 
Secondary malignancy* 
x 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse). 
*Modified from 21 CFR 312.32 
 
7.1.1.2 Unanticipated Problems Involving Risks to Subjects or Others 


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An unanticipated problem is any incident, experience, or outcome that meets all three of the following 
criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
 
7.1.1.3 Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events, regardless of seriousness, will be reported. 
 
7.1.2 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, assessing the severity (i.e. 
grade), expectedness, and attribution of all adverse events.  
 
7.1.2.1 Assessment of Adverse Event Name and Grade 
Adverse events will be characterized using the descriptions and grading scales found in The NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0.  A copy of the scale can be found at 
the NCI/CTEP web site. The determination of severity for all other events not listed in the CTCAE should 
be made by the investigator based on medical judgment and the severity categories of Grade 1 to 5 as 
defined below: 
x 
Grade 1 (mild) – An event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
x 
Grade 2 (moderate) – An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
x 
Grade 3 (severe) – An event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects the clinical status of the subject. 
x 
Grade 4 (life threatening) – An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect or limit the ability of the 
subject to perform activities of daily living (eating, ambulation, toileting, etc). 
x 
Grade 5 (fatal) – Death (loss of life) as a result of an event. 
 
7.1.2.2 Assessment of Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 


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x 
Unrelated – The event is clearly related to other factors such as the participant’s clinical state, 
other therapeutic interventions, or concomitant medications administered to the participant. 
x 
Unlikely – The event is doubtfully related to the investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
x 
Possible – The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s clinical 
state, other therapeutic interventions, or concomitant drugs.  
x 
Probable – The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions, or concomitant drugs.  
x 
Definite – The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions, or 
concomitant drugs, AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.  
 
7.1.2.3 Assessment of Expectedness 
The following definitions will be used to determine the expectedness of the event: 
 
x 
Unexpected– An adverse event is unexpected if it is not listed in the investigator’s brochure 
and/or package insert; is not listed at the specificity or severity that has been observed; is not 
consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk 
factor of the research participant experiencing the adverse event. *Modified from 21 CFR 
312.32 (a) 
x 
Expected – An adverse event is expected if it does not meet the criteria for an unexpected 
event, OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
 
 
7.1.3   Reporting of Adverse Events 
 
7.1.3.1 Routine Reporting of Non-Serious Adverse Events by Site Investigators  
Routine AE recording will occur via data entry into the study eCRF. Recording of adverse events will begin 
once the patient is consented and will continue until 30 days after the patient’s last dose. Adverse events 
will be monitored by the Protocol Management Team (PMT). Adverse events that do not meet the criteria 
of serious OR are not unanticipated problems do not require expedited reporting.  AEs reported through 
expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be reported in routine study 
data submissions.  
 
7.1.3.2  Expediting Reporting Requirements of SAEs and UPs by Site Investigators 
7.1.3.2.1 
Criteria for Reporting SAEs/UPs to the Coordinating Center 


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Serious Adverse Events meeting the criteria specified below will be reported to the Coordinating Center 
within 24 hours of notification that the event occurred.  
 
Adverse events that require expedited reporting include: 
x 
AEs or SAEs that meet the definition of an unanticipated problem 
x 
All deaths that occur within 30 days of active treatment 
x 
All deaths that occur after 30 days of active treatment that are unexpected and possibly, 
probably, or definitely related to the study agent or procedure 
x 
All serious adverse events, regardless of relationship to study agent or study procedure, that 
occur within 30 days of the last day of treatment 
x 
All serious adverse events that occurred after 30 days of active treatment/therapy that are 
considered possibly, probably, or definitely related to the study agent or procedure  
 
Note: Follow-up reports must be submitted for all events that require expedited reporting when the status 
of the event changes and until the resolution or stabilization of the event. 
 
Reportable serious adverse events must be followed until the event is resolved, stabilized, or determined 
to be irreversible by the participating investigator; for ongoing reportable adverse events that are 
unrelated to study agent, the follow-up period may end at the 30-days post study-drug assessment. The 
Coordinating Center should be consulted prior to ending the follow-up of events that have stabilized. 
 
7.1.3.2.2 
Non-COH Sites: Procedure for Reporting SAEs/UPs to the COH Data 
Coordinating Center  
1. Sites are to report to their local IRB per their site’s specific institutional and IRB 
guidelines. As soon as possible, non-COH sites will provide to the COH Data 
Coordinating Center copies of the IRB submission and corresponding IRB 
response.  
2. Document/describe the SAE/UP on each of the following:  
a. MedWatch 3500A   
i. Downloadable form at http://www.fda.gov/medwatch/getforms.htm 
 
b. UP/SAE Coversheet 
i. SAE Coversheet is found in Appendix [J].  A modifiable Microsoft 
Word document is also available from the Data Coordinating Center.  An 
electronic signature on the document will be accepted. 
3. Scan and email above documents to DCC@coh.org with the subject title as “IRB 
# SAE”.   
a. All SAE reports received at this account are forwarded immediately to 
study Principal Investigator, and to Coordinating Center personnel.  
b. While not required, if available and applicable, please also include the 
local IRB submission for this event in the submission.  
4. If an email receipt from Coordinating Center personnel is not received within one 
working day, please call 626-256-4673 x 83968 and/or email DCC@coh.org. 


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7.1.3.2.3 
COH Investigative Sites: Procedure for Reporting SAEs/UPs to the 
Coordinating Center 
1. Email the following information to DCC@coh.org and msedrak@coh.org.  
a. Participant ID, date the event met criteria for reporting, whether the 
event meets the definition of serious, whether the event is an 
unanticipated problem, grade of event, attribution of event, whether 
the event is a known expected toxicity to study agent. 
2. Complete the iRIS AE/UP reporting form per COH reporting timeline. 
 
 
7.1.3.3 Additional Reporting Requirements of the Study Principal Investigator  
7.1.3.3.1 
Reporting to COH IRB and DSMC 
The study PI (or designee) will report to COH IRB and DSMC via iRIS all reportable serious adverse 
events that occur at COH and non-COH sites and meet COH IRB and DSMC expedited reporting criteria 
according to City of Hope’s Institutional policy.  The study PI will also submit a Protocol Management 
Team (PMT) report to the COH DSMC at the frequency outlined in Section 3.6. This report will include a 
review of aggregate adverse event data.   
 
7.1.3.3.2 
Reporting to the FDA  
 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
 
The criteria that require reporting using the Medwatch 3500A are: 
x 
Any unexpected fatal or life threatening adverse experience associated with use of the drug 
must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)] 
x 
Any adverse experience associated with use of the drug that is both serious and unexpected 
must be submitted no later than 15 calendar days after initial receipt of the information [21 
CFR 312.32(c)(1)] 
x 
Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
 
7.1.3.3.3 
Reporting to Participating Investigators 
The study PI (or designee) will report all reportable serious adverse events to participating investigators 
as an IND Safety Report occurring within 30 calendar days of receipt of sponsor (lead site) notification, 
and indicate whether or not a protocol and/or consent form change is required.  A cover letter will 
indicate the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a 
statement that the report should be submitted to their local IRB for review as an IND safety report if 
applicable per local IRB policy. 
 


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The study PI will also forward to participating sites all IND safety reports received from Novartis, 
indicating whether a consent form or protocol change is required within 30 days of notification to study 
PI. 
 
7.1.3.3.4 
Reporting to Novartis 
All serious adverse events and AESIs (initial and follow-up information) will be reported by the study PI to 
Novartis within 24 hours of learning of its occurrence per the following guidelines: Novartis Adverse Event 
Reporting Guidelines (section 7.1).    
 
 
7.2.0 PROTOCOL DEVIATIONS AND SINGLE SUBJECT EXCEPTIONS 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. Brief interruptions and delays may occasionally 
be required because of travel delays, airport closures, inclement weather, family responsibilities, 
security alerts, government holidays, and so forth. Delays can also extend to complications of disease or 
unrelated medical illnesses not related to disease progression. The PI has the discretion to deviate from 
the protocol when necessary so long as such a deviation does not threaten patient safety or protocol 
scientific integrity. As a result of deviations, corrective actions are to be developed by the study staff 
and implemented promptly. 
 
7.2.1 Definitions 
7.2.1.1 Deviation 
A deviation is a divergence from a specific element of a protocol that occurred without prior IRB 
approval.  Investigators may deviate from the protocol to eliminate immediate hazard(s) for the 
protection, safety, and well-being of the study subjects without prior IRB approval.  
Examples include, but are not limited to: a) dose adjustments based on excessive patient weight; b) 
alteration in treatment schedule due to non-availability of the research participant for treatment; and c) 
laboratory test results which are slightly outside the protocol requirements but at levels that do not 
affect participant safety. 
 
 
7.2.1.2 
Single Subject Exceptions (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient.  It is a deviation that is 
anticipated and receives prior approval by the PI and the IRB.  
  
7.2.2 Reporting of Deviations and SSEs 
 
7.2.2.1 
Reporting Deviations 
For any deviation, the Investigator will notify the COH DSMC and IRB within 5 calendar days of its 
occurrence via iRIS in accordance with the Clinical Research Protocol Deviation policy.  
A list of deviations from all participating sites will be submitted along with the Protocol Management 
Team (PMT) progress report to the COH DSMC. 
 
For non-COH sites:  
o The local IRB and/or DSMC must be notified according to local institutional policies.  


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o The study Principal Investigator must be notified as soon as practical (within 24 hours of 
notification of the event) via email to msedrak@coh.org and dcc@coh.org.  This email 
should provide input on the following: 
 
Description of the event 
 
Impact on participant safety or the safety to others 
 
Impact on the study design 
 
A corrective and preventative action plan 
 
7.2.2.2 Reporting Single Subject Exceptions 
The SSE must be submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance 
with IRB guidelines and the Clinical Research Protocol Deviation policy.  An IRB approved SSE does not 
need to be submitted as a deviation to the DSMC. 
 
All non-emergency planned deviations from the protocol must have prior approval by the Study Principal 
Investigator, the Site Principal Investigator, COH IRB, and when applicable, the local IRB.  In addition, if 
contractually obligated, the sponsor must also approve the deviation.  
 
7.3.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
7.3.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
 
All Investigators agree to: 
x 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of 
subjects. 
x 
Personally conduct or supervise the study (or investigation).  
x 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
x 
Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
x 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
x 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
x 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study.  


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x 
Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
x 
Seek IRB and Sponsor approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.  
x 
Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
7.3.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities as defined in § 21 CFR 312. Subpart D are executed in accordance with federal 
regulations.  
 
7.3.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, site investigators, 
collaborating investigators, research nurse, clinical research associate/coordinator, and the study 
biostatistician, is responsible for ongoing monitoring of the data and safety of this study, including 
implementation of the stopping rules for safety/toxicity. 
 
The PMT is recommended to meet (in person or via teleconference) at least monthly to review study 
status. This review will include, but not be limited to, reportable AEs and UPs, and an update of the 
ongoing study summary that describes study progress in terms of the study schema. The meeting will be 
a forum to discuss study related issues including accrual, SAE/AEs experienced, study response, 
deviations/violations and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed. It is recommended that 
minutes of these discussions be taken to document the date of these meetings, attendees and the issues 
that were discussed (in a general format).   
 
7.3.4  Monitoring  
Clinical site auditing is conducted to ensure that the rights of human subjects are protected, that the study 
is implemented in accordance with the protocol and regulatory requirements, and that the quality and 
integrity of study data and data collection methods are maintained.  Auditing for this study will be 
performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM).  
 
