Conditions: Breast Cancer
Keywords: HR-positive/HER2-negative metastatic breast cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The aim is to determine the pharmacological and biochemical association between ribociclib exposure and CYP3A variants in African American/Blacks and Non-Hispanic White patients. The investigators hypothesize that patients treated with ribociclib who are CYP3A5 poor metabolizers may be exposed to higher levels of ribociclib than CYP3A5 intermediate or normal metabolizers. The findings could allow clinicians to tailor treatments to maintain therapeutic doses while limiting toxicities.

Detailed description:
This prospective, multicenter, cohort study will assess ribociclib (600 mg PO daily) pharmacokinetics and pharmacogenomics in female patients with HR+/HER2- metastatic breast cancer. This design will be used for two independent, race-based cohorts: 18 African American/Black patients and 18 Non-Hispanic White patients. Women are eligible if they are older than 18, have HR+/HER2- mBC and are candidates for treatment with a CDK 4/6 inhibitor and endocrine therapy. Patients are ineligible if currently prescribed a medication that inhibits or induces the CYP3A isoenzymes, have baseline electrocardiogram abnormalities, or are otherwise considered to be ineligible for ribociclib. Participants will provide serial blood samples during the first cycle (collected immediately prior to the ribociclib dose, and 0.5hr ± 5min, 1hr ± 5min, 2hr ± 15min, 4hr ± 15min, 6hr ± 15min after the daily dose of ribociclib). Plasma samples will be analyzed via mass spectrometry to characterize the pharmacokinetics (e.g., AUC0-24, Cmax). Pharmacogenetic testing will be performed using the PharmacoScanTM microarray, which tests 4,627 markers in 1,191 genes, including variants in CYP3A4 and CYP3A5.

Arms:
arm 1: Subject who self identify as African American or Black with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers) arm 2: Subjects who self-identify as non-Hispanic White with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers)

Interventions: intervention 1: Ribociclib
Intervention descriptions: intervention 1: Patients will receive ribociclib 600 mg oral (PO) daily for 21 consecutive days of 28-day cycles and endocrine therapy with either letrozole or fulvestrant. Fulvestrant 500 mg intramuscular (IM) will be administered on days 1, 15, 29 of cycle one, and then monthly. Letrozole 2.5 mg oral daily continuously. If premenopausal women have not undergone bilateral salpingo- oophorectomy, they will receive a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin leuprolide) for ovarian suppression in combination with fulvestrant or letrozole and ribociclib.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
evaLuation of variations pharmacokinEtics and 
phArmacogeNOmics of Ribociclib in rAce-based Cohorts:  
The LEANORA study 
 
 
Georgetown Protocol #: STUDY00003100 
Clinicaltrials.gov #: NCT04657679 
 
 
Protocol Version Date :   
Version 3.6, 9/28/2023 
 
 
 
 
 
Principal Investigator (PI): 
Sandra M. Swain, MD 
 
 
 
 
 
Georgetown University Medical Center 
 
 
 
 
 
4000 Reservoir Road, NW 
Washington, DC, 20057 
Sandra.swain@georgetown.edu 
 
Co-Principal Investigators: 
Nadia Ashai, MD 
 
  
 
 
 
 
Lombardi Comprehensive Cancer Center 
 
  
 
 
 
 
Georgetown University Medical Center 
 
3800 Reservoir Road, NW 
 
Washington, DC 20057 
 
nadia.ashai@medstar.net  
 
 
 
 
 
 
Christopher Gallagher, MD 
 
 
 
 
 
Medstar Washington Hospital Center 
 
 
 
 
 
110 Irving Street, NW 
Washington, DC 20010 
Christopher.Gallagher@medstar.net 
 
Shweta Kurian, MD 
Medstar Franklin Square Medical Center 
9103 Franklin Square Drive 
Baltimore, MD 21237 
shweta.kurian@medstar.net  
 
D. Max Smith, PharmD 
 
 
 
 
 
Georgetown University Medical Center 
 
 
 
 
 
MedStar Health 
 
 
 
 
 
3007 Tilden Ave, NW 


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Suite 7L 
 
 
 
 
 
Washington, DC, 20008 
 
 
 
 
 
 
 
 
 
 
 
Sub-Investigators:              
Georgetown Network 
Claudine Isaacs, MD 
Marc Lippman, MD 
 
 
 
 
 
Candice Mainor, MD 
 
 
 
 
 
 
Theresa Harrington, NP 
Elizabeth Strand, NP 
 
MedStar Washington Hospital Center 
 
Ami Chitalia, MD 
Maya Beplat, NP 
 
Medstar Franklin Square Hospital 
Dongyan Liu, MD 
 
Tufts Medical Center 
Ilana Schlam, MD 
Rachel Buchsbaum, MD 
Yu Cao, MD 
 
Cardio-oncology:  
 
Nanette Bishopric, MD 
 
 
 
 
 
MedStar Washington Hospital Center 
 
Statistician:  
 
 
Ming Tan, PhD 
 
 
 
 
 
Georgetown University Medical Center 
 
 
 
 
 
 
 
Funding Sources:  
 
Breast Cancer Research Foundation (BCRF) 
 
Study Drug:  
 
 
Ribociclib  
 
Clinical Phase: 
 
 
Phase IV 
 
Number of Patients: 
 
36 
 
The study will be conducted according to the protocol and in compliance with 
Good Clinical Practice (GCP), with the Declaration of Helsinki, and with other 
applicable regulatory requirements including but not limited to Institutional 
Review Board/Ethics Committee (IRB/EC) approval. 
 
INVESTIGATOR SIGNATURE PAGE 
 


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Version 3.6 – 9/28/2023 
 
 
 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree 
to conduct the clinical study, following approval by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), in accordance with the study protocol, the current 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP), and applicable regulatory requirements. I will ensure that all personnel involved 
in the study under my direction will be informed about the contents of this study protocol 
and will receive all necessary instructions for performing the study according to the study 
protocol. 
 
 
 
 
 
_____________________________________           _____________________ 
Sandra Swain, MD 
                                                   Date 
Georgetown University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 3.6 – 9/28/2023 
 
 
 
 
DOCUMENT HISTORY 
 
Document 
Version Date 
Summary of Changes and Rationale 
Original Protocol 
(Version 1.0) 
October 13, 2020  
Not applicable (N/A) 
Original Protocol 
(Version 2.0) 
December 7, 2020 
Clarified inclusion criteria about brain metastases, 
permitted not required for participation in the study.  
Clarified details about the study schedule. Added 
an adverse event monitoring form. Clarified 
inclusion criteria about required labs at screening. 
Corrected minor grammatical errors. 
Original Protocol 
(Version 3.0) 
January 4, 2021 
Updated investigator list – added Nanette 
Bishopric, removed Ian Chang 
Added NCT # 
Protocol Version 
3.1 
June 3, 2021 
• 
Updated protocol to include Medstar 
Franklin Square Medical Center as an 
additional site. 
• 
Added previously IRB approved clarification 
to inclusion criteria noting communication 
through an interpreter is acceptable. 
• 
Added clarification to inclusion criteria for 
CYP3A5 metabolizers “at least 3 
participants” and “No more than 15” 
• 
Modified inclusion criteria minimum value 
for hemoglobin to allow for 8g/dl given that 
the FDA does not require a dose 
adjustment for this level. Dose adjustments 
are still in place for GRADE 3 events 
(hemoglobin < 8 g/dL) or higher, which 
occurred in <4% of patients in all trials 
referenced in the FDA label. 
• 
Added clarification to exclusion criteria 
about concurrently using other anti-cancer 
therapy “besides those in the study 
protocol”; testing for hepatitis B, hepatitis C, 
and HIV is not required for enrollment but if 
results are available then the exclusion 
criteria may be assessed. 
• 
Added clarification to the definition of 
uncontrolled HIV 
• 
Added clarification on SAE reporting. 
• 
Table 14.4 and 14.5 added note “*List 
applies to formulations of medications that 
are absorbed systemically” 


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Version 3.6 – 9/28/2023 
 
 
 
 
Protocol Version 
3.2 
October 11, 2021 
• 
Modified language to allow gonadotropin 
releasing hormone agonist as a class. 
Previously a specific agent, goserelin, was 
listed. NCCN guidelines list goserelin and 
leuprolide as the only available agents in 
the US for ovarian suppression. 
• 
Added clarification on enrollment 
procedures in the event the Georgetown 
Project manager is not available to confirm 
eligibility. 
• 
Added additional site Tufts Medical Center 
• 
Modified the PI for MWHC and the 
Georgetown Network 
Protocol Version 
3.3 
November 10, 2021 
• 
Clarified inclusion criteria to indicate lab 
values for Sodium, Potassium, Calcium, or 
Magnesium must have values within 
normal limits or are not clinically 
significant per the Investigator. 
• 
Clarified exclusion criteria by merging 2 
related exclusion criteria into one criteria to 
state:  Patient is concurrently using other 
anti-cancer therapy besides those in the 
study protocol (e.g., letrozole, fulvestrant, 
goserelin, leuprolide).  Any other prior neo-
/adjuvant anti-cancer therapy must be 
stopped at least 5 half-lives or 7 days, 
whichever is longer, before the date of 
ribociclib initiation. 
• 
Clarified exclusion criteria for concurrent 
malignancy to state: Patients may still 
enroll with a concurrent malignancy after 
receiving approval from the study PI. 
• 
Removed “with a systolic blood pressure 
>160” from Uncontrolled hypertension 
definition in the exclusion criteria 
Protocol Version 
3.4 
January 6, 2022 
• 
Updated Co-Principal Investigator for 
Georgetown to Nadia Ashai, MD 
• 
Removed Dr. Rao and Added Dr. Liu to 
Medstar Franklin Square Hospital 
• 
Section 4.3.7 clarification added “If sample 
size requirements (sections 3.3 and 9.1; at 
least 3 participants in AA or Black cohort 
who are CYP3A5 poor metabolizers; at 
least 3 participants in the NHW cohort who 
are CYP3A5 intermediate or normal 
metabolizers) are met, then CYP3A5 