The site Investigator/Institution will permit the study auditors and appropriate regulatory authorities 
direct access to the study data and to the corresponding source data and documents to verify the accuracy 
of this data. The Investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
Details of clinical site monitoring are documented in the OCTAM SOP that is provided as a supplement to 
this document. This document specifies the frequency of monitoring, monitoring procedures, the level of 
clinical site monitoring activities (e.g., the percentage of subject data to be reviewed), and the distribution 
of monitoring reports.  Staff from OCTAM will conduct monitoring activities and provide reports of the 


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findings and associated action items in accordance with the details described in the SOP.  Documentation 
of monitoring activities and findings will be provided to the site study team, the site PI, study PI, and the 
COH DSMC.  
 
7.3.5  Quality Assurance  
The City of Hope Clinical Research Information Support will provide support for this multi-center trial as 
detailed in the COH DCC Operations Plan provided as a supplement to this document.  
 
7.3.6  City of Hope Data and Safety Monitoring Committee 
This is a risk level 3 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan. 
This determination was made because this study is a Phase IIA trial that is IND Exempt. 
 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board.  
 
The Study Principal Investigator is required to submit periodic status reports (the PMT report) according 
to the guidelines outlined in the City of Hope Institutional Data and Safety Monitoring Plan.  The PMT 
report will be submitted to the COH DSMC every six months from the date of activation.   
 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this trial. The DSMC will review up-to-date participant accrual; summary of all adverse events 
captured via routine and expedited reporting; a summary of deviations; any response information; 
monitoring reports, and summary comments provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. For Phase I studies, a Phase I Tracking Log will be 
utilized and reviewed by the DSMC to monitor data and safety for dose escalation.  A review of outcome 
results (response, toxicity and adverse events) and factors external to the study (such as scientific or 
therapeutic developments) is discussed, and the Committee votes on the status of each study. 
Information that raises any questions about participant safety will be addressed with the Principal 
Investigator, statistician and study team. The PMT report and DSMC recommendations will be circulated 
to all participating sites for submission to their IRBs, in accordance with NIH guidance. 
 
 


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7.4 
Novartis Adverse Event Reporting Guidelines 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided informed consent and until at least 30 days after the patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression 
of the initial SAE must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported separately 
as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug 
Safety and Epidemiology (DS&E) department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or 
as per national regulatory requirements in participating countries. 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the 
oncology Novartis Drug Safety and Epidemiology (DS&E) department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the 
Novartis study treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment 
in this study. Consent to report information regarding these pregnancy outcomes should be obtained 
from the mother. 
 


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8. 
AGENT INFORMATION 
8.1. Ribociclib  
8.1.1. Other Names 
Kisqali 
8.1.2. Description and Molecular Weight 
Structural formula:  
 
Empirical formula: 
C23H30N8O 
Molecular weight: 
434.254272 g/mol 
Chemical Name: 
7-Cyclopentyl-N,N-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7H-
pyrrolo[2,3-d]pyrimidin-6-carboxamid 
 
8.1.3. Mechanism of Action 
Inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling 
pathways which lead to cellular proliferation. In vitro, ribociclib reduced cellular proliferation of 
estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S 
phase of the cell cycle. Treatment of breast cancer cell lines with the combination of ribociclib and 
antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation, resulting in reduced E2F 
expression and signaling and increased growth arrest compared to treatment with each drug alone. In 
vitro treatment of ER-positive breast cancer cell lines with the combination of ribociclib and 
antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug 
removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model 
demonstrated that the combination of ribociclib and letrozole increased the inhibition of Rb 
phosphorylation, downstream signaling and tumor growth compared to each drug alone.[22] 
 


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8.1.4. Pharmacokinetics 
 
Absorption: 
Compared to a fasted state, oral administration with a high-fat, high-calorie 
meal has no effect on the rate and extent of absorption of ribociclib.  
Distribution: Vd (mean):  
1090 L 
Protein binding: 
~70% 
Metabolism:  
Extensively hepatic; Major pathways: Oxidation (dealkylation, C and/or N-
acetylation), sulfation, cysteine conjugation, glycosylation and 
glucuronidation. 
Bioavailability:  
Mean absolute bioavailability: 46% 
Half-life elimination:  
32 hours 
Time to peak:  
1 to 4 hours 
Excretion:  
Feces. 92% of dose recovered within 22 days; feces is the major route of 
excretion (69%), with 23% recovered in urine.  
 
8.1.5. Human Toxicity 
See Section 6.1.1. 
8.1.6. Formulation 
Ribociclib is supplied as a 600 mg, 400 mg, or 200 mg doses in assorted blister packs. Each film-coated 
contains 200 mg of ribociclib free base. Ribociclib is supplied as a light greyish violet, round tablet, 
curved with beveled edge, debossed with “RIC” on one side and “NVR” on the other. Inactive ingredients 
present in the tablet include: colloidal silicon dioxide, crospovidine, hydroxypropylcellulose,magnesium 
stearate, and microcrystalline cellulose.  
8.1.7. Storage  
The blister packs should be stored at 200C to 25oC (68oF to 77oF); excursions permitted between 15 to 
30oC (59 to 86oF). 
8.1.8. Preparation 
Ribociclib may be repackaged to provide appropriate capsule quantities to participants. Tabs should not 
be distributed if broken, cracked or otherwise not intact. 


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8.1.9. Dose and Administration 
See Section 6.2. 
8.1.10. Supplier 
Study drug is being provided by the drug manufacturer, Novartis. 
8.1.11. Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using the NCI Drug 
Accountability Record or another comparable drug accountability form.  
8.1.12. Destruction and Return 
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed 
according to institutional policies. Prior to the destruction of ribociclib, the DCC should be notified and 
an acknowledgement to proceed from the DCC should be received. Destruction will be documented in 
the Drug Accountability Record. 
8.2 Letrozole 
Please refer to the Package Insert for additional details for letrozole not provided in this section. 
8.2.1. Other names 
Femara. 
8.2.2. Description and Molecular Weight 
Structural formula:  
 
Empirical formula: 
C17H11N5 
Molecular weight: 
285.30 g/mol 
Chemical Name: 
4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile 
8.2.3.  
Mechanism of Action:  


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Nonsteroidal competitive inhibitor of the aromatase enzyme system which binds to the heme group of 
aromatase, a cytochrome P450 enzyme which catalyzes conversion of androgens to estrogens 
(specifically, androstenedione to estrone and testosterone to estradiol). This leads to inhibition of the 
enzyme and a significant reduction in plasma estrogen (estrone, estradiol and estrone sulfate) levels. 
Does not affect synthesis of adrenal or thyroid hormones, aldosterone, or androgens. 
8.2.4. Human Toxicity  
See Section 6.1.2. 
8.2.5. Pharmacokinetics  
Absorption: 
Rapid and well absorbed; not affected by food 
Distribution: Vd:  
~1.9 L/kg 
Protein binding plasma: 
Weak 
Metabolism:  
Hepatic via CYP3A4 and 2A6 to an inactive carbinol metabolite 
Half-life elimination:  
Terminal: ~2 days 
Time to steady state, 
plasma 
2 to 6 weeks; steady state serum concentrations are 1.5 to 2 times higher 
than single-dose values 
Excretion:  
Urine (90%; 6% as unchanged drug, 75% as glucuronide carbinol 
metabolite, 9% as unidentified metabolites) 
8.2.6. Supplier   
Letrozole is commercially available. 
8.3 Exemestane 
Please refer to the Package Insert for additional details for exemestane not provided in this section. 
8.3.2. Other names 
Aromasin 
8.3.3. Description and Molecular Weight 


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Structural formula:  
 
Empirical formula: 
C20H24O2 
Molecular weight: 
296.403 g/mol 
Chemical Name: 
6-Methylideneandrosta-1,4-diene-3,17-dione 
8.3.4. Mechanism of Action 
Exemestane is an irreversible, steroidal aromatase inactivator. It is structurally related to 
androstenedione, and is converted to an intermediate that irreversibly blocks the active site of the 
aromatase enzyme, leading to inactivation (“suicide inhibition”) and thus preventing conversion of 
androgens to estrogens in peripheral tissues. Exemestane significantly lowers circulating estrogens in 
postmenopausal breast cancers where growth is estrogen-dependent. 
8.3.5. Human Toxicity  
See Section 6.1.3. 
8.3.6. Pharmacokinetics  
Absorption: 
Rapid and moderate (~42%) following oral administration; AUC and Cmax 
increased by 59% and 39%, respectively, following a high-fat breakfast 
compared to fasted state 
Distribution:   
Extensive into tissues 
Protein binding plasma: 
90%, primarily to albumin and α1-acid glycoprotein 
Metabolism:  
Extensively hepatic; oxidation (CYP3A4) of methylene group, reduction of 
17-keto group with formation of many secondary metabolites; metabolites 
are inactive 
Half-life elimination:  
~24 hours 
Time to peak: 
Women with breast cancer: 1.2 hours 


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Excretion:  
Urine (<1% as unchanged drug, 39% to 45% as metabolites); feces (36% to 
48%) 
8.3.7. Supplier  
Exemestane is commercially available. 
8.4 Anastrozole 
Please refer to the Package Insert for additional details for anastrozole not provided in this section. 
8.4.2. Other names 
Arimidex 
8.4.3. Description and Molecular Weight 
Structural formula:  
 
Empirical formula: 
C17H19N5 
Molecular weight: 
293.37 g/mol 
Chemical Name: 
2-[3-(2-cyanopropan-2-yl)-5-(1,2,4-triazol-1-ylmethyl)phenyl]-2-
methylpropanenitrile 
8.4.4. Mechanism of Action 
Anastrozole is a selective non-steroidal aromatase inhibitor. By inhibiting aromatase, the conversion of 
androstenedione to estrone, and testosterone to estradiol, is prevented, thereby decreasing tumor 
mass or delaying progression in patients with tumors responsive to hormones.  
8.4.5. Human Toxicity  
See Section 6.1.4. 
8.4.6. Pharmacokinetics  
Onset of estradiol 
reduction: 
70% reduction after 24 hours; 80% after 14 days of daily dosing  


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Duration of serum 
estradiol reduction: 
6 days 
Absorption:  
Well absorbed; food reduces the rate but not the overall extent of 
anastrozole absorption 
Protein binding plasma: 
40% 
Metabolism:  
Extensively hepatic (~85%) via N-dealkylation, hydroxylation, and 
glucuronidation; primary metabolite (triazole) inactive 
Half-life elimination:  
~50 hours 
Time to peak, plasma: 
~2 hours without food; 2 to 5 hours with food 
Excretion:  
Feces; urine (urinary excretion accounts for ~10% of total elimination, 
mostly as metabolites) 
 
8.4.7. Supplier   
Anastrozole is commercially available. 
9. 
CORRELATIVE/SPECIAL STUDIES 
9.1 Blood Banking (Optional) 
With patient permission obtained (via informed consent), blood (10 mL- green top heparin OR lavender 
top K+EDTA) will be collected at baseline for future mRNA and DNA isolation and stored in order to be 
banked for future research.  Such studies might include genetic testing to determine how genetics 
influences chemotherapy toxicity. Samples will be stored between -60°C to -90°C at the COH Clinical 
Immunobiology Correlative Studies Laboratory (CICSL) until future downstream processing. 
Collection, Processing, Labeling and Shipping 
Refer to Appendix D1 for collection and to Appendix D2 for shipping (non-COH sites only) 


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10. 
RIBOCICLIB PHARMACOKINETICS 
10.1  
Clinical Pharmacology Objectives 
To determine average plasma steady-state ribociclib Ctrough concentrations in patients over the 
age of 70 years. Further, we will determine the relationship between average plasma Ctrough and 
percent decreases in neutrophil and platelet counts in patients. [24] 
 
10.2        Blood Sample Collection 
Blood samples will be collected from a peripheral vein or indwelling venous catheter or by 
venipuncture. At each time point indicated in the table below, peripheral blood will be collected 
into a single 10 ml green-top tube (sodium or lithium heparin) to prevent blood clotting. Tubes 
will be inverted several times and then immediately placed on ice for transportation to the 
Analytical Pharmacology Core Facility (APCF), the processing laboratory. 
Blood samples will be collected at the times indicated in table 10.2.1 below. Patients will be 
instructed not to take their ribociclib on these days until after they have had their blood drawn 
in the clinic.  
 Table 10.2 Time Points for Blood Sample Collection for PK Studies 
Time Point 
Cycle 
Day 
Date 
(mm/dd/yy) 
Time 
(hr:min)             
Pretreatment 
1 
1* 
 
 
C1D8 
1 
8 
 
 
C1D15 
1 
15 
 
 
 
 
 
 
 
C2D1 
2 
1 
 
 
C2D8 
2 
8 
 
 
C2D15 
2 
15 
 
 
 
*All samples to be drawn prior to the dose of ribociclib on that day. 
10.3         Sample Processing 
Anti-coagulated whole blood samples (one 10 ml green-top tube) will be processed by 
centrifugation for 10 minutes at 1500 x g at 4⁰C. The resulting plasma will be transferred to 
appropriately labeled polypropylene tubes and frozen at < -70⁰C until analysis. 
10.4         Analytical Method 
For analysis of ribociclib in human plasma, a sensitive and selective LC/MS/MS method will be 
developed and qualified in the Analytical Pharmacology Core Facility at the City of Hope. The 
method will be based on the published method of Kala et al.[25] 
10.5        Pharmacokinetic Data Analysis Methods 
Average plasma Ctrough will be calculated for each subject and the population results will be 
summarized using standard statistical methods. 
 
 


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11. 
STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated. 
Table 11.0 Study Activity Calendar  
Evaluations & 
activities 
Screening a  
Treatment b 
Off  Tx 
30-days 
post-last 
dosef 
 Long-
Term 
Follow-
Up 
Cycles 1  
Cycle 2 
Cycles 
3+ 
Day 
1c,d 
Day 
8 
Day 
15e 
Day 
1 
Day 
8 
Day 
15 
Day 1d 
 
 
 
MD Evaluation 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Informed 
consent g 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
criteria h 
X 
 
 
 
 
 
 
 
 
 
 
Registration i 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
j 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs k 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Physical exam l X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Performance 
status m 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Hematology 
Xn 
X 
 
X 
X 
 
X 
X 
X 
 
 
Chemistry 
(including LFTs) Xn 
X 
 
X 
X 
 
X 
X 
X 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
Xgg 
 
 
 
Urinanalysis / 
BUN 
X 
 
 
 
 
 
 
 
 
 
 


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Blood banking 
sample p 
 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinet
ic blood draw 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant 
meds q 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
AE evaluation r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X s 
 
Pill diary t 
 
X t 
 
 
Xt 
 
 
X t 
Xhh 
 
 
Geriatric 
assessmentu 
 
Xv 
 
 
 
 
 
Xw 
Xhh 
 
 
WIWI and OTU 
x 
 
 
 
 
 
 
 
 
Xhh 
 
 
Radionuclide 
Bone Scan, 
Whole Body  
Xy 
 
 
 
 
 
 
Xz 
 
 
 
CT aa 
Xy 
 
 
 
 
 
 
Xw 
 
 
 
ECG (12-lead) 
X 
 
 
X 
X 
 
X 
 
 
 
 
Disease/Respo
nse 
Assessment bb 
 
 
Xw 
 
 
 
Ribociclib cc 
 
Orally once daily on Days 1-21 of each 
cycle (See Section 5.3) 
 
 
 
 
AI cc 
 
Per treating investigator’s discretion. Dosing per 
package insert in each cycle.  
(See Section 5.3) 
 
 
 
Chart review 
dd 
 
 
 
X dd 
Survival ee 
 
 
 
X ee 
 


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a. Screening procedures to be performed within 28 days from start of protocol therapy, except labs which are 
to be performed within 14 days of start of study agents (footnotes ‘n’).   
b. Treatment will last until unacceptable toxicity or disease progression (see Section 5.4 for more 
comprehensive list).  
c. 
Cycle 1 Day 1 will be defined as the day the participant initiates the combined ribociclib and endocrine 
therapy regimen. 
d. Each treatment cycle lasts 28 days, with a fixed window of ± 2 days for participant convenience. The cycle 
duration does not change, even if ribociclib is held (Note: exceptions under certain circumstances are 
permitted; see Section 6.2). Day 1 safety assessments must be performed and reviewed within 48 hours of 
initiating ribociclib during a new cycle.  
e. Windows for Day 8 and 15 assessments are +/-2 days. 
f. 
A contact/visit for review of adverse events, performance status (see Appendix A), and concomitant 
medication review, is to be performed at 30 ± 2 days after the last study drug is given. In lieu of a clinic 
visit, this may be performed via documented phone conversation with a study nurse or clinician. All 
participants will be followed until resolution or stabilization of all events requiring expedited reporting and 
occurring during treatment or starting within 30 days of last study drug. 
g. 
Informed consent process to be fully documented (see Section 17.4). Informed consent must occur prior to 
any research only (non-SOC) screening procedures.  
h. Eligibility criteria: refer to Section 3.0. The site will maintain a screen-failure log for all persons screened for 
eligibility (see Section 4.3).  
i. 
See Section 4.2 for registration process. The DCC must be notified of all persons who sign consent, 
including screen failures or participants who fail to initiate protocol therapy (see Section 4.3). 
j. 
Medical history: to include any ongoing medical conditions and medical history pertaining to eligibility on 
study and involvement during study.  
k. 
Vital signs: Weight, heart rate, blood pressure, respiration rate, and temperature.  Height required only at 
baseline. 
l. 
Physical exam to include Clinical Evaluation of Superficial Disease for use in disease evaluation.  
m. See Appendix A for Karnofsky performance status. 
n. CBC and metabolic panel to be performed within 14 days prior to start of protocol therapy. 
o. Metabolic panel: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, total protein, albumin, alkaline 
phosphatase, and glucose). 
p. From participants who consent to research samples only, 10 mL blood sample to be collected in a lavender 
(K-purple (EDTA) or green (Heparin) top tube, inverted several times, placed on ice and stored at -80°C. See 
Section 9.1 and Appendix D1. 
q. Concomitant medications: All prescription and over-the-counter medications that have been taken within 
30 days prior to the first dose of protocol therapy up to 30-day post-last dose will be recorded in the CRFs. 
See Section 5.7.1 for concomitant medication restrictions. 
r. 
Adverse events (AEs) experienced by participants will be collected and recorded from the pre-treatment 
Cycle 1 Day 1 safety assessments up to 30 days of the last dose of study medication. See Section 7.0 for 
reporting guidelines). AEs will be recorded by MD on C1D1, C1D15, C2D1, C2D15, and C3D1. AEs will be 
recorded by RN on C1D8 and C2D8.  
s. 
The period for collection, recording and reporting of AEs is extended for participant with ongoing adverse 
events requiring expeditious reporting (see Section 7.3).  
t. 
Ribociclib pill diary: The participant will be given a pill diary (see Appendix E) which will be reviewed for 
adherence. It will not be a deviation if the diary it not returned prior to initiation of the subsequent cycle.  
u. Geriatric Assessment (GA) to be administered either via paper (from PDF supplement) or tablet data entry. 
Duration for completion is usually between 20 and 40 minutes. Appendix F details the GA content, but is 
not for administration.  


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v. 
GA to be administered within seven days of Cycle 1 Day 1 protocol therapy. GA will not be administered for 
Cycle 2 Day 1.  
w. GA and CT to be performed prior to Cycle 3 (± 7 days), then every 3 cycles (± 7 days).  
x. 
Was It Worth It (WIWI) Questionnaire (See Appendix G for content only but not for administration, a 
separate PDF can be requested from the lead study team) and Overall Treatment Utility (OTU) 
Questionnaire (See Appendix H). 
y. 
Imaging to be performed within 28 days prior to enrollment.  
z. 
Post-baseline radionucleotide imaging to be performed only as clinically indicated or to confirm complete 
response.  
aa. CT of chest, abdomen, pelvis, any clinically indicated sites of disease, and of bone lesions.  
bb. Confirmatory scans following documentation of progression or response will not be required; 
progression/response will be determined based on results of the single time point. See Section 11.0. 
cc. Refer to Section 6.2 for dose modification/ dose delay guidelines.  
dd. Medical chart review for disease progression/response will also occur until progression or the initiation of 
a new therapy at least twice annually or as requested by the lead study team. Post-study new therapy 
regimens will be collected. 
ee. Survival analysis will be conducted by the site and/or by the lead study coordinator at least annually or as 
requested by the lead study team. All patients will be followed for survival information. The following will 
be collected: the participant's first and last name, middle initial, social security number, date of birth, and 
gender. The investigators will utilize the Social Security Death Index and the National Death Index to 
establish survival status. 
ff. ECG to be initiated at baseline mid-cycle of cycle 1 and beginning of cycle 2. Based in observed QT 
prolongation during treatment, ribociclib may require dose interruption, reduction or discontinuation.   
gg. Every 4th cycle. 
hh. Off Tx questionnaires to be completed within 30 days of date patient is taken off treatment or before the 
patient begins a new treatment, whichever occurs first.  
 


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12.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new updated international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee version 1.1.[26]  Per 
the new RECIST criteria, as disease response is not the primary endpoint of this trial, confirmatory scans 
following documentation of progression or response will not be required. Rather, progression/response 
will be determined based on results of the single scan. 
12.1 Definitions 
Evaluable for toxicity:   
All patients will be evaluable for toxicity from the time of their first treatment with ribociclib. 
Evaluable for objective response:  
Only those patients who have measurable disease present at baseline, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated below.  (Note:  Patients 
who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
12.2 Disease Parameters 
Measurable disease:   
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as >10mm with conventional techniques (CT, MRI, or caliper 
measurement) and as >20mm by chest X-ray (if clearly defined and surrounded by aerated lung.) Lymph 
nodes greater than 10mm on short axis are considered measureable as well. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease:   
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm by chest X-ray or 
<10 mm using CT, MRI or caliper measurement), are considered non-measurable disease.  
Organomegaly, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI) are all 
non-measurable. 
Bone-Only Disease:  
No distant metastases other than in bone.  
Target lesions:   
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline. Lymph 
nodes less than 15mm in the short axis cannot be used as target lesions.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 


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Non-target lesions:   
All other lesions (or sites of disease) including any measurable lesions over and above the 10 target 
lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up.  
12.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 30 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the antitumor effect of 
a treatment. 
Clinical lesions:   
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:   
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  
These techniques should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral 
CT should be performed using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of 
the chest, abdomen, and pelvis.  Head and neck tumors and those of extremities usually require specific 
protocols such as CT head and neck or MRI brain. 
Ultrasound (US):  
When the primary endpoint of the study is objective response evaluation, US should not be used to 
measure tumor lesions.  It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might also be useful to confirm 
the complete disappearance of superficial lesions usually assessed by clinical examination. 
Endoscopy, Laparoscopy:   
The utilization of these techniques for objective tumor evaluation has not yet been fully and widely 
validated.  Their uses in this specific context require sophisticated equipment and a high level of 
expertise that may only be available in some centers.  Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference centers. However, 
such techniques may be useful to confirm complete pathological response when biopsies are obtained. 