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Version 3.6 – 9/28/2023 
 
 
 
 
phenotype screening may be bypassed per 
Principal Investigator discretion.” 
• 
Table 14 footnote clarification added 
“CYP3A5 Screening may be bypassed per 
Principal Investigator discretion if the 
necessary number of participants with each 
phenotype are enrolled (cohort of AA or 
Black participants - at least 3 poor 
metabolizers; cohort of NHW participants - 
at least 3 intermediate or normal 
metabolizers). If CYP3A5 is already 
performed it does not need to be repeated 
within the window of < 28 days.” 
• 
Clarified Inclusion criteria that consent must 
be obtain prior to any screening procedures 
that are not standard of care. 
• 
Removed upper limit of mean resting heart 
rate (90 bpm) from Inclusion criteria. The 
eligibility criterion of a heart rate between 
50-90 bpm was derived from the early 
MONALEESA studies as that is what they 
used. The recent COMPLEEMENT-1 trial 
has removed the upper limit on the heart 
rate in their eligibility criteria and only 
screen for bradycardia (< 50 bpm). 
Tachycardia is not listed in the FDA label 
as an adverse reaction, a warning, or a 
precaution.  
• 
Clarified the grammar in section 5.6.2. 
Protocol Version 
3.5 
January 30, 2023 
• 
Clarified that leukopenia is not a secondary 
endpoint and that the last few endpoints 
(i.e., 2.4.4 through 2.47) are exploratory 
endpoint. Not secondary endpoints. See 
sections 2.4 and 2.5. 
Protocol Version 
3.6 
September 28, 
2023 
• 
Clarifying title of Table 12 by adding “that 
are deemed related and clinically significant 
by the treating physician” to the title 
 
 
 


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Table of Contents 
Glossary of Abbreviations and Terms ................................................................................... 11 
Study Synopsis ..................................................................................................................... 13 
1. Background and Justification ........................................................................................... 17 
1.1 
Background ....................................................................................................................... 17 
1.2 
Ribociclib .......................................................................................................................... 17 
1.2.1 
Preclinical data .................................................................................................................................. 18 
1.2.2 
Pharmacokinetics ............................................................................................................................. 18 
1.2.3 
Clinical Activity .................................................................................................................................. 19 
1.2.4 
Toxicity ................................................................................................................................................ 20 
1.3 
Minority Enrollment in Clinical Trials ................................................................................. 23 
1.4 
CYP3A ............................................................................................................................... 23 
1.5 
Study Rationale and Purpose ............................................................................................. 25 
2. 
Study Objectives and Endpoints .................................................................................... 27 
2.1 
Primary Objective.............................................................................................................. 27 
2.2      Primary Endpoint ................................................................................................................ 27 
2.3 
Secondary Objectives ........................................................................................................ 27 
2.4 
Secondary Endpoints ......................................................................................................... 28 
2.5 
Exploratory Endpoints ....................................................................................................... 28 
3 
Patient selection ........................................................................................................... 28 
3.1 
Indication .......................................................................................................................... 28 
3.2 
Patient Population, Number of Patients, and Feasibility ..................................................... 28 
3.2.1 
Patient Population ............................................................................................................................ 28 
3.2.2 
Number of Patients ........................................................................................................................... 29 
3.2.3 
Feasibility ............................................................................................................................................ 29 
3.3 
Inclusion Criteria ............................................................................................................... 29 
3.4 
Exclusion Criteria ............................................................................................................... 31 
3.5 
Additional Study Restrictions ............................................................................................. 33 
3.6 
Removal or Replacement of Patients ................................................................................. 33 
3.6.1 
Screening Failures ............................................................................................................................ 33 
3.6.2 
Safety and Tolerability ..................................................................................................................... 34 
3.7 
Multicenter Trial Management .......................................................................................... 34 
3.7.1 
Study Personnel ................................................................................................................................ 34 
3.7.2 
Patient Enrollment ............................................................................................................................ 35 
3.7.3 
Data Collection and Management ................................................................................................. 35 


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3.7.4 
Conference Calls ............................................................................................................................... 35 
3.7.5 
Trial Auditing ...................................................................................................................................... 35 
4 
Study Design ................................................................................................................. 35 
4.1 
Study Design ..................................................................................................................... 35 
4.2 
Study Regimen .................................................................................................................. 37 
4.3 
Patient Screening, Enrollment, Monitoring......................................................................... 37 
4.3.1 
Informed Consent ............................................................................................................................. 38 
4.3.2 
Medical History .................................................................................................................................. 38 
4.3.3 
Demographics .................................................................................................................................... 38 
4.3.4 
Patient Eligibility Criteria ................................................................................................................ 38 
4.3.5 
Review Concomitant Medications ................................................................................................ 38 
4.3.6 
Physical Exam and Assessment of Performance Status ....................................................... 38 
4.3.7 
CYP3A5 Phenotype Screening ...................................................................................................... 39 
4.3.8 
Laboratory Samples ......................................................................................................................... 39 
4.3.9 
Electrocardiogram ............................................................................................................................ 41 
4.3.10 
Adverse Event Assessment ....................................................................................................... 41 
4.3.11 
Removal of Patients from Study ............................................................................................... 41 
4.3.12 
Discontinuation of Individual Patients .................................................................................... 41 
4.3.13 
Patient Replacement Criteria ..................................................................................................... 42 
4.3.14 
Discontinuation of the Entire Study ........................................................................................ 42 
4.3.15 
Protocol Deviations ..................................................................................................................... 42 
5 
Study Treatments ......................................................................................................... 42 
5.1 
Allocation to Treatment .................................................................................................... 43 
5.2 
Compliance ....................................................................................................................... 43 
5.3 
Drugs ................................................................................................................................ 43 
5.3.1 
Ribociclib ............................................................................................................................................ 43 
5.3.2 
Fulvestrant .......................................................................................................................................... 43 
5.3.3 
Letrozole.............................................................................................................................................. 43 
5.3.4 
Luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin, leuprolide) .. 44 
5.4 
Dose Modifications ........................................................................................................... 44 
5.5       Drug Accountability ........................................................................................................... 51 
5.6 
Concomitant Medications .................................................................................................. 51 
5.6.1 
Permitted Concomitant Medications ........................................................................................... 51 
5.6.2 
Medications Prohibited ................................................................................................................... 52 
5.6.3 
Medications Not Recommended ................................................................................................... 52 
6 
Study Procedures .......................................................................................................... 52 
6.1 
Schedule of Events ............................................................................................................ 52 
6.2 
Patient Withdrawal ........................................................................................................... 54 
7 
Assessments ................................................................................................................. 55 


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7.1 
Safety Assessments ........................................................................................................... 55 
7.1.1 
Physical Examination ...................................................................................................................... 55 
7.1.2 
Safety Assessments......................................................................................................................... 55 
8 
Adverse Event Reporting ............................................................................................... 56 
8.1 
Adverse Events .................................................................................................................. 56 
8.2 
Reporting Period ............................................................................................................... 56 
8.3 
Definition of Adverse Events .............................................................................................. 56 
8.3.1 
Medication Errors ............................................................................................................................. 57 
8.4 
Abnormal Test Findings ..................................................................................................... 57 
8.5 
Serious Adverse Events ...................................................................................................... 58 
8.6 
Hospitalization .................................................................................................................. 59 
8.7 
Severity Assessment .......................................................................................................... 60 
8.8 
Causality Assessment ........................................................................................................ 61 
8.9 
Withdrawal Due to Adverse Events .................................................................................... 61 
8.10 
Eliciting Adverse Event Information ................................................................................... 61 
8.11 
Reporting Requirements .................................................................................................... 61 
8.11.1 
Serious Adverse Events ............................................................................................................. 61 
8.11.2 
Non-Serious Adverse Events .................................................................................................... 62 
9 
Data Analysis and Statistical Methods .......................................................................... 62 
9.1 
Sample Size, Accrual and, Study Duration .......................................................................... 62 
9.2 
Statistical Analysis Plan ..................................................................................................... 63 
9.3 
Correlative Studies ............................................................................................................ 63 
9.4 
Safety Analysis .................................................................................................................. 64 
9.5 
Data Safety Monitoring Committee ................................................................................... 64 
10 
Quality Control and Quality Assurance ...................................................................... 66 
11 
Data Handling and Record Keeping ........................................................................... 66 
11.1 
Case Report Forms and Electronic Data Record .................................................................. 66 
11.2 
Record Retention .............................................................................................................. 67 
11.3 
Collaboration with the National Cancer Institute ................................................................ 67 
12 
Ethics ........................................................................................................................ 68 
12.1 
Institutional Review Board (IRB) ........................................................................................ 68 
12.2 
Ethical Conduct of the Study .............................................................................................. 68 
12.3 
Patient Information and Consent ....................................................................................... 68 


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12.4 
Risk/Benefit Assessment ................................................................................................... 69 
12.4.1 
Risks ................................................................................................................................................ 69 
12.4.2 
Protections Against Risks .......................................................................................................... 69 
12.4.3 
Benefits ........................................................................................................................................... 70 
12.5 
Reporting of Safety Issues ................................................................................................. 70 
12.6 
Amendments to the Protocol ............................................................................................. 71 
13 
References ................................................................................................................ 72 
14. Appendices .................................................................................................................... 75 
14.1. PROMIS Medication Adherence............................................................................................ 75 
14.2 Patient Reported Outcomes of CTCAE .................................................................................... 77 
14.3 Medication Diary .................................................................................................................. 80 
14.4 Prohibited medications ......................................................................................................... 81 
14.5 Medications not Recommended ............................................................................................ 83 
14.6 Adverse event monitoring log (CTCAE 5.0): ............................................................................ 84 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Glossary of Abbreviations and Terms  
Table 1. Abbreviations and Terms  
AA 
African American  
AE 
Adverse event  
AI 
Aromatase inhibitors  
ALT 
Alanine transaminase  
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase  
AUC 
Area under the curve 
CABG 
Coronary artery bypass graft  
CBC 
Complete blood count  
CDK 
Cyclin-dependent kinases  
CMP 
Comprehensive metabolic panel  
CRF 
Case report form 
CYP450 
Cytochrome P450  
DLT 
Dose-limiting toxicity  
ECOG 
European Cooperative Oncology Group  
eGFR 
Estimated glomerular filtration rate  
EKG 
Electrocardiogram 
ER 
Estrogen receptor  
ET 
Endocrine therapy  
FDA 
Food and Drug Administration 
GCSF 
Granulocyte Colony-Stimulating Factor  
GI 
Gastrointestinal  
HER2 
Human epidermal growth factor receptor 2  
HR 
Hormone receptor  
ICF 
Informed consent form  
LVEF 
Left Ventricular Ejection Fraction  
MI 
Myocardial infarction  
NHW 
Non-Hispanic White 
NIH 
National Institutes of Health 
ORR 
Overall response rate 
OS 
Overall survival 
PFS 
Progression-free survival 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PR 
Partial response 


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AA 
African American  
 
 
PR 
Progesterone receptor 
PS 
Performance status 
Rb 
Retinoblastoma 
SBP 
Systolic blood pressure  
SD 
Stable disease 
SERD 
Selective estrogen receptor  
TdP 
Torsades de Pointe  
ULN 
Upper limit of normal  


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Study Synopsis  
 
Table 2. Study Synopsis 
Title 
evaLuation of variations pharmacokinEtics and 
phArmacogeNOmics of Ribociclib in rAce-based Cohorts:  The 
LEANORA study 
Short Title 
Effect Racial Disparities in the Metabolism of Ribociclib 
Protocol  
Number 
STUDY00003100 
Clinicaltrials.gov 
number: 
NCT04657679 
Phase 
Phase IV 
Agents 
Ribociclib 
Fulvestrant 
Letrozole  
Goserelin or Leuprolide 
Indication 
Advanced HR+/HER2- breast cancer 
Study Overview 
Ribociclib is an inhibitor of the cyclin-dependent kinases 4 and 6 
(CKD4/6) and is approved in combination with endocrine therapy for 
patients with advanced hormone receptor (HR) positive metastatic breast 
cancer (mBC). CYP3A inhibitors increase ribociclib area-under-the-curve 
(AUC) by 3.2-fold; this is of clinical concern given possible associations 
between exposure and toxicity (e.g., QTc prolongation and neutropenia). 
Although there is an FDA recommendation to modify therapy for patients 
prescribed CYP3A inhibitors, it is unknown if modifications are needed in 
patients who intrinsically lack enzyme activity (e.g., genetic CYP3A5 poor 
metabolizers). 
 