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Tumor markers:   
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response.  
Cytology, Histology:  
These techniques can be used to differentiate between partial responses (PR) and complete responses 
(CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
12.4 Response Criteria 
12.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions. Lymph node CR is when 
the lymph node has decreased to less than 10mm in the 
short axis. 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started (including the baseline scan if 
that is the smallest), and at least a 5mm increase or the 
appearance of new lesions. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
 
 
 
 


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12.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level. 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Incomplete Response/Stable 
Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
However, unequivocal progression should not normally 
trump target disease status.  It must be representative of 
overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances. 
12.4.3 Evaluation of Overall Response and Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of measurement criteria on the results of a single timepoint. Response will be determined 
by radiologist.  
Table 12.4.3: Assessment of Best Overall Response Using Target and Non-Target Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document the objective progression even after discontinuation of treatment. 
12.5. Duration of Response  
All response measurements will be from start of treatment to the defined endpoint. 
13 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This study will be an open label, single arm, Phase IIA safety and tolerability study to describe the 
toxicity profile of ribociclib in combination with an aromatase inhibitor in patients aged 70 and older 
with hormone receptor positive metastatic breast cancer. We plan to study 40 evaluable participants.  
Participants that receive one dose of treatment will be considered evaluable, anyone that does not 
receive treatment will be replaced. We plant to stratify based on age such that at least 20 participants 
are aged 75 years or older.  There will be one interim analysis after 20 participants have completed one 
cycle of the drug. 
13.1.1 Primary Objective:  
To estimate the safety and tolerability of the combination of ribociclib and an aromatase inhibitor in 
adults age 70 or older with hormone receptor positive metastatic breast cancer 
13.1.2 Secondary Objectives: 
1. To describe the full toxicity profile including all grades 
2. To estimate the rate of worst grades of myelosuppression (neutropenia, leukopenia, 
thrombocytopenia, and anemia), neutropenic fever, GI side effects (nausea, diarrhea, decreased 
appetite, vomiting, stomatitis), fatigue, neuropathy, and thromboembolism 
3. To describe rates of dose reductions, dose holds, and hospitalizations  
4. To estimate objective response rate and clinical benefit rate as defined by modified RECIST (1.1) 
criteria 
5. To estimate median progression-free and overall survival  
6. To determine average plasma steady-state ribociclib Ctrough concentrations in patients over the 
age of 70 years 
 
13.1.3 Exploratory Objectives 
7. To estimate the rate of adherence to ribociclib 
8. To explore factors other than chronologic age that can affect toxicity rates as identified using a 
cancer-specific geriatric assessment 
9. To describe the results of the Was It Worth It (WIWI) and Overall Treatment Utility (OTU) 
Questionnaires 


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13.1.4 Primary Endpoints 
The primary endpoint is the incidence of grade 2 and above toxicities attributed (possible or above) to 
ribociclib. 
13.1.5 Secondary Endpoints 
1. All toxicities associated with the combinations as measured by NCI CTCAE v.4.0 
2. Dose reductions  
3. Dose holds  
4. Hospitalizations 
5. Response as determined by RECIST criteria 
6. Progression free survival defined as the time from start of treatment to the first of the 
following disease events:  local/regional/distant recurrence, invasive contralateral breast 
disease, second primary or death due to any cause 
7. Overall survival defined as the time from start of treatment to death due to any cause 
8. To determine average plasma steady-state ribociclib Ctrough concentrations in patients over 
the age of 70 years 
 
 13.1.6     Exploratory Endpoints 
 
1. Adherent to ribociclib will be defined as taking 19/21 pills  (90%)  of their  dose of ribociclib. 
 
2. Toxicity Risk Score 
 
3. WIWI response 
 
4. OTU response 
 
 
13.2 Sample Size and Accrual Rate  
Given a sample size of 40 evaluable subjects the half-width of the 95% confidence limits for the rate of 
grade 2 or higher toxicities will be less than or equal to 0.16. For example if we saw a toxicity rate of 0.5 
(20 subjects/40) the 95% lower and upper confidence limits would be 0.34 and 0.66, respectively.  
Further a sample size of 40 will allow us to see a toxicity with a true rate equal to 0.05 in 87 out of 100 
trials.  
13.3 Interim Analyses  
After approximately 20 subjects have completed at least one full cycle of treatment, the study team will 
review the data (including the toxicity profile, rates of dose reduction, holds and hospitalizations) and 
assess if the dose being studied is too high, requiring too many patients, in the opinion of the team, to 
experience a dose reduction.  If so, a reduction of the dose will be considered, otherwise the study will 
continue to completion at the planned dose.  


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13.4 Analysis Plan 
Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for 1) 
grade 2 or higher other toxicities, and 2) dose reductions, dose holds and hospitalizations, and 3) 
objective response rate (CR+PR) and clinical benefit rate (CR+PR+SD) as determined by RECIST.  
Progression free survival and overall survival will be estimated using the product limit method of Kaplan 
and Meier/ Cox proportional hazards methods.  
Tables will be created to summarize the toxicities and side effects by age strata, course, organ, severity 
and attribution for all patients.  Descriptive statistics will be provided for study participant 
demographics, number of drug cycles completed, responses from the WIWI Questionnaire and the OTU 
by age strata and overall.  General linear models and graphical methods will be used to explore factors 
as identified by a cancer-specific geriatric assessment that may be predictive of toxicity/dose reduction, 
dose holds or hospitalizations. 
The relationship between plasma trough and percent drop in neutrophil and platelet counts will be 
analyzed used linear models methods. 
 
14. DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
14.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are relevant to 
the clinical trial.  The Site Investigator or their designee will prepare and maintain adequate and 
accurate source documents.  These documents are designed to record all observations and other 
pertinent data for each patient enrolled in this clinical trial.  Source documents must be adequate to 
reconstruct all data transcribed onto the case report forms. 
14.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture system. 
Medidata RAVE is a web based, password protected system that is fully compliant with global regulatory 
requirements, including 21CRF Part 11 compliant.  
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF).   
14.3 Case Report Forms/Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to 
that visit is available.  
The investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy 
by the investigator. All case report forms must be completed by designated study personnel.  The 
completed case report forms must be reviewed, signed and dated by the Site Investigator or designee in 
a timely fashion. 


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All data will be collected using the electronic data collection system described in Section 14.2, and will 
be submitted according to the timelines indicated in Table 14.3. 
Table 14.3: Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Within 14 calendar days of the study visit 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications, chemistry, hematology etc.) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of data collection 
 
14.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. Additional information regarding required documents is 
provided in the DCC Operations Manual, a supplement to this protocol. 
 
15. ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
15.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the 
following considerations: 
Ⴠ US Code of Federal Regulations (CFR) governing clinical study conduct 
o Title 21 Part 11 – Electronic Records; Electronic Signatures  
o Title 21 Part 50 – Protection of Human Subjects  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
o Title 21 Part 56 – Institutional Review Boards  


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o Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
o Title 21 Part 312 – Investigational New Drug Application  
o Title 45 Part 46 – Protection of Human Subjects  
Ⴠ US Federal legislation, including but not limited to 
o Health Insurance Portability and Accountability Act of 1996  
o Section 801 of the Food and Drug Administration Amendments Act   
Ⴠ Applicable state and local laws. For research occurring in California, this includes but is not limited 
to State of California Health and Safety Code, Title 17 
Ⴠ Applicable institutional research policies and procedures  
15.3 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17, must review and approve this protocol and the informed consent form prior to initiation of the 
study. All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’s written unconditional approval of the study protocol and the informed consent document will be 
in the possession of the Investigator. The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional 
adverse experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, 
as developed and provided by the Study PI, will require review and approval by the IRB before the 
changes are implemented in the study.  The protocol and consent will be reviewed and approved by the 
COH IRB before submission to a participating site IRB. 
15.4 Informed Consent 
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and 
the HIPAA research authorization form.  Research subjects will be informed that they may withdraw 
from the study at any time and for any reason without prejudice, including as applicable, their current or 
future care or employment at their hospital or any relationship they have with their hospital.   
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative before study participation.  The method of obtaining 
and documenting the informed consent and the contents of the consent must comply with the ICH-GCP 
and all applicable regulatory requirements. 


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Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB/IEC and signed and dated by the patient or the patient’s 
legally authorized representative at the time of consent.  A copy of the signed informed consent will be 
given to the patient or patient’s legally authorized representative.  The original signed consent must be 
maintained by the Site Investigator and available for inspection sponsor designated representatives, or 
regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation.  
15.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study 
procedures (safety visit) and chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart 
review and survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form.  Once the PI is notified of this 
withdrawal of informed consent, the research specimens will not be used in any research. At that time, 
any of the existing specimens will be destroyed. 
15.6 Special and Vulnerable Populations  
15.6.1 Inclusion of Women and Minorities 
The study is open to anyone regardless of gender or ethnicity; however, we anticipate that the majority 
of participants will be female based on the demographics of breast cancer.  Efforts will be made to 
extend the accrual to a representative population in term of ethnicity and race.   
15.6.2 Exclusion of Pediatric Patients 
Pediatric recipients (children <18 years old of age) are excluded from this study because this study is 
being conducted in the geriatric population.   
15.6.3 Exclusion of HIV Positive Individuals 
Persons with HIV are not expressly excluded from this study. 
15.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  


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Adults lacking capacity to consent are not excluded from participation. This study does not pose 
additional risks for adults lacking capacity than for the general population.  In such instances, informed 
consent will be sought and documented from the prospective participant’s legally authorized 
representative in agreement with institutional policies and local IRB approval. 
15.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents.  This confidentiality is extended to cover testing of biological samples in addition to any 
study information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, and the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out 
in accordance with the  Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements.   All data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned patient number. 
Source documents provided to coordinating center for the purpose of auditing or monitoring will be de-
identified and labeled with the study number, subject ID, and patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations. 
15.8 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 


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15.9 Financial Obligations, Compensation, and Reimbursement of Participants 
Neither the research participant nor the insurance carrier will be responsible for the research 
procedures related to this study. 
The standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The research participant will be 
responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as 
set forth by the insurance carrier.  The research participant and/or the insurance carrier will be billed for 
the costs of treatment and diagnostic procedures in the same way as if the research participant were 
not in a research study.   
In the event of physical injury to a research participant resulting from research procedures, appropriate 
medical treatment will be available at City of Hope to the injured research participant. There are no 
plans for City of Hope to provide financial compensation in the event of physical injury to a research 
participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
15.10 Publication/Data Sharing  
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of Dr. Mina Sedrak and Dr. Arti Hurria. Any 
investigator involved with this study is obligated to provide City of Hope with complete test results and 
all data derived from the study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among City of Hope and 
participating institutions. The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier.  
 
 


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16. REFERENCES 
1. 
Hurria, A., et al., Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference 
recommendations. J Clin Oncol, 2014. 32(24): p. 2587-94. 
2. 
Hurria, A., M. Naylor, and H.J. Cohen, Improving the quality of cancer care in an aging population: 
recommendations from an IOM report. JAMA, 2013. 310(17): p. 1795-6. 
3. 
Hortobagyi G., et al., Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J 
Med, 2017; 375: 1738-1748 
4. 
Sawhney, R., M. Sehl, and A. Naeim, Physiologic aspects of aging: impact on cancer management and 
decision making, part I. Cancer J, 2005. 11(6): p. 449-460. 
5. 
Sehl, M., R. Sawhney, and A. Naeim, Physiologic aspects of aging: impact on cancer management and 
decision making, part II. Cancer J, 2005. 11(6): p. 461-473. 
6. 
Duthie, E., Comprehensive Geriatric Oncology. 2004: Taylor and Francis. 
7. 
Yuen, G., Altered pharmacokinetics in the elderly. Clin Geratr Med, 1990. 6(2): p. 257-267. 
8. 
Baker, S. and L. Grochow, Pharmacology of chemotherapy in the older person. Clin Geratr Med, 1997. 
13(1): p. 169-183. 
9. 
Kastrissios, H. and T. Blaschke, Medication compliance as a feature in drug development. Annu Rev 
Pharmacol Toxicol, 1997. 37: p. 451-475. 
10. 
Vestal, R.E., Aging and pharmacology. Cancer, 1997. 80(7): p. 1302-1310. 
11. 
Baker, S., et al., Factors affecting cytochrome P-450 activity in cancer patients. Clin Cancer Res, 2004. 
10(24): p. 8341-8350. 
12. 
Sotaniemi, E., et al., Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 
subjects with equal histopathological conditions. Clin Pharmacol Ther, 1997. 61(3): p. 331-339. 
13. 
Brenner, B.M., T.W. Meyer, and T.H. Hostetter, Dietary protein intake and the progressive nature of 
kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of 
progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Eng J Med, 1982. 
307: p. 652-659. 
14. 
Lichtman, S.M., et al., International Society of Geriatric Oncology (SIOG) recommendations for the 
adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer, 2007. 43(1): p. 14-34. 
15. 
Hurria, A. and S.M. Lichtman, Pharmacokinetics of Chemotherapy in the Older Patient. Cancer Control, 
2007. 14(1): p. 32-43. 
16. 
Balducci, L. and M. Corcoran, Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin 
N Am, 2000. 14: p. 193-212. 
17. 
Maione, P., et al., Pretreatment quality of life and functional status assessment significantly predict 
survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic 
analysis of the multicenter Italian lung cancer study in the elderly study. J Clin Oncol, 2005. 23(28): p. 
6865-6872. 
18. 
Freyer, G., et al., Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in 
elderly patients with advanced ovarian carcinoma: a GINECO study. Ann Oncol, 2005. 16(11): p. 1795-
1800. 
19. 
Repetto, L., et al., Comprehensive geriatric assessment adds information to Eastern Cooperative Group 
performance status in elderly cancer patients; an Italian Group for Geriatric Oncology Study. J Clin Oncol, 
2002. 20(2): p. 494-502. 
20. 
Rao, A., et al., Geriatric evaluation and management units in the care of the frail elderly patient. J Gerontol 
A Biol Sci Med Sci, 2005. 60(6): p. 798-803. 
21. 
Extermann, M., et al., Use of coprehensive geriatric assessment in older cancer patients: recommendation 
from the task force on CGA of the International Society of Geriatric Oncology. Crit Rev Oncol Hematol, 
2005. 55(3): p. 241-252. 


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22. 
Giacinti, C. and A. Giordano, RB and cell cycle progression. Oncogene, 2006. 25(38): p. 5220-7. 
23. 
Crown, J., et al., Efficacy and safety of first-line Palbociclib plus letrozole compared with letrozole alone in 
patients aged >= 65 years with estrogen receptor-positive, HER2-negative advanced breast cancer: A 
subgroup analysis by age of the PALOMA-1/TRIO-18 trial. Journal of Clinical Oncology, 2015. 33(15). 
24.  
Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson 
JR, Crystal AS, Parasuraman S, Shapiro GI. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor 
Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2016 Dec 
1;22(23):5696-5705 
25. 
Kala A, Patel YT, Davis A, Stewart CF. Development and validation of LC-MS/MS methods for the 
measurement of ribociclib, a CDK4/6 inhibitor, in mouse plasma and Ringer's solution and its application 
to a cerebral microdialysis study. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jul 1;1057:110-117. 
26. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). European Journal of Cancer, 2009. 45(2): p. 228-247. 
27. 
Hurria, A., et al., Developing a cancer-specific geriatric assessment. Cancer, 2005. 104(9): p. 1998-2005. 
28. 
Fillenbaum, G. G. and M. A. Smyer (1981). "The development, validity, and reliability of the OARS 
multidimensional functional assessment questionnaire." J Gerontol 36(4): 428-34. Medline ID: 7252074. 
29. 
Stewart, A. L. and J. E. Ware, Jr., Eds. (1992). Measuring functioning and well-being: the medical outcomes 
study approach. Durham, Duke University Press. ISBN 0822312123. 
30. 
Loprinzi, C. L., J. A. Laurie, et al. (1994). "Prospective evaluation of prognostic variables from patient-
completed questionnaires. North Central Cancer Treatment Group." J Clin Oncol 12(3): 601-7. Medline ID: 
8120560. 
31. 
Sherbourne CD, Steward AL: The MOS social support survey. Soc Sci Med 32: 705-714, 1991. 
32. 
Koenig, H., G. R. Parkerson, and K. G. Meador (1997). “Religion index for psychiatric research.” Am J 
Psychiatry 154(6): 885-6. Medline ID: 9167530. 
33. 
Locke, D. E., P. A. Decker, et al. (2007). “Validation of single-item linear analog scale assessment of quality 
of life in neuro-oncology patients.” J Pain Symptom Manage 34(6): 628-38. Medline ID: 17703910. 
34. 
Karnofsky, D. A. and J. H. Burchenal (1949). The clinical evaluation of chemotherapeutic agents in cancer. 
In Evaluation of Chemotherapeutic Agents. C. M. MacLeod (ed.). New York, Columbia University Press.  
pps. 199-205. . 
35. 
Podsiadlo, D. and S. Richardson (1991). "The timed "Up & Go": a test of basic functional mobility for frail 
elderly persons." J Am Geriatr Soc 39(2): 142-8. Medline ID: 1991946. 
36. 
Katzman, R., T. Brown, et al. (1983). "Validation of a short Orientation-Memory-Concentration Test of 
cognitive impairment." Am J Psychiatry 140(6): 734-9. Medline ID: 6846631. 
 
 
 
 


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APPENDIX A: KARNOFSKY PERFORMANCE STATUS 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 
 


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APPENDIX B: PROHIBITED MEDICATIONS / MEDICATIONS TO BE USED WITH CAUTION 
List of prohibited medications during study drug treatment 
 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors  
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, darunavir/ritonavir, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, 
troleandomycinvoriconazole 
Strong CYP3A4/5 inducers 
carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, 
St. John's wort (hypericum perforatum)2,3 
CYP3A4/5 substrates with NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus 
Medications with a known risk for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, 
azithromycin, chloroquine, chlorpromazine, cilostazol, 
ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, gatifloxacine, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, methadone, moxifloxacin, 
ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sulpiride, sultopride, 
terlipressin, terodiline, thioridazine, vandetanib 
Herbal preparations/ medications 
Herbal preparations/medications known as strong inducers 
or inhibitors of CYP3A4/5 or those with a known risk of QT 
prolongation are prohibited throughout the study. These 
herbal medications include, but are not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, 
and ginseng. Patients should stop using these herbal 
medications 7 days prior to first dose of study drug. 
Other investigational and antineoplastic therapies 
Other investigational therapies must not be used while the 
patient is on the study. Anticancer therapy (chemotherapy, 
all SERMS (including raloxifene), biologic or radiation 
therapy, and surgery) other than the study treatments must 
not be given to patients while the patient is on the study 
medication. If such agents are required for a patient then 
the patient must be discontinued study drug. 


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1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure 
levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de 
Pointes) or drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective 
concentrations in the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list 
for the most updated list. 
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of 
ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, 
or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers. 
 
List of medications to be used with caution during study drug treatment  
Category 
Drug Name  
Moderate CYP3A4/5 inhibitors  
Aprepitant, amprenavir, asafoetida resin (Ferula 
asafoetida) cimetidine, crizotinib, diltiazem, 
faldaprevir, imatinib, isavuconazole, netupitant, 
nilotinib, tofisopam, Schisandra sphenanthera 
(nan wu wei zi), verapamil 
Moderate CYP3A4/5 inducers 
Bosentan, dabrafenib, efavirenz, etravirine, 
genistein,lopinavir5, modafinil, nafcillin, 
telotristat 
Sensitive CYP3A4/5 substrates1 
Alpha-dihydroergocryptine, aprepitant, 
atorvastatin, avanafil, bosutinib,brotizolam, 
budesonide, buspirone, cobimetinib, darifenacin, 
dasatininb, ebastine, eletriptan, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, 
ibrutnib, isavuconazole, ivabradine, ivacaftor, , 
levomethadyl (LAAM), lomitapide, lovastatin, 
lumefantrine, lurasidone, maraviroc, midazolam, 
midostaurin, naloxegol, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, sildenafil, 
simeprevir, simvastatin, ticagrelor, tilidine, 
tolvaptan, triazolam, ulipristal, vardenafil, 
venetoclax, vicriviroc, voclosporin 
BSEP inhibitors 
 
 
Alectinib, atorvastatin, bromocriptine, 
candesartan, clobetasol, clofaziminie, dabigatran, 
dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine,rifamycin, 
simeprevir, telmisartan,timcodar, troglitazone, 


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valinomycin, velpatasvir 
Medications that carry a possible risk for QT 
prolongation2 
 Alfuzosin, apomorphine, aripiprazole, 
artenimol+piperaquine , asenapine, atomoxetine, 
bedaquiline, bendamustine, bortezomib, 
bosutinib, buprenorphine, cabozantinib, 
capecitabine, ceritinib, clomipramine, 
crizotinib,clozapine, cyamemazine 
(cyamepromazine), dabrafenib, dasatinib, 
degarilix, delamanid, desipramine, 
dexmedetomidine, dolasetron, efavirenz, 
eliglustat, epirubicin, eribulin mesylate, 
ezogabine(retigabine), famotidine, felbamate, 
fingolimod, flupentixol, gemifloxacin, granisetron, 
hydrocodone-ER, iloperidone, imipramine 
(melipramine), isradipine, ketanserin, lapatinib, 
lenvatinib, leuprolide, lithium, melperone, 
midostaurin, mifepristone, mirabegron, 
mirtazapine, moexipril/HCTZ, necitumumab, 
nicardipine, nilotinib, norfloxacin, nortriptyline, 
nusinersen, ofloxacin, osimertinib, oxytocin, 
paliperidone, palonosetron, panabinostat, 
pasireotide, pazopanib, perflutren lipid 
microspheres, perphenazine, pilsicainide, 
pimavanserin, pipamperone, promethazine, 
prothipendyl, rilpivirine, risperidone, romidepsin, 
sertindole, sorafenib, sunitinib, tamoxifen, 
tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene,trimipramine, tropisetron, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, 
ganciclovir, glycopyrronium, metformin, pindolol, 
plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
Amantadine, 6-beta-hydroxycortisol, carboplatin, 
cisplatin, cephalexin, cephradine, ipratropium, 
lamivudine, linagliptin, metformin, oxyplatin, 
oxybutynin, phenformin, picoplatin, pilsicainide, 
pindolol, ranitidine, sorafenib, tropisetron, 
trospium, umeclidinium,, and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, 
hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, 
irinotecan, ethinyl estradiol, simvastatin, 
sulfasalazine, sofosbuvir, tenofovir, topotecan, 
venetoclax 


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1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor. 
2 The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-providers/drug-list for 
the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity. 
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir is prohibited when combined with ritonavir (see Table 14-1) 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: REGISTRATION COVERSHEET 
COH IRB 17471: A Phase IIa Trial Assessing the Tolerability of Ribociclib in Combination with an Aromatase 
Inhibitor or in Patients Aged 70 and Older with Hormone Receptor Positive Metastatic Breast Cancer. 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-256-4673 x 83968  
Email:  DCC@coh.org (use #secure# in subject line) 
Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 
Hispanic 
Codes: 
 
Caucasian 
 
Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 
Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of payment  
(no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other________________
___________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
Reason for Failing to Initiate Protocol Therapy: 


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APPENDIX D-1: BLOOD BANKING COLLECTION FORM (OPTIONAL) 
Patient MRN (COH Only): 
Patient Initials (F, M, L): 
Institution:  
Sample Collection: 
1. A 10 mL baseline sample should be collected from consenting patients.  
2. Label each sample with the participants’ initials, study ID number, date of collection, and sample 
collection time. 
3. A green top heparin OR a lavender top K+EDTA tube should be used for collecting the sample. 
4. After collection, gently invert the tube several times (at least 4 times) and place on ice. 
5. For COH-Duarte Campus:  
Ⴠ Samples placed on ice may be taken immediately to CICSL in Shapiro (room 1042) on the 
day of collection; arrangements should be made ahead of time with Vivi Tran (email: 
vtran@coh.org  or ext. 62634). Samples will then be frozen at -60°C to -90°C at CICSL. 
 