CYP3A function is largely derived from CYP3A4 and CYP3A5 isozymes 
in adults. It is difficult to differentiate relative contributions of CYP3A4 and 
CYP3A5 on CYP3A function due to sequence homology (~ 84%) and 
overlapping substrate specificity. Genetic variations in CYP3A5 can 
translate into poor, intermediate, or normal CYP3A5 metabolism of 
different substrates. The association between CYP3A5 genotype and 
drug concentrations has previously informed therapy for other drugs. 
Dosing recommendations based on CYP3A5 genotype tacrolimus are 
published by the Clinical Pharmacogenetics Implementation Consortium 
(CPIC). It is unknown if a similar relationship could be present for 
CYP3A5 and ribociclib. We hypothesize that patients prescribed ribociclib 
with CYP3A5 poor metabolism experience increased exposure to 
ribociclib and likely more toxicities.  
 
Race is likely to be a significant factor when exploring ribociclib 
pharmacokinetics and the role of CYP3A.  There are known race-based 
differences in CYP3A4 and CYP3A5, with CYP3A4 dominant in Non-
Hispanic Whites and CYP3A5 dominant in African American/Blacks.  
Ribociclib pharmacokinetics have not been adequately studied in African 


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Version 3.6 – 9/28/2023 
 
 
 
 
Americans/Blacks as only 3% of participants in the pivotal trials ribociclib 
were African American/Blacks.   We aim to determine the 
pharmacological and biochemical association between ribociclib 
exposure and CYP3A variants in African American/Blacks and Non-
Hispanic White patients. Our findings should allow clinicians to tailor 
treatments to maintain therapeutic doses while limiting toxicities. 
Study Duration 
24-36 months 
Study Center(s) 
MedStar Georgetown University Hospital, Lombardi Comprehensive 
Cancer Center, Washington, DC 
MedStar Washington Hospital Center, Washington, DC 
MedStar, Franklin Square Medical Center, Baltimore, MD 
Tufts Medical Center, Boston, MA 
Objectives 
Primary 
To compare the pharmacokinetics of ribociclib at steady-state between 
CYP3A5 poor metabolizers and CYP3A5 intermediate or normal 
metabolizers in each independent race-based cohort of women with 
advance breast cancer.  
 
Secondary 
1. Evaluate toxicity profiles (e.g., QTc prolongation, leukopenia) 
between each race-based cohort  
2. Characterize ribociclib pharmacokinetics in African American/Black 
and the Non-Hispanic White patient cohorts. 
3. Conduct an exploratory candidate gene analysis of other genes with a 
biologically plausible role in ribociclib pharmacokinetics or therapeutic 
response   
Number of 
Patients 
36 patients 
Diagnosis and 
Main Inclusion 
and Exclusion 
Criteria 
Key Inclusion Criteria 
1) Histologically or cytologically proven diagnosis of HR+/HER2- breast 
cancer with evidence of metastatic or locally advanced disease, not 
amenable to curative treatment by surgery or radiotherapy 
2) Women age ≥ 18 years 
3) Self identify as Black, African American, or non-Hispanic White 
4) Signed informed consent form 
5) Adequate hepatic, hematologic, and renal function as defined below in 
the body of the protocol 
6) Normal baseline QTc (<450 ms) 
7) Asymptomatic and treated brain metastases are permitted  
 
Key Exclusion Criteria 
1)    Patient on active treatment with CDK4/6 inhibitors  
2)    Any other prior neo-/adjuvant anti-cancer therapy must be stopped at 
least 5 half-lives or 7 days, whichever is longer, before the date of 
ribociclib initiation. 
3)   Patient is concurrently using other anti-cancer therapy (including 
systemic therapy or radiation) 


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4)   Patient has impairment of gastrointestinal (GI) function or GI disease 
that may significantly alter the absorption of the study drug 
5)   Patient has clinically significant, uncontrolled heart disease and/or 
cardiac repolarization abnormality, as defined below in the body of the 
protocol 
6) Patient is currently receiving any of the following substances and 
cannot be discontinued  7  days prior to Cycle 1 Day 1: strong inducers 
or inhibitors of CYP3A4/5 -including herbal medications-, chronic dosing 
of corticosteroids and medications that prolong the QTc interval 
7)  Patient with symptomatic visceral disease or any disease burden that 
makes the patient ineligible for endocrine therapy per the investigator’s 
judgment.  
8)  Patient has received extended-field radiotherapy ≤ 4 weeks or limited 
field radiotherapy ≤ 2 weeks prior to ribociclib initiation and has not 
recovered to grade 1 or better from related side effects of such therapy 
(with the exception of alopecia or other toxicities not considered a safety 
risk for the patient at investigator’s discretion).  
9)  Patients with central nervous system (CNS) involvement unless they 
meet specific stability criteria 
10) Liver or allogeneic bone marrow transplant  
Study Design 
 
This prospective, multicenter, cohort study will assess ribociclib (600 mg 
PO daily)  pharmacokinetics and pharmacogenomics in female patients 
with HR+/HER2- metastatic breast cancer. This design will be used for 
two independent, race-based cohorts: 18 African American/Black patients 
and 18 Non-Hispanic White patients.  Women are eligible if they are older 
than 18, have HR+/HER2- mBC and are candidates for treatment with a 
CDK 4/6 inhibitor and endocrine therapy. Patients are ineligible if 
currently prescribed a medication that inhibits or induces the CYP3A 
isoenzymes, have baseline electrocardiogram abnormalities, or are 
otherwise considered to be ineligible for ribociclib. Participants will 
provide serial blood samples during the first cycle. Plasma samples will 
be analyzed via mass spectrometry to characterize the pharmacokinetics 
(e.g., AUC0-24, Cmax). Pharmacogenetic testing will be performed using the 
PharmacoScanTM microarray, which tests 4,627 markers in 1,191 genes, 
including variants in CYP3A4 and CYP3A5. 
The primary outcome is powered to detect a minimum clinically 
meaningful change, a 2-fold change in AUC, which is less than the 3.2-
fold change seen in the mentioned CYP3A drug interaction 
pharmacokinetic study. Based on CYP3A5 allelic frequencies, a sample 
size of 36 will provide 80% power to independently test the primary 
outcome in the two race-based cohorts. 
Multi-Institutional 
Trial 
Management 
Personnel 
At each site, personnel dedicated to this protocol will be: 
- 
A study PI 
- 
A research coordinator 
- 
A data manager 
 


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Patient Enrollment 
If a patient is being screened for enrollment, the local research 
coordinator must send an email within 24 hours containing the patient’s 
name to the local Principal Investigator (PI), and to the multicenter project 
managers. If a patient is successfully screened, the local research 
coordinator must send all supporting documentation to the Principal 
Investigator and multicenter project managers. Patients should not start 
therapy until the Principal Investigator, or the local PI and the multicenter 
project managers have reviewed the patient’s records and confirmed that 
the patient is indeed eligible for enrollment. 
 
Data Collection and Management  
Patient data will be entered into the on-line accessible database. This 
database is housed at Lombardi-Georgetown but is accessible anywhere 
there is internet access. The data manager and research coordinator at 
each site will attend an on-line training session so that they may learn 
how to enroll data into the database. All screening data should be 
entered prior to starting therapy, and all ongoing patient data should be 
entered within 10 business days of each patient visit.   
 
Conference Calls 
The Chairs of the study along with investigators when available and 
research staff  will review the accrual, toxicities, and other protocol issues  
at weekly protocol meetings and on monthly network disease group 
teleconferences.  
Duration of 
therapy 
Study will evaluate patients during the first cycle of ribociclib and 
endocrine therapy and on day 28 prior to the second cycle of treatment to 
evaluate toxicities. The protocol portion of the study will be done at this 
point and drug treatment  will be continued  as determined by the treating 
physician per standard of care.   
Statistical Design, 
Feasibility, and 
Trial Duration 
This study will be performed at MWHC and LCCC as a part of our 
combined Breast Cancer Research Group. This group has a joint IRB 
and extensive experience collaborating in clinical trials. Each institution 
sees 300-400 new patients diagnosed with breast cancer each year. 
MWHC serves a large number of minority and underserved patient 
groups, including 62% African American/Black patients. A previous study 
in patients with breast cancer (INSPIRE) conducted at MedStar 
Washington Hospital Center (MWHC) enrolled 75% of all patients 
approached (1).  Thus, 48 patients would need to be screened to enroll 
36 patients. Over the past 12 months, 47 patients were treated with 
CDK4/6 inhibitors in these institutions.  
 
The funding for this work has already been obtained. Dr. Swain’s award 
from the Breast Cancer Research Foundation will be used for this study. 
The National Cancer Institute) has agreed to provide for 
pharmacogenetic testing, pharmacokinetic analyses, perform the  
PharmacoScanTM microarray and provide some statistical support . 