6. For COH Community Practices:  
Ⴠ Store samples in a -60°C to -90°C freezer. Frozen -60°C to -90°C samples should be taken 
on dry ice to the Clinical Immunobiology Correlative Studies Laboratory (CICSL) in 
Shapiro (room 1042).  
 
7. For Non-COH sites:  
Ⴠ Store in a -60°C to -90°C freezer until shipment. Refer to Appendix D-2 for shipping 
details. 
 
Sample # 
Schedule 
Collected 
Volume 
Tube Type Used 
(Select One) 
Time of Collection 
Date of Collection 
1 
Day 1: Prior to 
protocol 
therapy 
_____ mL 
 Sodium heparin 
 Lithium heparin 
 K2EDTA 
 K3EDTA 
____:____ AM/ PM 
____/____/____ 
 
 
A copy of this form should be maintained by the institution and a copy should accompany the sample 
to CICSL. 
CRA/Study Coordinator:   
Contact Number: 
CRA/Study Coordinator Signature:   
Date: 
 


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APPENDIX D-2: BLOOD BANKING SHIPPING DETAILS- NON-COH SITES 
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety, Biosafety Branch site. 
 
1. Samples should be shipped at the request of the lead COH study team.  
2. If applicable, samples should be batched if multiple participants are recruited at the site. 
3. Ship samples on Monday to Thursday via overnight FedEx on dry ice. There should be enough 
dry ice to last for at least 72 hours in the shipment. 
4. Do not ship on either a Friday, weekend or a holiday. 
5. Sites should request pre-paid shipping labels from Vani Katheria (vkatheria@coh.org). 
6. Prior to shipment: 
a. Send pending shipping notifications to Vivi Tran (vtran@coh.org) and copy Vani Katheria 
(vkatheria@coh.org). 
7. On the day of shipment:  
a. Include a copy of Appendix D-1 with the shipment. 
b. Ship to the below address: 
City of Hope 
Attn: Vivi Tran,  
CICSL Core Laboratory,  
Shapiro Bldg, Rm 1044,  
Beckman Research Institute of the City of Hope 
1500 E. Duarte Road  
Duarte, CA 91010-3000. 
Tel: 626-256-4673 ext 62634.  
Email: vtran@coh.org 
 
c. Email the FedEx tracking number to Vivi Tran (vtran@coh.org) and copy Vani Katheria 
(vkatheria@coh.org). 
 
 
 
 
 


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APPENDIX E: RIBOCICLIB PILL DIARY 
Study Accession #: 
Patient Initials (F, M, L): 
Institution:  
Cycle #:  
Ribociclib should be taken once every day for 21 days by mouth. Ribociclib should be taken at 
approximately the same time each day. If you miss or vomit a dose do not make up the missed/ 
vomited dose that day; instead take the ribociclib dose the next day at the regularly scheduled time. 
Ribociclib pills should be swallowed whole.  
 
Record all side effects, missed ribociclib doses, supplements and other medication you are taking in 
the Pill Diary.  
 
Bring the study drug bottle to every clinic visit to show _________________________________. 
At the end of each cycle, please return this diary and study drug bottle 
to____________________________________________________________. 
 
How to fill the Pill Diary (Example Only) 
To be filled in by the institution 
Cycle #: 1                            Cycle Start Date: 9/7/2016      
           
 Ribociclib Dose: 125 mg/ day      Take: 1 pill per day                          
 
To be filled in by the patient 
# of pills 
taken 
Comments 
Side effects, supplements, other medication, missed 
doses 
Day Date 
Time 
1 
9/7/16 
8:20     am/pm 
1 
Nausea. Muscle pain. 
2 
9/8/16 
8:20     am/pm 
1 
Vomited the pill but did not take an extra pill today. 
 
 
 


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Cycle #: ________   Cycle Start Date: ____________     
     
Ribociclib Dose: _______ mg/ day            Take: ______ pill per day                   
 
Week 1 
# of 
pills 
taken 
Comments 
Side effects, supplements, other medication, missed 
doses 
Day 
Date 
Time 
1 
 
___:___ am/pm 
 
 
2 
 
___:___ am/pm 
 
 
3 
 
___:___ am/pm 
 
 
4 
 
___:___ am/pm 
 
 
5 
 
___:___ am/pm 
 
 
6 
 
___:___ am/pm 
 
 
7 
 
___:___ am/pm 
 
 
 
Ribociclib Dose: _______ mg/ day            Take: 1 pill per day                    
 
Week 2 
# of 
pills 
taken 
Comments 
Side effects, supplements, other medication, missed 
doses 
Day 
Date 
Time 
8 
 
___:___ am/pm 
 
 
9 
 
___:___ am/pm 
 
 
10 
 
___:___ am/pm 
 
 
11 
 
___:___ am/pm 
 
 


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12 
 
___:___ am/pm 
 
 
13 
 
___:___ am/pm 
 
 
14 
 
___:___ am/pm 
 
 
 
 
Ribociclib Dose: _______ mg/ day            Take: 1 pill per day                    
 
Week 3 
# of 
pills 
taken 
Comments 
Side effects, supplements, other medication, missed 
doses 
Day 
Date 
Time 
15 
 
___:___ am/pm 
 
 
16 
 
___:___ am/pm 
 
 
17 
 
___:___ am/pm 
 
 
18 
 
___:___ am/pm 
 
 
19 
 
___:___ am/pm 
 
 
20 
 
___:___ am/pm 
 
 
21 
 
___:___ am/pm 
 
 
 
 
Rest Week                    
 
Week 4 
# of 
pills 
taken 
Comments 
Side effects, supplements, other medication, missed 
doses 
Day 
Date 
Time 
22 
 
Do not take Ribociclib this 
week.  
 
23 
 
 
24 
 
 


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25 
 
 
26 
 
 
27 
 
 
28 
 
 
 
 
Participant Signature (please sign at the end of the cycle when submitting your diary) 
 
_____________________________________________________________   
Date: 
 
____/______/_____ 
 
 
Nurse Signature  
 
_____________________________________________________________   
Date: 
 
____/______/_____ 


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APPENDIX F-2: GERIATRIC ASSESSMENT SURVEY  
Completed via touchscreen computer survey (preferable) or paper assessment forms. A PDF version 
formatted to collect information will be provided to participating sites.[27]  
 
Patient Questionnaire 
Responsible person name (Physician, Nurse, or CRA) ______________________________________________ 
Assessment Period (as applicable to this study) □ Pre-treatment   □□ Cycle #   □ End of Treatment 
 
Patient Instructions:  If you are unable to complete the questionnaire, a member of your health care team will assist you. 
Please do not have a family member complete the questionnaire for you. 
□ Mark box with an “X”, if form was not completed at specified timepoint and specify reason:  
   (Mark one with an X.) 
□ Patient refused  □ Patient withdrew consent □ Not done 
 
 
 
□ Other, specify ______________________________________________________ 
 
 
 
 
 
(For assessment date, record approximate date form was to be completed.) 
A. BACKGROUND INFORMATION 
1. What is the highest grade you finished in school? (Mark one with an X.) 
□ Less than 9 years of school 
□ Some college or technical school 
□ Post graduate education, but 
no higher degree 
□ Some high school (9-11 years) 
□ College degree graduate 
□ High school graduate, or GED 
□ Graduate degree 
□ I prefer not to answer 
 
 
 
2. What is your marital status? (Mark one with an X.) 
□ Married 
□ Divorced 
□ I prefer not to answer 
□ Domestic partnership 
□ Separated 
 
□ Widowed 
□ Never married 
 
 
3. With whom do you live? (Mark all that apply with an X.) 
□ Spouse / partner 
 
 
□ Parents/ parents-in-law 
□ Girlfriend / boyfriend 
 
 
□ Live alone 
□ Children aged 18 years or younger 
□ Others, specify: ________________ 
□ Children aged 18 years or older  
□ Other relative, specify: ________________ 
 
4. What is your current employment status?  (Mark one with an X.) 
□ Employed ≥ 32 hours per week 
□ Unemployed 
□ Employed ≤ 32 hours per week 
□ Retired 
□ Homemaker 
 
 
□ Student full-time 
□ Disabled 
 
 
□ Student part-time 
□ On medical leave 
 
□ Other, specify: ________________ 


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5. 
How old are you? 
__ years old 
6.   What is your race? 
□ White  
 
 
□ Asian 
□ Black or African American 
□ Native Hawaiian or Other Pacific Islander 
□ Native Indian or Alaskan Native □ Unknown 
7.  What is your ethnicity? 
□ Hispanic or Latino 
 
□ Non-Hispanic  
□ Unknown 
B. DAILY ACTIVITIES* 
PATIENT INSTRUCTIONS: Indicate your response by marking an X in one box per question. 
1. 
Can you use the telephone… 
□ Without help, including looking up and dialing 
□ With some help (can answer phone or dial operator in an emergency, but need a special phone or help in getting the 
phone number or dialing) 
□ Completely unable to use the telephone 
 
2. 
Can you get to places out of walking distance… 
□ Without help (can travel alone on busses, taxis, or drive your own car) 
□ With some help (need someone to help you or go with you when traveling) 
□ Completely unable to travel unless emergency arrangements are made for a specialized vehicle like an ambulance 
 
3. 
Can you go shopping for groceries or clothes (assuming you have transportation) … 
□ Without help (taking care of all shopping needs yourself, assuming you have transportation) 
□ With some help (need someone to go with you on all shopping trips) 
□ Completely unable to do any shopping 
 
4. 
Can you prepare your own meals… 
□ Without help (plan and cook full meals yourself) 
□ With some help (can prepare some things but unable to cook full meals yourself)  
□ Completely unable to prepare any meals 
 
5. 
Can you do your housework… 
□ Without help (can clean floors, etc.) 
□ With some help (can do light housework but need help with heavy work) 
□ Completely unable to do any housework 
 
6. 
Can you take your own medicines… 
□ Without help (in the right doses at the right time) 
□ With some help (able to take medicine if someone prepares it for you and/or reminds you to take it) 
□ Completely unable to take your medicines 
 
7. 
Can you handle your own money… 
□ Without help (write checks, pay bills, etc.) 
□ With some help (manage day-to-day buying but need help with managing your checkbook and paying your bills) 
□ Completely unable to handle money 
 
* OARS IADL [28] 
 
 
 


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C. PHYSICAL ACTIVITIES*  
1. 
The following items are activities you might do during a typical day. Does your health limit you in these activities?  (Mark 
an X in the box on each line that best reflects your situation.) 
 