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1. Background and Justification  
 
1.1 Background 
 
Breast cancer is the most common type of cancer and the second leading cause of 
cancer-related death in women in the United States (2). Five breast cancer subtypes 
have been identified by receptor and genetic expression; these have a significant impact 
on prognosis and treatment (3). The hormone receptor (HR) positive and human 
epidermal growth factor receptor 2 (HER2) negative or luminal A subtype accounts for 
60-70% of all breast cancer cases (3, 4).  These cancers have a generally good 
prognosis and respond well to endocrine therapy (ET). However, one-third of the 
patients have disease recurrence, often years after the initial presentation (5).  
 
ET remains the backbone of treatment of HR+/HER2- breast cancer; the estrogen 
receptor modulator tamoxifen is often utilized in premenopausal women – in combination 
with ovarian suppression with gonadotropin-releasing hormone analogs, such as 
goserelin or leuprolide in the metastatic setting. Aromatase inhibitors (AI), such as 
anastrozole, letrozole, and exemestane, are used for postmenopausal women (6, 7). 
Fulvestrant is a selective estrogen receptor degrader (SERD) approved for HR+/HER2- 
breast cancer in postmenopausal women (8). These antiestrogen therapies function on 
susceptible cell populations on the G1 phase of the cell cycle; while the G1/S transition 
is under the control of cyclin-dependent kinases (CDK) activated by specific complex 
formation with regulatory cyclins (9).  
 
The CDK 4/6-p16-retinoblastoma (Rb) pathway plays a key role in cell division and 
proliferation in breast cancer; CDK 4/6 inhibition is a novel therapeutic target that may 
delay the development of endocrine resistance (10-12). The CDK 4/6 inhibitors ribociclib, 
palbociclib, and abemaciclib have been approved for HR+/HER2- metastatic breast 
cancer. CDK4/6 inhibitors  have shown improvement in progression-free survival (PFS) 
and recently ribociclib was also associated to improvement in overall survival (OS) (11). 
 
1.2 Ribociclib 
 
Ribociclib is a highly selective orally bioavailable small molecule inhibitor of CDK 4 and 
6.  Ribociclib has been explored for different tumor types, including breast cancer, 
melanoma, and neuroblastoma.  Ribociclib is metabolized by CYP3A (12). The 
compound inhibits cell proliferation by preventing progression of the cell cycle from G1 
into the S phase (9). Ribociclib (Kisqali®) was approved in 2017 by the United States 
Food and Drug Administration (FDA) as a treatment of HR+/HER2- locally advanced and 
metastatic breast cancer in combination with ET (12). 
 
Lastly, commercially available ribociclib in combination with endocrine 
therapy is standard of care and will be prescribed by participants’ primary 
oncologist. 


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Version 3.6 – 9/28/2023 
 
 
 
 
1.2.1 Preclinical data  
 
Breast tumors often harbor abnormalities of the cyclin D–CDK4/6–p16–Rb pathway (12). 
In a preclinical study of 50 breast cancer cell lines, ribociclib demonstrated activity 
predominantly against HR+ cell lines (12). In vivo, in xenograft models the combination 
of ribociclib and letrozole or fulvestrant lead to significant inhibition of tumor growth (12, 
13). Ribociclib preclinical data indicate that it may be expected to have a direct effect on 
growth arrest as well as potential secondary cytotoxic activity.  
 
1.2.2 Pharmacokinetics  
 
According to the FDA label for ribociclib, repeated 600 mg once daily administration, 
steady-state was achieved after 8 days; the time to reach maximum concentration is 
between one and four hours after administration of ribociclib; the half-life of ribociclib is 
32 hours (14).  
 
The FDA label indicates clinical activity is primarily due to the parent drug and ribociclib 
is metabolized to other compounds that have a negligible contribution on clinical activity. 
The primary metabolic pathways of ribociclib include oxidation, N-acetylation, sulfation, 
cysteine conjugation, glycosylation, and glucuronidation (14). Ribociclib is the major 
circulating drug in plasma, accounting for 44%, however there is a possible contribution 
to ribociclib effect from circulating metabolites: M13 represents 22% of ribociclib 
exposure, M4 accounts for 20% and, M1 for 15% (14).  Ribociclib is eliminated mainly 
via feces with a small contribution from the renal route (14).  
 
Ribociclib undergoes hepatic metabolism mainly via CYP3A (14). Ritonavir is a strong 
CYP3A inhibitor, when ritonavir was given in combination with ribociclib there was an 
increase of the maximum concentration (Cmax) and the area-under-the-curve (AUC) of 
ribociclib increased by 1.7 and 3.2-fold, respectively (14, 15). Ribociclib in combination 
with erythromycin, a moderate CYP3A inhibitor, the Cmax and AUC of the CDK 4/6 
inhibitor increased by 1.3 and 1.9-fold, respectively (14). The opposite effect in ribociclib 
concentrations was noted with CYP3A inducers, such as rifampicin (14).  
 
 


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1.2.3 Clinical Activity  
 
Several phase 1b trials have been conducted utilizing ribociclib in patients with breast 
cancer (12). The NCT01857193 trial was a dose-escalation study that combined 
ribociclib (600 mg daily for 21 days out of 28-day cycles) with exemestane (25 mg daily, 
continuous) and everolimus (continuous) in six patients with metastatic breast cancer, 
two had partial response (PR) and six stable disease; hematologic adverse events (AEs) 
were reported in that study (16). Then the NCT01872260 study ribociclib (600 mg daily 
for 21 days out of 28-day cycles) and letrozole (2.5 mg daily, continuous) were given; of 
the six patients with evaluable response, one had PR, 2 stable disease, one no 
measurable disease and two progression of disease (16). A second arm of the study 
included ribociclib, letrozole, and a PI3K inhibitor, there was one dose-limiting toxicity 
(neutropenia),  the most commonly reported AEs from both arms were neutropenia, 
nausea, hyperglycemia, anorexia, diarrhea, nausea  (17). The NCT02088684 phase 
1b/2 trial assessed safety and efficacy of ribociclib and fulvestrant (arm A: ribociclib 600 
mg daily for 21 days; arm B: 400 mg daily; all received fulvestrant) 24 women (arm A= 
13, arm B=11) were treated with the combination, four women had PR and 15 stable 
disease (18).  
 
Based on the data demonstrating efficacy and safety of ribociclib in combination 
endocrine therapy, the phase 3, randomized, placebo-controlled MONALEESA-2 study 
was conducted (19). In this study, 668 postmenopausal women with recurrent or 
metastatic HR+/HER2 breast cancer were randomized to receive ribociclib (600 mg daily 
for 21 days of 28-day cycles) plus letrozole (2.5 mg daily) vs placebo plus letrozole. The 
PFS was longer in the ribociclib group than in the placebo group (95% CI 0.43-0.72, HR 
0.56); the 18-month PFS was 63% vs 42% respectively (19). The objective response 
rate (ORR) was 52% in the ribociclib group vs 37% in the placebo group (p < 0.001) 
(19). The improvement in outcomes in the ribociclib arm was maintained in a second 
planned interim analysis after 26 months that revealed a median PFS of 26 months in 
the ribociclib group vs 16 in the placebo group (20). 


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Slamon and colleagues conducted the MONALEESA-3 trial in which 484 
postmenopausal women with locally advanced or metastatic HR+/HER2 breast cancer 
that were treatment naïve or had receive one line of endocrine therapy, were 
randomized to receive ribociclib (600 mg daily for 21 days of 28-day cycles) plus 
fulvestrant (500 mg on day 1 of each cycle with an additional dose on day 15 of cycle 1) 
vs placebo plus fulvestrant (21). The median PFS was 20 months in the ribociclib group 
vs 12 in the placebo group (HR 0.5, p < 0.001) (21). Treatment benefits were seen in 
patients that were treatment naïve and in the ones who had one prior line of endocrine 
therapy (21).  The ORR was 40% vs 28% respectively. The overall survival at 42 months 
was 57% in the ribociclib group and 45% in the placebo arm (22). There was a 28% 
difference in the relative risk of death and the benefit was consistent across most 
subgroups (HR 0.72, 95% CI 27.1 to 41.3) (22).  
 
In the MONALEESA-7 phase 3 trial, Tripathy et. al. studied ribociclib (600 mg daily for 
21 days of 28-day cycles) in combination with AI and ovarian suppression (goserelin 3.6 
mg on day one of each 28-day cycle) in premenopausal women with HR+/HER2 
advanced breast cancer that received up to one line of therapy (no previous treatment 
with CDK 4/6 inhibitors) (23). Randomization of 672 patients assigned them to receive 
ribociclib plus AI (letrozole or anastrozole) and ovarian suppression or placebo plus AI 
and ovarian suppression (23). The median PFS was 23 months in the ribociclib group vs 
13 months in the placebo group (HR 0.55, p < 0.0001), the median OS was not reached 
(23).  
 
Several ongoing trials are exploring the use of ribociclib in combination with ET and 
other targeted agents, such as PI3K and mTOR inhibitors in patients with advanced 
breast cancer; additionally, multiple studies are assessing the use of CDK 4/6 inhibitors 
in the neoadjuvant and adjuvant settings (24).  
 
1.2.4 Toxicity  
 
CDK 4/6 inhibitors are overall well tolerated, either as monotherapy or in combination 
with ET; however hematologic toxicities –particularly neutropenia- often leads to delays 
in treatment and dose reductions (21, 23). The prevalence of toxicities and subsequent 
dose adjustments (38% to 77%) vary based on the concomitant therapy and are 
discussed below and in Table 3. 
 
Table 3: Adverse effects and associated changes in ribociclib therapy 
 
MONALEESA-2 (14) 
MONALEESA-3 (14) 
MONALEESA-7 (14) 
Most Common AEs (> 
20%) 
Neutropenia, Nausea, 
Fatigue, Diarrhea, 
Leukopenia, Alopecia, 
Vomiting, 
Constipation, 
Headache, Back pain 
Neutropenia, 
Infections, 
Constipation, 
Diarrhea, Leukopenia, 
Nausea, Rash, 
Cough, Vomiting 
Neutropenia, 
Infections, Arthralgia, 
Nausea, Leukopenia, 
Alopecia 


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Version 3.6 – 9/28/2023 
 
 
 
 
Most Common Grade 
3 or 4 AE (>5%) 
Neutropenia, 
Leukopenia, 
Abnormal liver 
function tests, 
Lymphopenia 
Neutropenia, 
Leukopenia, ALT 
Increased 
Neutropenia, 
Leukopenia, ALT 
Increased 
Dose reductions due 
to AE 
45% a 
32% 
33% 
Discontinued 
ribociclib due to AE 
7% b 
9% c 
3% d 
a Neutropenia was the most common AE leading to a dose reduction 
b Increases in liver enzymes and vomiting were the most common AEs leading to 
treatment discontinuation (20). 
c AEs leading to permanent discontinuation of ribociclib included ALT increased (5%), 
AST increased (3%), and vomiting (1%). 
d AEs leading to permanent discontinuation of ribociclib included ALT increased (2%), 
AST increased (2%), and drug-induced liver injury (1%). 
 
 
In the phase 1b/2 trial NCT02088684 patients received fulvestrant and ribociclib 600 mg 
on day 1-21 of 28-day cycles or a continuous (n= 13) dose of 400 mg (n=11); Tolaney et. 
al. described neutropenia as a common and dose-dependent AE, grade 3/4 neutropenia 
occurred in 62% of the patients that received 600 mg of ribociclib daily and in 36% of the 
patients treated with 400 mg of ribociclib (18). QTc prolongation was also reported in this 
study in 4 patients in the 600 mg arm and in 1 on the 400 mg group; again suggesting a 
dose-dependent effect (18, 21, 23).  
 
In the MONALEESA-2 study, neutropenia was reported in 74% of patients in the 
experimental arm, of these 49% had grade 3/4 neutropenia; in the placebo arm only 5% 
of patients reported neutropenia; anemia was reported in 18% of the ribociclib arm and 
4.5% of the placebo arm; most cases were grade 1/2, leukopenia was also reported in 
the ribociclib arm. Nausea was reported in 51% of patients in the experimental arm and 
28% of the placebo arm. Alopecia in 32% and 15% respectively.  Transaminitis was also 
reported in 15% of the patients in the experimental arm and only 3-4% in the placebo 
arm (mostly grade 1/2). An increase of more than 60 milliseconds from baseline in the 
QTc interval occurred in 2.7% in the ribociclib group and in no patients in the placebo 
group (19). Serious AEs occurred in 71 patients (21.3%) in the ribociclib group and in 39 
(11.8%) in the placebo group (19).  Dose adjustments secondary to an adverse effect 
were required for 182 (54.5%) of patients treated with ribociclib plus letrozole, which was 
higher than placebo plus letrozole (14, 4.2%). Median time to first dose reduction was 
2.9 (range 0 to 29.4) months. Dose interruptions secondary to an adverse effect were 
required for 239 (71.6%) of patients treated with ribociclib plus letrozole, which was 
higher than placebo plus letrozole (54, 16.4%). Neutropenia was the most common 
reason for dose adjustments and dose interruptions. 
 
In the MONALEESA-3 trial, neutropenia was again the most common reported AE, in the 


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Version 3.6 – 9/28/2023 
 
 
 
 
ribociclib group 69% of the patients developed neutropenia, 53% grade 3/4 while 2% of 
patients in the placebo arm developed neutropenia. Other common grade 3/4 AE were 
nausea (45%), fatigue (31%), leukopenia (28%), vomiting (26%), pruritus (19%), 
alopecia (18%), anemia (17%). ALT and AST elevation occurred in 4-6% of the ribociclib 
arm and 1% of the placebo arm. QTc prolongation occurred in 6% of patients in the 
ribociclib arm; three cases discontinued treatment due to QTc prolongation, there were 
no cases reported of Torsades de Pointes (21). Serious AE occurred in 138 (28.6%) and 
40 patients (16.6%) in the ribociclib plus fulvestrant and placebo plus fulvestrant arms, 
respectively; of these, 54 (11.2%) and six (2.5%) were attributed to the study medication. 
The most common all-grade all-causality serious AEs reported in ≥ 1% of patients 
(ribociclib plus fulvestrant v placebo plus fulvestrant) were pneumonia (1.9% v 0%) and 
dyspnea (1.2% v 2.1%) (21). Ribociclib or placebo dose reductions were reported in 183 
(37.9%) and 10 patients (4.1%) in the ribociclib plus fulvestrant and placebo plus 
fulvestrant arms, respectively; 148 (30.6%) and nine (3.7%) had a single dose reduction. 
AEs were the most common reason for dose reduction (160 of 183 patients with a dose 
reduction) (21).  
 
Similarly, in the MONALEESA-7 study, 76% of patients in the ribociclib arm developed 
neutropenia (61% grade 3/4) while 8% of patients in the placebo arm developed 
neutropenia. Other common AEs were leukopenia (31%), anemia (21%), alopecia 
(19%), transaminitis (12%). QTc prolongation was reported in 11% of the ribociclib group 
vs 4% of the placebo arm (23). Dose interruptions or reductions owing to an AE of QTc 
interval prolongation occurred in 13 (4%) of 335 patients in the ribociclib group and three 
(1%) of 337 patients in the placebo group. None of the patients with a QTc prolongation 
event had clinical symptoms or arrhythmias. Overall, dose adjustments occurred in 255 
(77%) of patients who received ribociclib compared to 126 (38%) of those who received 
placebo. Serious AEs occurred in 60 (18%) of 335 patients in the ribociclib group and 39 
(12%) of 337 in the placebo group (23). 
 
Hematologic toxicities are seen with CDK 4/6 inhibitors in general, even though 
neutropenia is common, the incidence of neutropenic fever is low with these treatments 
(19, 21, 23, 25). There are limited data on the hematologic safety profile of CDK 4/6 
inhibitors in African Americans/Blacks. The PALINA study assessed the safety of 
palbociclib in African American/Black women with and without benign ethnic neutropenia 
(BEN). A polymorphism in the Duffy antigen has been implicated in the pathophysiology 
of BEN. A total of 35 African American/Black patients (58% with Duffy null phenotype) 
with a baseline absolute neutrophil count >1000/uL were enrolled in this phase 2 study. 
Women with duffy null phenotype required more dose reductions due to neutropenia; 
however, this did not result in treatment discontinuation or febrile neutropenia. This study 
showed that palbociclib is safe in African American/Black women, including those with 
Duffy null phenotype and baseline absolute neutrophil count 1000-1499/uL (26).  
 
Transaminitis and QTc prolongation are AEs reported with ribociclib (19, 21, 23, 25). 
Lung toxicity is a rare but often fatal AE of CDK 4/6 inhibitors, it was reported in one 
patient in MONALEESA 3, and in several case reports (21). 
 
Based on a dedicated hepatic impairment Study A2109 in healthy subjects with normal 
hepatic function (N=11) and volunteers with hepatic impairment (N=17), mild (Child-


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Version 3.6 – 9/28/2023 
 
 
 
 
Pugh class A; N=6) hepatic impairment did not affect the exposure of ribociclib. The 
mean exposure for ribociclib was increased less than 2-fold in patients with moderate, in 
6 patients with  Child Pugh class B AUC increased to 1.32 and 5 patients with; Child 
Pugh class C AUC increased to 1.34. Based on a population pharmacokinetic analysis 
that included 160 patients with normal hepatic function and 47 patients with mild hepatic 
impairment, mild hepatic impairment did not affect the exposure of ribociclib, further 
supporting the findings from the dedicated hepatic impairment study there are no dose 
reduction recommendations for patients with hepatic impairment  (27).  
 
1.3 Minority Enrollment in Clinical Trials  
 
The National Institute of Health (NIH) guidelines on the inclusion of women and 
minorities in clinical trials published in 1994 and updated in 2017 called for the initiation 
of programs and support for outreach efforts to recruit underrepresented groups into 
clinical trials (28). Despite multiple efforts, racial and ethnic minorities are still 
underrepresented in clinical trials. This diversity gap can lead to sub-optimal 
development of new medicines, compromise the generalization of clinical trial results, 
and further exacerbate minority health disparities. According to a 2011 report from the 
conference "Dialogues on Diversifying Clinical Trials," sponsored by the FDA, African 
Americans/Blacks represent 12% of the U.S. population but only 5% of clinical trial 
participants and Hispanics make up 16% of the population but only 1% of clinical trial 
participants. Recent work by Al Hadidi et. al. found that just 1507 of 22,075 (6.8%) of 
participants were African Americans/Blacks among those included in clinical trials new 
drugs approved by the FDA to treat breast cancer between 2014 to 2018. This under 
representation remained apparent after accounting for the number of African 
Americans/Blacks with breast cancer as seen be a participation to prevalence ratio of 
0.29 (0.8 to 1.2 equates to similar representation) (29).   
 
Race is likely to be significant factor when exploring ribociclib pharmacokinetics and the 
role of CYP3A.In the mentioned MONALEESA trials only 23 (1.9%) out of the 1153 
women treated with ribociclib were African Americans/Blacks (19, 21, 23).   The FDA’s 
review of ribociclib concluded that “it is difficult to draw meaningful conclusions regarding 
the effect of race on the safety of ribociclib,” which is unsurprising given that the African 
Americans/Blacks population was underrepresented in the initial studies (27). 
 
1.4 CYP3A  
 
The cytochrome P450 (CYP) are a superfamily of enzymes that play a critical role in the 
metabolism of endogenous and exogenous substances (30).  More than 50 individual 
CYP have been identified in humans and some of the reactions carried out by CYP 
are N-dealkylation, O-dealkylation, aromatic hydroxylation, N-oxidation, S-oxidation, 
deamination, and dehalogenation (30). There are large differences in levels of 
expression of each CYP between individuals; interindividual variability in CYP 
expression is due to the presence of genetic polymorphisms and differences in gene 
regulation (30).  
 


24 
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A limited number of (~15) CYP enzymes are responsible for the metabolism of the 
majority of drugs, most fall into the CYP families 1, 2 and, 3 (30).  The most active CYP 
for drug metabolism are those in the CYP2C, CYP2D, and CYP3A subfamilies 
(30). CYP3A4, the most abundantly expressed in liver, is involved in the metabolism of 
over 50% of clinically used drugs (30). The human CYP3A subfamily consists of 
CYP3A4, CYP3A5, CYP3A7, and CYP3A43 (31). CYP3A7 expression is down-regulated 
after birth and CYP3A43 expression in the liver is small while CYP3A4 and CYP3A5 are 
responsible for activity in adults (31).  
 