Activities 
Limited  
a lot 
Limited  
a little 
Not limited  
at all 
a. 
Vigorous activities such as: running, lifting heavy objects, 
participating in strenuous sports 
□ 
□ 
□ 
b. 
Moderate activities such as: moving a table, pushing a vacuum 
cleaner, bowling, or playing golf 
□ 
□ 
□ 
c. 
Lifting or carrying groceries 
□ 
□ 
□ 
d. 
Climbing several flights of stairs 
□ 
□ 
□ 
e. 
Climbing one flight of stairs 
□ 
□ 
□ 
f. 
Bending, kneeling, or stooping 
□ 
□ 
□ 
g. 
Walking more than a mile 
□ 
□ 
□ 
h. 
Walking several blocks 
□ 
□ 
□ 
i. 
Walking one block 
□ 
□ 
□ 
j. 
Bathing or dressing yourself 
□ 
□ 
□ 
 
* MOS, Physical Functioning Scale [29] 
 
 
D. CURRENT HEALTH RATING* 
 
  Which one of the following phrases best describes you at this time? (Mark one with an X.) 
□ Normal, no complaints, no symptoms of disease 
□ Able to carry on normal activity, minor symptoms of disease 
□ Normal activity with effort, some symptoms of disease 
□ Care for self, unable to carry on normal activity or do active work 
□ Require occasional assistance but able to care for most of personal needs 
□ Require considerable assistance for personal care 
□ Disabled, require special care and assistance 
□ Severely disabled, require continuous nursing care 
 
* Patient KPS[30]  
 
E. FALLS 
How many times have you fallen in the last 6 months?  □□□ 
 
 
 


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F. YOUR HEALTH  
1. 
Your General Health* 
Patient Instructions: Do you have any of the following illnesses at the present time, and if so, how much does it interfere with 
your activities: Not at all, Somewhat or A Great Deal? (Mark an X in the box that best reflects your answer.)  
 
 
If you have this illness:  
How much does it interfere with your activities? 
Illness 
No 
Yes 
 
Not  
at all 
A little 
A great 
deal 
a. 
Other cancers or leukemia 
□ 
□ 
→ 
□ 
□ 
□ 
b. 
Arthritis or rheumatism 
□ 
□ 
→ 
□ 
□ 
□ 
c. 
Glaucoma 
□ 
□ 
→ 
□ 
□ 
□ 
d. 
Emphysema or chronic bronchitis 
□ 
□ 
→ 
□ 
□ 
□ 
e. 
High blood pressure 
□ 
□ 
→ 
□ 
□ 
□ 
f. 
Heart disease 
□ 
□ 
→ 
□ 
□ 
□ 
g. 
Circulation trouble in arms or legs 
□ 
□ 
→ 
□ 
□ 
□ 
h. 
Diabetes 
□ 
□ 
→ 
□ 
□ 
□ 
i. 
Stomach or intestinal disorders 
□ 
□ 
→ 
□ 
□ 
□ 
j. 
Osteoporosis 
□ 
□ 
→ 
□ 
□ 
□ 
k. 
Chronic liver or kidney disease 
□ 
□ 
→ 
□ 
□ 
□ 
l. 
Stroke 
□ 
□ 
→ 
□ 
□ 
□ 
m. Depression 
□ 
□ 
→ 
□ 
□ 
□ 
 
 
* OARS IADL[28]  
 
2. 
How is your eyesight (with glasses or contacts)?  (Mark one with an X.) 
□ Excellent  
□ Good 
 
□ Fair 
 
 
□ Poor 
 
 
□ Totally blind 
 
If fair, poor, or totally blind, how much does it interfere with your activities? 
 □ Not at all  
 
□ Somewhat 
 
□ A great deal 
 
3. 
How is your hearing (with a hearing aid, if needed)? (Mark one with an X.) 
□1 Excellent 


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□2 Good 
 
□3 Fair 
 
 
□4 Poor 
 
 
□5 Totally deaf 
 
If fair, poor, or totally deaf, how much does it interfere with your activities? 
 □ Not at all 
 
□ Somewhat 
 
□ A great deal 
 
4. 
Do you have any other physical problems or illnesses (other than listed in questions 1-4) at the present time that seriously 
affect your health? 
□ No 
 
□ Yes, specify:  
 
If yes, how much does this interfere with your activities?  (Mark one with an X.) 
 
 
□ Not at all 
 
□ Somewhat 
 
□ A great deal 
 
* OARS IADL[28]  
 
G. NUTRITIONAL STATUS 
1.  Have you lost weight involuntarily over the past 6 months?   
 
□ No 
 
□ Yes 
 
 
 
If yes, how much? 
 
 
 
□□□ pounds 
2.  What is your weight now? 
  
 
 □□□ pounds 
3. 
What was your weight 6 months ago? 
 
 □□□ pounds 
 
 
Notation for Study Build Team: If a medication form is being used for the main study, this medication form does not need to be 
included in the Patient Questionnaire.  
 
How many medications (either prescribed or over-the-counter), herbs, or vitamins do you currently take? 
____ 
 
Please list all prescribed or over-the-counter medicines, herbs, or vitamins you are currently taking (doses 
not necessary). 
 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 


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7. 
 
 
8. 
 
 
9. 
 
 
10. 
 
 
11. 
 
 
12. 
 
  
13.  
 
 
14. 
 
 
15. 
 
H. HEALTH QUESTIONNAIRE* 
INSTRUCTIONS: These questions are about how you have been feeling within the past month. Please mark an “X” in the box 
on each line that best reflects your situation. 
 
 
How much of the time during the past two 
weeks: 
All  
of the 
Time 
Most 
of the 
Time 
A Good Bit 
of the 
Time 
Some  
of the 
Time 
A Little 
of the 
Time 
None 
of the 
Time 
1. 
has your daily life been full of things that 
were interesting to you? 
□ 
□ 
□ 
□ 
□ 
□ 
2. 
did you feel depressed? 
□ 
□ 
□ 
□ 
□ 
□ 
3. 
have you felt loved and wanted? 
□ 
□ 
□ 
□ 
□ 
□ 
4. 
have you been a very nervous person? 
□ 
□ 
□ 
□ 
□ 
□ 
5. 
have you been in firm control of your 
behavior, thoughts, emotions, feelings? 
□ 
□ 
□ 
□ 
□ 
□ 
6. 
have you felt tense or high-strung? 
□ 
□ 
□ 
□ 
□ 
□ 
7. 
have you felt calm and peaceful? 
□ 
□ 
□ 
□ 
□ 
□ 
8. 
have you felt emotionally stable? 
□ 
□ 
□ 
□ 
□ 
□ 
9. 
have you felt downhearted and blue? 
□ 
□ 
□ 
□ 
□ 
□ 


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10. have you felt restless, fidgety, or 
impatient? 
□ 
□ 
□ 
□ 
□ 
□ 
11. have you been moody, or brooded about 
things? 
□ 
□ 
□ 
□ 
□ 
□ 
12. have you felt cheerful, light-hearted? 
□ 
□ 
□ 
□ 
□ 
□ 
13. have you been in low or very low spirits? 
□ 
□ 
□ 
□ 
□ 
□ 
14. were you a happy person? 
□ 
□ 
□ 
□ 
□ 
□ 
15. did you feel you had nothing to look 
forward to? 
□ 
□ 
□ 
□ 
□ 
□ 
16. have you felt so down in the dumps that 
nothing could cheer you up? 
□ 
□ 
□ 
□ 
□ 
□ 
17. have you been anxious or worried? 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
* MHI-17 [29]– Stewart, A.L. and Ware, J.E., 1992 
I. SOCIAL ACTIVITIES* 
1. 
During the past 4 weeks, how much time has your physical health or emotional problems interfered with your social 
activities (like visiting with friends, relatives, etc.)?  
□ All of the time 
□ Most of the time 
□ Some of the time 
□ A little of the time 
□ None of the time 
 
2. 
Compared to your usual level of social activity, has your social activity during the past 6 months decreased, stayed the 
same, or increased because of a change in your physical or emotional condition?   
□ Much less socially active than before 
□ Somewhat less socially active than before 
□ About as socially active as before 
□ Somewhat more socially active as before 
□ Much more socially active than before 
 
3. 
Compared to others your age, are your social activities more or less limited because of your physical health or emotional 
problems?  
□ Much more limited than others 
□ Somewhat more limited than others 
□ About the same as others 
□ Somewhat less limited than others 
□ Much less limited than others 
* MOS, Social Activities [29] 
J. SOCIAL SUPPORT* 
 
INSTRUCTIONS: People sometimes look to others for companionship, assistance or other types of support. How often is each 
of the following kinds of support available to you if you need it? (Mark an X in the box on each line that best reflects your 
situation.) 
 


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None  
of the 
Time 
A Little of 
the Time 
Some  
of the 
Time 
Most  
of the 
Time 
All  
of the 
Time 
1. 
Someone to help you if you were confined to bed. 
□ 
□ 
□ 
□ 
□ 
2. 
Someone you can count on to listen to you when you 
need to talk. 
□ 
□ 
□ 
□ 
□ 
3. 
Someone to give you good advice about a crisis. 
□ 
□ 
□ 
□ 
□ 
4. 
Someone to take you to the doctor if needed. 
□ 
□ 
□ 
□ 
□ 
5. 
Someone to give you information to help you understand 
a situation. 
□ 
□ 
□ 
□ 
□ 
6. 
Someone to confide in or talk to about yourself or your 
problem. 
□ 
□ 
□ 
□ 
□ 
7. 
Someone to prepare your meals if you were unable to do 
it yourself. 
□ 
□ 
□ 
□ 
□ 
8. 
Someone whose advice you really want. 
□ 
□ 
□ 
□ 
□ 
9. 
Someone to help you with daily chores if you were sick. 
□ 
□ 
□ 
□ 
□ 
10. Someone to share your most private worries and fears 
with. 
□ 
□ 
□ 
□ 
□ 
11. Someone to turn to for suggestions about how to deal 
with a personal problem. 
□ 
□ 
□ 
□ 
□ 
12. Someone who understands your problems. 
□ 
□ 
□ 
□ 
□ 
 
 
* MOS Social Support Survey [31] 
 
K.  SPIRITUALITY/RELIGION 
Directions: Please answer the following questions about your religious beliefs and/or involvement. (Please mark an “X” in 
the box on each line that best reflects your situation.) 
1. 
How often do you attend church, synagogue, or other religious meetings? 
 □ More than once per week 
□ Once a week 
□ A few times a month 
□ A few times a year 
□ Once a year or less 
□  Never 
 
2. 
How often do you spend time in private religious activities, such as prayer, meditation, or Bible study? 
□ More than once a day 
□ Daily 
□ Two or more times per week 
□ Once a week 
□ A few times a month 
□  Rarely or never 
 


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The following section contains 3 statements about religious belief or experience. Please mark the extent to which each 
statement is true or not true for you. 
 
3.  In my life, I experience the presence of the Divine (i.e., God).  
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 
 
4.    My religious beliefs are what really lie behind my whole approach to life. 
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 
 
5.   I tried hard to carry my religion over into all other dealings in my life. 
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 
 
*DUREL: Duke University ReligionIndex [32]– Koenig et al., 1997 
 
L.  YOUR FEELINGS* 
1.  Do you often feel sad or depressed?  
□ No 
□ Yes 
 
2.  How would you describe your level of anxiety, on average? Please circle the number (0-10) best reflecting your  
 
response to the following that describes your feelings during the past week, including today. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No anxiety  
 
 
 
 
 
 
 
 
Anxiety as bad as 
It can be 
*Mahoney et al., 1994; LASA [33] 
 
M.  QUESTIONS CONCERNING THE QUESTIONNAIRE 
1. 
Were there any questions difficult to understand?  
□ No     □ Yes 
If Yes, which questions were they? 
 
 
 
2. 
Was the time it took to answer all the questions too long, just right or too short? 
□ Too short  →  How long would you have liked the questionnaire to be?   □□ minutes 
□ Just right 
□ Too long →  How long would you have liked the questionnaire to be?   □□ minutes 
 
Which items would you remove? 
 
 
 
 
3. 
Did you find any of the questions upsetting? 
□ No     □ Yes 
 
If Yes, which questions were they? 
 
 
 


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Could you tell me why they were upsetting? 
 
 
 
 
 
4. 
Do you think the questionnaire left out any questions that were important to ask? 
 
 
 
 
 
Thank you for your participation. 
 