The enzymes CYP3A4 and CYP3A5 are encoded by genes of the same name. CYP3A4 
and CYP3A5, respectively. It can be difficult to differentiate relative contributions 
between CYP3A4 and CYP3A5 due to significant sequence homology (approximately 
84%) between CYP3A4 and CYP3A5 and overlapping substrate specificity (31). It is 
common for substrates to be metabolized by both CYP3A4 and CYP3A5, although one 
enzyme may preferentially metabolize a substrate. CYP3A-dependent drug clearance is 
variable due to multiple factors, including genetic mutations in CYP3A5 and CYP3A4 
(31). CYP3A5 genotype can be translated to phenotypes that reflect enzyme function: 
poor metabolism, intermediate metabolism, or normal metabolism. Genetic testing 
interpretation is based on allelic expression of CYP3A5: normal metabolizers carry two 
functional alleles (haplotype: *1/*1, more common in African American/Blacks), while 
intermediate metabolizers carry one functional and one nonfunctional allele (*1/*3, *1/*6, 
*1/*7), finally poor metabolizers carry two non-functional alleles (*3/*3, *6/*6, *7/*7, *3/*6, 
*3/*7, *6/*7, more common in non-Hispanic Whites) (32). Importantly, these terms reflect 
enzyme function and are unrelated to prevalence (e.g., normal metabolism reflects 
normal enzyme function, but this could be a common or uncommon phenotype). 
 
There are known race-based differences in CYP3A4 and CYP3A5, with CYP3A4 
dominant in Whites and CYP3A5 dominant in African Americans/Blacks (31). 
Counterintuitively, it is common (~85%) for White patients to have CYP3A5 poor 
metabolism and uncommon (~15%) for White patients to have CYP3A5 normal or 
intermediate metabolism. The scenario is reversed for African American/Black patients 
as it is common (~85%) to have CYP3A5 normal or intermediate metabolism and 
uncommon (~15%) to have CYP3A5 poor metabolism. This differential enzyme 
expression may have an enhanced importance as many drugs (e.g., ribociclib) have 
dosing regimens established in predominantly White populations, which do not express 
an enzyme that metabolizes the drug.  
 
The clinical significance of CYP3A5 has been described in the pharmacogenetic studies 
of a calcineurin inhibitor, tacrolimus, which is an active drug metabolized by CYP3A and 
has a narrow therapeutic index (32). This drug is often utilized after bone marrow and 
solid organ transplantation to prevent rejection (33). Individuals who are normal or 
intermediate CYP3A5 metabolizers exhibit lower dose-adjusted trough concentrations of 
tacrolimus when compared with poor metabolizers. This is of significant concern as low 
trough concentrations increase the risk of transplant rejection and higher concentrations 
increase risk for adverse events, such as nephrotoxicity (32). Initial tacrolimus dosing 
was based  predominantly (92%) on White populations, which are more likely to have 
CYP3A5 poor metabolism;  as stated above, ~85% of Whites have poor CYP3A5 
metabolism and only ~15% of African American/Blacks, since most of the data on the 


25 
Version 3.6 – 9/28/2023 
 
 
 
 
dosing of tacrolimus were based on White population there is a concern that if African 
American/Blacks are metabolizing the drug faster, they may have lower drug 
concentrations and therefore risk for transplant rejection (31). Recent studies have 
demonstrated different rates of toxicity and graft rejection between African 
American/Blacks and Non-Hispanic Whites. These differences have been attributed to 
CYP3A5 polymorphisms (33). This work and other studies have led to the publication of 
dosing guidelines for tacrolimus based on specific pharmacogenetic variants (32). This 
application of pharmacogenomics-guided dosing could be translated to other drugs 
metabolized by CYP3A, like ribociclib. 
 
1.5 Study Rationale and Purpose  
 
There is an unmet need to evaluate the genomic characteristics and their effect on drug 
metabolism and toxicities, especially in racial and ethnic minorities. This prospective 
cohort study aims to determine the impact of CYP3A in ribociclib metabolism.  
 
Ribociclib is metabolized by CYP3A and the FDA recommends avoidance of CYP3A 
inhibitors or dose adjustments to compensate for altered ribociclib metabolism (section 
1.2.2). Based on drug interaction data (section 1.2.2), a reduction in CYP3A activity can 
lead to clinically relevant changes in ribociclib exposure. Higher ribociclib exposure is 
known to be associated with toxicities (e.g., neutropenia, prolonged QTc interval) and 
decreased exposure can potentially lead to loss of efficacy (14). 
 
Genetic variation in CYP3A, and specifically in CYP3A5, may be associated with altered 
ribociclib exposure but this has not been studied. Separate studies in African 
Americans/Black and Non-Hispanic White patients are justified given allelic frequencies 
and the potential for factors (e.g., CYP3A4) that may confound the association between 
CYP3A5 and ribociclib exposure.  
 
Due to underrepresentation in clinical trials and race-based differences in CYP3A5 
expression, African Americans/Blacks may be at particular risk of atypical ribociclib 
exposure. However, the dearth of pharmacokinetic evidence for ribociclib use in African 
Americans/Blacks patients make clinical predictions difficult. It is reasonable to suggest 
that African Americans/Blacks may be either 1) more dependent on metabolic activity 
from CYP3A5 and thus CYP3A5 poor metabolism may lead to increase ribociclib 
exposure and possibly toxicity or 2) normal CYP3A5 metabolizers have increased 
metabolic activity compared to the “average” White patient, which results in lower 
ribociclib exposure and a lack of efficacy. In order to predict which scenario is more 
plausible, it is critical to first understand if differences in ribociclib pharmacokinetics are 
associated with CYP3A5 metabolizer status. We hypothesize that patients treated 
with ribociclib who are CYP3A5 poor metabolizers may be exposed to higher 
levels of ribociclib than CYP3A5 intermediate or normal metabolizers. These 
differences can then inform the plausible clinical risk. 
 
This work is focused on ribociclib but has potential implications for other medications 
metabolized by CYP3A. Many drugs have dosing regimens determined in predominantly 
White populations and thus may dosing regimens confounded by differential CYP3A5 


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Version 3.6 – 9/28/2023 
 
 
 
 
expression. If our hypothesis is correct, it would serve as a strong similar to perform 
similar work in other medications metabolized by CYP3A (note, CYP3A metabolizes 
more drugs than any other cytochrome), particularly if no previous pharmacogenetic 
studies have been performed. 
 
Two cohorts of women -one of 18 women self-identified as African American/Black and 
one of 18 women self-identified as Non-Hispanic White women- with HR+/HER2- 
metastatic breast cancer will be followed prospectively to assess the pharmacokinetics 
(AUC, Cmax, Cmin) and CYP3A5 pharmacogenomics in each population. We aim to 
identify the effect of CYP3A5 variants in the metabolism of ribociclib.  
 
There are known race-based differences in CYP3A4 and CYP3A5; CYP3A4 is dominant 
in Non-Hispanic White patients and while CYP3A5 plays a larger role in African 
American/Black patients (32, 33). By assessing pharmacogenomics and 
pharmacokinetics in two separate cohorts we aim to understand the effect of CYP3A 
variants in the metabolism of ribociclib and to determine if there is a clinically significant 
correlation based on toxicity and drug concentration (assessed by AUC). We 
hypothesize that there will be a difference in the AUC and toxicity profile by race as the 
CYP3A variants in different racial groups have been well established. Also note, 
pharmacokinetic studies of similar size had direct clinical implications by resulting in 
recommended dose adjustments in the FDA label.   
 
Women will be eligible if they are premenopausal receiving ovarian suppression (with 
goserelin or leuprolide) or post-menopausal. The endocrine therapy selected for this 
study includes fulvestrant or letrozole. As seen in Table 4, this decision was made after 
an assessment of the FDA label for each endocrine therapy option, in vitro data, in vivo 
data, a well-known resource (Flockhart Table (34)), and previous major clinical trials 
(MONALEESA trials). This topic is not thoroughly studied but our decisions are justified 
by the totality of evidence. Guidelines from the National Comprehensive Cancer Network 
(NCCN) recommend the use of ovarian suppression (i.e., goserelin or leuprolide) in this 
population if patients are premenopausal.(35) The use of ovarian suppression in 
combination with ribociclib and a non-steroidal aromatase inhibitor in premenopausal 
women was shown to be safe and effective in the MONALEESA 7 clinical trial and 
ovarian suppression  has no known effect on CYP3A (23). Letrozole and fulvestrant 
appear to have minimal to no effect on CYP3A (as inhibitors, inducers, or substrates) 
and therefore they are unlikely to have an effect in the pharmacokinetic studies. 
Additionally, the combinations have shown to be safe in the MONALEESA 2 and 3 trials 
(21, 25). Tamoxifen, anastrozole and exemestane are substrates of CYP3A and 
therefore their use may have an effect on the pharmacokinetic studies through 
competitive inhibition. Thus tamoxifen, anastrozole, and exemestane will not be used in 
this study. Also note, during a presentation to the GLCCC Breast Cancer Program on 
July 29, 2020, we had significant discussion regarding the evidence for the potential 
effect of letrozole and anastrozole on CYP3A. This discussion and additional data added 
to the investigators’ confidence in permitting the use of letrozole and excluding 
anastrozole. 
 
 
 
 


27 
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Table 4: Effect of Endocrine Therapy in CYP3A 
Drug 
FDA Label1 
In vitro  
CYP3A 
In vivo  
CYP3A 
Flockhart 
Table2 
MONALEESA 
Trials 
Fulvestrant 
Negative 
Substrate 
Negative 
Not listed 
Allowed (#3) 
Letrozole 
Substrate 
No inhibition (PMID 
19198839) 
Unclear 
Not listed 
Allowed (#2, #7) 
Anastrozole 
Inhibitor per in 
vitro data 
Substrate (PMID: 
21175441) 
Inhibitor but not 
expected in vivo (PMID 
9152599) 
Unclear 
Not listed 
Allowed (#7) 
Goserelin 
N/A 
N/A 
N/A 
N/A 
Allowed (#7) 
Leuprolide 
N/A 
N/A 
N/A 
N/A 
N/A 
Exemestane 
Substrate 
Avoid 
inducers 
No further justification required beyond 
FDA label 
Not listed 
N/A 
Tamoxifen 
Substrate 
Avoid 
inducers 
Inhibitor 
(PMID: 12419016) 
Inducer (PMID: 
11950795) 
Negative 
(PMID: 
16041611) 
Substrate 
Allowed (#7) 
Toremifene 
Substrate 
Avoid 
inhibitors 
No further justification required beyond 
FDA label 
Not listed 
N/A 
Negative: study or studies did not identify an association between CYP3A and the drug 
1https://www.accessdata.fda.gov/scripts/cder/daf/ Accessed 07/29/20. 
2https://drug-interactions.medicine.iu.edu/MainTable.aspxAccessed 07/29/20 
2. Study Objectives and Endpoints  
 
2.1      Primary Objective  
 
To compare the pharmacokinetics of ribociclib at steady-state between CYP3A5 poor 
metabolizers and CYP3A5 intermediate or normal metabolizers in each independent 
race-based cohort of women with advance breast cancer.  
 
2.2      Primary Endpoint 
 
Ribociclib AUC (visit between days 8-16 of cycle 1) CYP3A5 poor metabolizers and 
CYP3A5 intermediate or normal metabolizers. 
 
2.3 
Secondary Objectives  
 


28 
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1. To evaluate toxicity profiles (e.g., QTc prolongation, leukopenia) between each race-
based cohort. 
2. To characterize ribociclib pharmacokinetics in African American/Black and the Non-
Hispanic White patient cohorts. 
3. Conduct an exploratory candidate gene analysis of other genes with a biologically 
plausible role in ribociclib pharmacokinetics or therapeutic response (e.g., CYP3A4).    
 
 
2.4 
Secondary Endpoints 
 
1. Ribociclib pharmacokinetic properties: maximum concentration (Cmax), the time to 
reach Cmax (Tmax), AUC, clearance, volume of distribution(vd), elimination half-life, and 
mean residence time (MRT) at steady state (visit between days 8-16 of cycle 1). 
2. Change in QTc interval between: 
1) baseline and between days 8-16 of cycle 1, 
 2) baseline and scheduled visit prior to initiation of cycle 2 
3. Laboratory abnormalities: neutropenia, ALT, and AST, between  
1) baseline and between days 8-16 of cycle 1, 
2) baseline and scheduled visit prior to initiation of cycle 2 
 
 
2.5 
Exploratory Endpoints 
 
4. Correlations between toxicities based on the Common Terminology Criteria for 
Adverse Events-Patient Reported Outcomes (CTCAE-PRO) questionnaire and 
ribociclib pharmacokinetic properties (e.g., AUC, Cmax, Cmin). 
5. Correlation between candidate pharmacokinetic genes (e.g., CYP3A4, overall 
CYP3A phenotype) and pharmacokinetic properties (e.g., AUC, Cmax, Cmin). 
6. Correlation between candidate pharmacodynamic variants or genes (e.g., Duffy 
antigen receptor) and toxicity (e.g., change in white blood cells [WBC]). 
3 Patient selection  
 
3.1 
Indication  
 
Women with HR-positive, HER2 negative advanced breast cancer. This phase IV trial 
will enroll a pre-defined number of patients (n=36) with HR+/HER2- advanced/metastatic 
breast cancer.  
 
3.2 
Patient Population, Number of Patients, and Feasibility  
 
3.2.1 Patient Population  
 


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This trial will enroll 36 patients with advanced HR-positive and HER2 negative breast 
cancer that are eligible for treatment with a CDK4/6 inhibitor as well as adequate cardiac 
and hepatic function. 
 
3.2.2 Number of Patients 
 
Thirty-six patients will be enrolled in total. More specifically, 18 patients will be enrolled 
into each cohort based on self-identified race. 
 
3.2.3 Feasibility  
 
This study will be performed at MedStar Washington Hospital Center (MWHC), MedStar 
Franklin Square, and Lombardi Comprehensive Cancer Center (LCCC) as a part of our 
combined Breast Cancer Research Group. Each institution sees 300-400 new patients 
diagnosed with breast cancer each year, which is. MWHC serves a large number of 
minority and underserved patient groups, including 62% African Americans/Blacks 
patients. The study will be additionally open at Tufts Medical Center.  
 
Approximately 30 patients were treated with CDK4/6 inhibitor (i.e., ribociclib, palbociclib, 
abemaciclib) at MWHC or Lombardi LCCC in the past 6 months.  
 
At the multiple centers participating in this study, we anticipate being able to enroll ~20 
patients per year. The expected accrual duration will be approximately 24-36 months. 
 
3.3 
Inclusion Criteria  
 
Patients must meet all the following inclusion criteria to be eligible for enrollment in the 
study:  
 
▪ 
Signed informed consent must be obtained prior to any screening procedures that are 
not standard of care.   
▪ 
Female ≥18 years old at the time of informed consent.   
▪ 
Those who self-identify as African American or Black are eligible for that respective 
cohort 
▪ 
Those who self-identify as non-Hispanic White are eligible for that respective cohort 
▪ 
Postmenopausal or premenopausal. Patient has a known menopausal status at the time 
of the informed consent form signature. The patient is considered postmenopausal if: i) 
she has had prior bilateral oophorectomy; ii) is age ≥ 60 years; iii) is age <60 years and 
has had amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH) 
and estradiol in the postmenopausal range per local normal ranges. All other patients 
who do not meet the criteria for postmenopausal status are considered premenopausal 
and will receive a luteinizing hormone-releasing hormone (LHRH) agonist (i.e., goserelin, 
leuprolide) for ovarian suppression  
▪ 
Each race-based cohort has a predetermined number of patients with each CYP3A5 
phenotype per the sample size calculation (section 9.1). Patients will be screen for 
CYP3A5 according to section 3.6.1. 


30 
Version 3.6 – 9/28/2023 
 
 
 
 
o African American or Black 
▪ 
At least 3 participants who are CYP3A5 poor metabolizers 
▪ 
No more than 15 participants who are CYP3A5 intermediate or normal 
metabolizers 
o Non-Hispanic White 
▪ 
At least 3 participants who are CYP3A5 intermediate or normal 
metabolizers 
▪ 
No more than 15 participants who are CYP3A5 poor metabolizers 
▪ 
Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not 
amenable to curative therapy 
▪ 
Treated, stable and asymptomatic brain metastases are permitted 
▪ 
ECOG performance status 0-3 
▪ 
Documentation of estrogen receptor (ER) positive and/or progesterone receptor (PR) 
positive tumor (≥1% positive stained cells) based on most recent tumor biopsy (discuss 
with the Principal Investigator if results in different biopsies are discordant in terms of 
hormone receptor positivity) utilizing an assay consistent with local standards. 
▪ 
Documented HER2-negative tumor based on local testing on most recent tumor biopsy: 
HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by 
in situ hybridization (FISH/CISH/SISH) defined by current ASCO/CAP (American Society 
of Clinical Oncology/College of American Pathologists) guidelines. Patients with 
equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines 
are eligible, as long as they have not received and are not scheduled to receive anti-
HER2 treatment.  
▪ 
Must be capable of understanding and complying with parameters as outlined in the 
protocol and able to sign and date the informed consent, approved by the IRB, prior to 
the initiation of any screening or study-specific procedures. 
▪ 
Patient must be able to swallow ribociclib tablets.   
▪ 
Patient must be able to communicate with the investigator and comply with the 
requirements of the study procedures. (Note: Communication through an interpreter is 
acceptable)  
▪ 
Patient has adequate bone marrow and organ function as defined by the following 
laboratory values:   
- 
Absolute neutrophil count (ANC) ≥ 1,200/mm; Patients must be able to meet the 
criteria without receipt of colony stimulating factors within 2 weeks before 
obtaining sample 
- 
Platelets ≥ 100,000/mm3; Patients must be able to meet the criteria without 
receipt of transfusion within 2 weeks before obtaining sample 
- 
Hemoglobin ≥ 8 g/dL; Patients must be able to meet the criteria without receipt of 
transfusion within 2 weeks before obtaining sample 
- 
Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the 
CKD EPI equation (Note: if the eGFR is not calculated from the serum creatinine 
using CKD EPI equation, please enter the most recent data into this calculator: 
https://www.kidney.org/professionals/kdoqi/gfr_calculator)  
- 
Total bilirubin < ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.   
- 
Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver 
metastases, who are only included if the AST is <5 × ULN.   


31 
Version 3.6 – 9/28/2023 
 
 
 
 
- 
Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver 
metastases, who are only included if the ALT is < 5 × ULN.   
- 
Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone metastases present)  
▪ 
Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements, or are not clinically significant per the Investigator:  
- 
Sodium 
- 
Potassium 
- 
Calcium   
▪ 
The following tests are not necessary. However, if results are available, values should 
be as follows: 
o INR ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the 
therapeutic range of intended use for that anticoagulant within 7 days prior to the 
first dose of study drug).  
o Magnesium within normal limits or corrected to within normal limits with 
supplements, or is not clinically significant per the Investigator.  
 
▪ 
Standard 12-lead electrocardiogram values defined as (obtained from baseline 
electrocardiogram):   
- 
QTc interval at screening < 450 ms (using Fridericia’s correction)   
- 
Mean resting heart rate > 50 bpm (determined from the electrocardiogram) 
 
3.4 
Exclusion Criteria  
 
Patients meeting any of the following criteria are not eligible for inclusion in this study: 
 
▪ 
Patient with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s judgment.   
▪ 
Patient currently/actively taking a CDK4/6 inhibitor  (e.g., ribociclib, abemaciclib, or 
palbociclib).  
▪ 
Patients with central nervous system (CNS) symptomatic or untreated metastases 
▪ 
History of liver transplant or allogeneic bone marrow transplantation   
▪ 
Patient with a known hypersensitivity to any of the excipients of ribociclib (e.g. ribociclib 
tablets coating contains soya lecithin, and therefore should not be taken by patients who 
are allergic to peanuts or soya) or of fulvestrant. 
▪ 
Patient is concurrently using other anti-cancer therapy besides those in the study 
protocol (e.g., letrozole, fulvestrant, goserelin, leuprolide). Any other prior neo-/adjuvant 
anti-cancer therapy must be stopped at least 5 half-lives or 7 days, whichever is longer, 
before the date of ribociclib initiation.   
▪ 
Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major toxicities.   
▪ 
Patient has not recovered from acute clinical and laboratory toxicities related to prior 
anticancer therapies to NCI CTCAE v5.0 grade ≤ 1 (except for alopecia, neuropathy, and 
amenorrhea or other toxicities not considered a safety risk for the patient at investigator's 
discretion).   
▪ 
Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy 
≤ 2 weeks prior to ribociclib initiation and has not recovered to grade 1 or better from 