 


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APPENDIX F-2: GERIATRIC ASSESSMENT: HEALTHCARE PROFESSIONAL QUESTIONNAIRE  
Completed via touchscreen computer survey (preferable) or paper assessment forms. A PDF version 
formatted to collect information will be provided to participating sites.  
I. This form completed by: (Mark all that apply with an X.) 
Assessment Period (as applicable to this study) 
□ Physician 
    □ Nurse 
   □ CRA          □ Pre-treatment   □□ Cycle #   □ End of Treatment 
 
 
□ Mark box with an “X”, if form was not completed at specified timepoint and specify reason:  
   (Mark one with an X.) 
□ Patient refused  □ Patient withdrew consent □ Not done 
 
 
 
□ Other, specify ______________________________________________________ 
(For assessment date, record approximate date form was to be completed.) 
 
II.  FUNCTIONAL STATUS 
A. 
KPS  (Healthcare professional rated*) 
Please rate your assessment of patient’s Karnofsky Performance Status as of date this form is completed. (Scale is listed 
below.) 
___ % 
% 
CRITERIA 
100 
Normal: no complaints; no evidence of disease. 
90 
Able to carry on normal activity; only minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, but unable to carry on normal activity or do active work. 
60 
Requires occasional assistance, but is able to care for most personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospitalization is indicated although death not imminent. 
20 
Very sick; hospitalization necessary; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
 
* Physician KPS[34]  
 
 


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B. 
Timed “Up and Go”* 
INSTRUCTIONS: The timed “Up and Go” measures, in seconds, the time it takes for an individual to  stand up from a 
standard arm chair (approximate seat height of 46 cm [approximately 1.5 ft]), walk a distance of 3 meters (approximately 
10 feet), turn, walk back to the chair, and sit down again. The subject wears his/her regular footwear and uses their 
customary walking aid (none, cane, walker, etc.) No physical assistance is given. The subject starts with his back against the 
chair, his arm resting on the chair’s arm, and his walking aid in hand.  He is instructed that on the word “go”, he is to get up 
and walk at a comfortable and safe pace to a line on the floor 3 meters (approximately 10 feet) away, turn, and return to 
the chair and sit down again. The subject walks through the test once before being timed in order to become familiar with 
the test. Either a wrist watch with a second hand or a stop-watch can be used to time the performance. 
 
 
Time to perform “Up and Go”  □□.□ seconds 
* Timed “Up and Go” [35] 
 


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III.  
COGNITION This section is only completed Pretreatment and at the end of treatment 
 
6-ITEM ORIENTATION-MEMORY-CONCENTRATION TEST** 
 
Patient’s 
Response 
Maximum 
errors 
                                         Final 
Score          Weight          score 
1. 
What year is it now? 
[without looking at a calendar] 
□□□□ 
1 
□□  x               4        =      □□ 
2. 
What month is it now? 
[without looking at a calendar] 
□□ 
1 
□□   x               3        =      □□ 
Memory Phrase: 
Repeat this phrase after me:  
‘John Brown, 42 Market Street, Chicago’  
 
 
3. 
About what time is it? 
[within 1 hour – without looking at 
your watch] 
□□:□□ 
1 
□□   x               3        =      □□ 
4. 
Count backwards 20 to 1. 
 
2 
□□   x               2        =      □□ 
5. 
Say the months in reverse order. 
 
2 
□□   x               2        =      □□ 
6. 
Repeat the Memory Phrase. 
 
5 
□□   x               2        =      □□ 
 
 
 
                  TOTAL SCORE:     □□ 
 
 
Scoring: For items 1 to 3, the response is either correct (score 0) or incorrect (score 1). For items 4 to 6, add one point for each 
error (item 4 and 5 maximum error is 2; for item 6, maximum error is 5); total all scores in “Final Score” column. Data from 
participants found to have gross cognitive impairment as determined by the Orientation-Memory-Concentration Score ≥11 will 
be excluded from the analysis. Maximum score = 28. 
** OMC[36] 
  
IV.  SCORING This section is only applicable if OMC-Test is completed Pretreatment and Post treatment 
Did the patient score ≥11 on the 6-Item Orientation-Memory-Concentration Test? 
□ No 
□ Yes (If yes, notify the patient’s treating physician.) 
 
This question is only applicable to question #1 in “Section K. Your Feelings” from the Patient Questionnaire. 
1. How did the patient answer the question “Do you often feel sad or depressed?” in the Patient  Questionnaire (Section K)? 
 No 
 Yes (If yes, notify the patient’s treating physician.) 
 
 
 


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V. NUTRITION 
What is the patient’s height? (from patient’s chart)    □□□ cm 
What is the patient’s current weight? (from patient’s chart)    □□□ kg 
What was the patient’s weight approximately 6 months ago? (from patient’s chart or patients self report)  □□□ kg 
Calculated Body Mass Index: □□.□ 
Percent Unintentional Weight Loss:  □□.□% 
 
VI. QUESTIONS REGARDING THE QUESTIONNAIRES 
A. 
Were any of the questionnaires in the “Geriatric Assessment – Healthcare Professional Questionnaire” difficult for you to 
administer? 
□Yes     □No 
 
If no, please proceed to the next question. 
If yes, please indicate which questionnaire was difficult to administer? (Mark all that apply with an X.) 
□ KPS Healthcare Professional Rated (page 1) 
□ Timed Up and Go (page 2) 
□ 6-Item Orientation-Memory-Concentration Test (page 2) 
□ Other: Please specify _________________________________ 
 
B. 
Were any of the questionnaires in the “Geriatric Assessment – Patient Questionnaire” difficult for the patient to complete? 
□Yes     □No 
If no, please proceed to the next question. If yes, please indicate which questionnaire(s) was difficult for the patient to 
complete? (Mark all that apply with an X.) 
□ Background Information (page 1) 
□ Daily Activities (page 2-3) 
□ Physical Activities (page 3) 
□ Current Health Rating (page 4) 
□ Falls (page 4) 
□ Your Health (page 4-5) (Mark all that apply with an X.) 
□ 1. Your general health (page 4-5) 
□ 2.  Medications (page 6) 
□ Your Mood (page 7-8) 
□ Social Activity (page 9) 
□ Social Support (page 10) 
 
C. 
Was the patient able to complete “Geriatric Assessment – Patient Questionnaire” on his/her own? 
□Yes     □No 
If no, why? (Mark all that apply with an X.) 
□ Not literate (does not read or write) 
□ Visual problem 
□ Fatigue 
□ Questions too difficult (above the patient’s reading ability) 
□ Other: specify_________________________________________________ 
 
D. 
Length of time to complete both the Patient and Healthcare Professional Questionnaires 
Length of time to complete healthcare professional questionnaire 
□□□ minutes 
Length of time to complete patient questionnaire 
 
 
□□□ minutes 
Total length of time to complete both questionnaires 
 
 
□□□ minutes 
 
Completed by: ____________________________ 
Date form completed: □□ / □□ / □□□□ 
 
(Last name, First name) 
 
 
 
   M M  D D  Y Y YY 


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APPENDIX G: WAS IT WORTH IT (WIWI) QUESTIONNAIRE  
A PDF version formatted to collect information will be provided to participating sites.  
 
Patient MRN (COH Only): 
Patient Initials (F, M, L): 
Institution:  
 
Undergoing cancer treatment is a personal choice and an individual experience. We would like to get 
feedback on your experience following cancer treatment.  
 
Directions: Please answer each question by circling Y (for yes), N (for no), or U (for Uncertain). 
 
Was it worthwhile for you to undergo cancer treatment? 
 
Y            N            U 
If you had to do it over, would you undergo cancer treatment?                  Y            N            U 
Would you recommend this cancer treatment to others?  
 
Y            N            U 
Overall, did your quality of life change by undergoing cancer treatment? (Circle one response) 
 
It improved 
 
It stayed the same 
 
It got worse 
Overall how was your experience following cancer treatment? (Circle one response) 
 
Better than I expected  
The same as I expected  
Worse than I expected 
 
If there was one thing that could have been done to improve your experience following cancer 
treatment, what would it be?  
 
 
 
 
 
 
 
 
 
 


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APPENDIX H: OVERALL TREATMENT UTILITY (FOR CLINICIAN ONLY) 
Patient MRN (COH Only): 
Patient Initials (F, M, L): 
Institution:  
OTU is a novel clinical outcome measure incorporating objective and subjective measures of anticancer 
efficacy, tolerability, and acceptability, assessed at the end of protocol therapy and condensed into a 
simple 3 point score.  
OTU may be regarded as asking the clinician: “With the benefit of hindsight, are you glad you gave this 
treatment?” and asking the patient: “With the benefit of hindsight, are you glad you received it? OTU is 
scored as good, intermediate or poor, corresponding to “yes”, “uncertain” or “no” replies to these 
questions. 
To score the OTU, the patient is assessed at the end of protocol therapy (see Section 10.0) using the 
following criteria: 
1) Clinical benefit? Categorized as: 
a. Both radiologically progression- free (RECIST response or stable disease) and no clinical 
deterioration as assessed by treating consultant 
b. Either radiologically progression- free (RECIST progressive disease) or clinical 
deterioration as assessed by treating consultant 
2) Tolerable and acceptable? Categorized as: 
a. All of the following: 
 No SAE or SUSAR attributed to treatment 
 No episodes of grade ≥3 non-hematological toxicity 
 Patient response to “How much has your treatment interfered with your normal 
daily activities” is not “Very much”  
 Patient response to “How worthwhile do you think your treatment has been?” is 
not “Not at all” 
b. Any of the following: 
 An SAE or SUSAR (suspected unexpected serious adverse reaction) attributed to 
treatment 
 An episode of grade ≥3 non-hematological toxicity 
 Patient response to “How much has your treatment interfered with your normal 
daily activities” is “Very much”  
 Patient response to “How worthwhile do you think your treatment has been?” is 
“Not at all” 
Scoring (tick one):  
 
 Good OTU: Patient is alive and scores 1a/2a 
 
 Intermediate OTU: Patient is alive and scores 1a/2b or 1b/2a 
 
 Poor OTU: Patient is alive and scores 1b/2b, or patient is dead  
 
Authorized Investigator Name:   
Signature:   
Date: 


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APPENDIX I: LIST OF SUPPLEMENTAL MATERIALS 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They 
are stored and modified separately. As such, modifications to these documents do not require protocol 
amendments. 
 COH DCC Operations Manual- This document will serve as guidance as to the 
responsibilities of the Data Coordinating Center, as well as those of the participating 
sites. 
 COH Office of Clinical Trial Auditing and Monitoring (OCTAM) SOP 
 COH DSMC Committee Charter 
 
 
 


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APPENDIX J: SAE/UP REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG 
WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM  
COH IRB #17471- Participating Site IRB # ___________ 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
F Initial  F  Follow-up 
CTCAE Grade:   
F G1/mild   F G2/moderate    F G3/severe  F  G4/life threatening   
F G5 
Attribution to Ribociclib: 
F Unrelated  F Unlikely  F Possible   F Probable  F Definite 
Attribution to endocrine 
therapy: 
F Unrelated  F Unlikely  F Possible   F Probable  F Definite 
Historical/Known Correlation 
to Ribociclib: 
F Expected   F Unexpected 
Historical/Known Correlation 
to endocrine therapy: 
F Expected   F Unexpected   
Meets Definition of Serious 
AE:   
F   Serious    F  Non-serious 
Meets Definition of 
Unanticipated Problem: 
F   UP    F  Not a UP 
Has the event been reported 
to the following institution’s 
IRB? 
F   No    F  Yes; Date:_____/____/_____ 
 
 


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Authorized Investigator Signature:   
Date:____/____/____