32 
Version 3.6 – 9/28/2023 
 
 
 
 
related side effects of such therapy (with the exception of alopecia or other toxicities not 
considered a safety risk for the patient at investigator’s discretion). 
▪ 
Patient has a concurrent malignancy, with the exception of adequately treated basal or 
squamous cell skin carcinoma, stage 1 melanoma, or curatively resected cervical 
carcinoma in situ. Patients may still enroll with a concurrent malignancy after receiving 
approval from the study PI.    
▪ 
Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drug (e.g., uncontrolled ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection).   
▪ 
Patient has any other concurrent severe and/or uncontrolled medical condition that 
would in the investigator’s judgment, cause unacceptable safety risks to the patient, 
contraindicate patient participation in the clinical study, or compromise compliance with 
the protocol.   
▪ 
Patient has clinically significant, uncontrolled heart disease or who are at significant risk 
of developing QT prolongation, including any of the following:  
- 
Documented myocardial infarction (MI), angina pectoris, coronary artery 
intervention, or pericarditis within 6 months prior to study entry 
- 
Documented cardiomyopathy, congestive heart failure, valvular heart disease, 
congenital heart disease, or prior cardiac surgery    
- 
Left Ventricular Ejection Fraction (LVEF) < 50%  (testing is not mandatory)   
- 
Personal diagnosis of long QT syndrome, cardiac channelopathies, family history 
of idiopathic sudden death, congenital long QT syndrome or channelopathies 
- 
Personal risk factors for Torsades de Pointe (TdP) including uncorrected 
hypokalemia, hypomagnesemia, or need for concomitant medications with a 
known risk to prolong the QT interval and/or known to cause TdP that cannot be 
discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 
7 days prior to starting study drug, whichever is longer)  
- 
Clinically significant cardiac arrhythmias or conduction abnormalities, including, 
but not limited to ventricular tachycardia, atrial tachyarrhythmia, left bundle 
branch block, right bundle branch block, QRS prolongation (greater than 120 
ms), intraventricular conduction delay, high-grade AV block (e.g. bifascicular 
block, Mobitz type II and third-degree AV block)   
- 
Uncontrolled hypertension  
- 
Inability to determine the QTc interval   
▪ 
Patient is currently receiving any of the following substances and cannot be discontinued 
7  days prior to Cycle 1 Day 1:  
- 
Concomitant medications, herbal supplements, and/or fruits that are strong 
inducers or inhibitors of CYP3A4/5 (section 5.6).  
- 
Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5 (section 5.6).    
- 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is 
known to lead to induction of CYP3A enzymes, thereby potentially reducing 
ribociclib drug exposure to sub-therapeutic levels. Systemic corticosteroid 
treatment should not be given during the study treatment with ribociclib, except 
for:  


33 
Version 3.6 – 9/28/2023 
 
 
 
 
o Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive 
airways diseases), eye drops or local injections (e.g. intra-articular) 
o A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-
inflammatory potency of 4 mg dexamethasone (e.g. for chronic 
obstructive pulmonary disease or as an antiemetic).   
o Medications that prolong the QTc interval (section 5.6). 
▪ 
Inability to comply with study requirements. 
▪ 
Psychiatric illness or social situation that would limit compliance with study requirements. 
▪ 
Patients with clinically significant liver disease, including active viral or other known 
hepatitis, current alcohol abuse, or cirrhosis. 
▪ 
Known active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg]) or known active hepatitis C (defined as a positive test for hepatitis C viral load 
by polymerase chain reaction [PCR]). 
o Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test) are eligible.  
o Patients with positive hepatitis C antibody AND negative quantitative hepatitis C 
by PCR AND no clinical/laboratory evidence of cirrhosis are eligible. Patients 
who have completed curative therapy for HCV are eligible if they meet all other 
parameters for enrollment.  
o Patients are not required to undergo testing for HBV or HCV for enrollment. 
▪ 
Known uncontrolled HIV infection defined as any of the following criteria:  
o CD4 counts ≤ 350 cells/μL; or 
o HIV viral load ≥ 400 copies/mL; or, 
o Have been taking an antiretroviral regimen for < 4 weeks prior to treatment with 
study drugs, if anti-retroviral therapy is deemed necessary or appropriate by the 
investigator.  
o Patients are not required to undergo testing for HIV for enrollment. 
 
3.5 
Additional Study Restrictions  
 
Granulocyte Colony-Stimulating Factor (GCSF): GCSF administration should not be 
given within 2 weeks of study drug initiation or during the study treatment. 
 
Other Anticancer Therapy: For purposes of this protocol, anti-tumor treatment may be 
defined as, but is not limited to, anti-cancer agents (anti-estrogen endocrine therapy, 
cytotoxic chemotherapy, immunotherapy, or biologic therapy), radiotherapy, and 
investigational agents. No other anticancer therapy is permitted during the course of the 
study treatment for any patient. If the patient discontinues study treatment, this 
restriction no longer applies; however, the patient will remain enrolled in the study for the 
purpose of collecting subsequent outcomes.  
 
3.6 
Removal or Replacement of Patients 
 
3.6.1 Screening Failures 
 


34 
Version 3.6 – 9/28/2023 
 
 
 
 
All patients must continue to meet the inclusion and exclusion criteria up to and including 
the first day of treatment. Reasons for patients who have enrolled, but become ineligible 
could include (but are not limited to): 
 
- 
The patient’s performance status has declined 
 
Patients who become ineligible prior to initiation of therapy per protocol will be 
considered screen failures. Screen failures must be replaced until 36 patients with 
advanced HR+/HER2- breast cancer are enrolled. 
 
Each race-based cohort has a predetermined number of patients with each CYP3A5 
phenotype per the sample size calculation (section 9.1). In order for the study to be 
powered at least: 1) 3 participants who are CYP3A5 poor metabolizers and identify as 
African American or Black and 2) 3 participants who are CYP3A5 intermediate or normal 
metabolizers and identify as non-Hispanic White. While allelic frequencies (section 9.1) 
suggest the study will enroll the appropriate number of patients, there is a chance the 
study may encounter a different allelic frequency than anticipated. Thus, CYP3A5 
genetic testing will be provided after participants provide informed consent. Details for 
the CYP3A5 screening test are described in section 4.3.7. Participants will be 
considered a screen failure if: 
• 
The participant is a CYP3A5 poor metabolizer AND identifies as non-Hispanic 
White AND the study has already enrolled 15 participants who meet these 
criteria. 
OR 
• 
2) The participant is a CYP3A5 intermediate or normal metabolizer AND 
identifies as African American AND the study has already enrolled 15 participants 
who meet these criteria. 
 
 
3.6.2 Safety and Tolerability  
 
Any patient who received ribociclib and  undergoes complete pharmacokinetic and 
pharmacogenomic studies will be valuable for safety and tolerability as measured by NCI 
CTCAE v5.0.  
 
3.7 
Multicenter Trial Management  
 
3.7.1 Study Personnel  
 
At each site, personnel dedicated to this protocol will be: 
 
a. A study PI  
b. A research coordinator 
c. A data manager 
 
In addition, Georgetown University’s Multicenter Project Management Office will oversee 
the conduct of the trial at Lombardi-Georgetown and additional sites. Georgetown 


35 
Version 3.6 – 9/28/2023 
 
 
 
 
University’s Multicenter Project Management Office will be the main point of contact for 
the PIs for any study-related concerns, including data management and regulatory.  
 
3.7.2 Patient Enrollment  
 
Enrollment at the sites will be competitive. If a patient is being screened for enrollment, 
the local research coordinator must send an email containing the patient’s initials to the 
local PI, and to the Georgetown University’s Multicenter Project Management Office. If a 
patient is successfully screened, the local research coordinator must send all supporting 
documentation to Georgetown University’s Project Management Office by secure email 
to confirm eligibility. Patients should not start therapy until  a principal investigator and/or 
Georgetown University’s Project Management Office have reviewed the patient’s records 
and confirmed that the patient is indeed eligible for enrollment. In the event the 
multicenter project manager is not available, then another Georgetown CRMO staff 
member (CRC, CRN, or Clinical Manager) may review the records and confirm eligibility. 
 
3.7.3 Data Collection and Management  
 
Patient data will be entered into an online accessible database. This database is housed 
at Georgetown Lombardi, but is accessible anywhere there is internet access. The data 
manager and research coordinator at each site will attend an online training session so 
that they may learn how to enter data into the database. All screening data should be 
entered prior to starting therapy, and all ongoing patient data should be entered within 
10 business days of each patient visit.   
 
3.7.4 Conference Calls  
 
The Principal Investigator and with other investigators (when available) and research 
staff will review the accrual, toxicities, and other protocol issues  at weekly protocol 
meetings and on monthly network disease group teleconferences.  
 
3.7.5 Trial Auditing  
 
Georgetown University’s Multicenter Project Management Office will arrange all primary 
source documents for the patients to be audited. This will include collecting copies of the 
primary source data for any patients treated at other sites. Full details can be found in 
SOP GU-ORQA-P01.01, version date 07/01/2019.  
 
4 Study Design  
 
4.1 
Study Design  
 
Two separate cohorts, based on self-identified race, will be followed prospectively during 
this study. Eighteen African Americans/Blacks and 18 Non-Hispanic White women with 
metastatic HR+/HER2- advanced breast cancer will be enrolled. Patients will receive 
ribociclib 600 mg oral (PO) daily for 21 consecutive days of 28-day cycles and endocrine 


36 
Version 3.6 – 9/28/2023 
 
 
 
 
therapy with either letrozole or fulvestrant. Fulvestrant 500 mg intramuscular (IM) will be 
administered on days 1, 15, 29 of cycle one, and then monthly. Letrozole 2.5 mg oral 
daily continuously. If premenopausal women have not undergone bilateral salpingo- 
oophorectomy, they will receive a luteinizing hormone-releasing hormone (LHRH) 
agonist (e.g., goserelin leuprolide) for ovarian suppression  in combination with 
fulvestrant or letrozole and ribociclib.  
 
The Clinical Research Unit (CRU) is located in Georgetown University (7 East, Main 
Hospital, 3800 Reservoir Road, NW, Washington DC) and it provides specialized 
institutional resources in which clinical investigators can observe and study human 
physiology and treat diseases with innovative approaches. Subjects may have the visit 
between day 8 and day 16 of cycle 1 at the CRU or locally at the site.  
 
Between days 8 and day 16 (i.e., steady state) of cycle 1 of ribociclib and fulvestrant, 
participants will provide serial blood samples at the Georgetown University Clinical 
Research Unit or locally at the enrolling site, immediately prior to the ribociclib dose, and 
0.5hr ± 5min, 1hr ± 5min, 2hr ± 15min, 4hr ± 15min, 6hr ± 15min after the daily dose of 
ribociclib. Plasma samples will be analyzed at the National Cancer Institute via mass 
spectrometry to facilitate the measurement of pharmacokinetic properties. A blood 
sample will be utilized for pharmacogenetic testing on the PharmacoScan™ 
(ThermoFisher) microarray, which includes 51 variants in CYP3A4 and 22 in CYP3A5.  
 
Per FDA labeling, periodic electrocardiogram will be obtained prior to the first cycle, 
between C1D8-C1D16, at the start of the second cycle, and as clinically indicated. 
Additionally, a complete blood count (CBC) with differential and comprehensive 
metabolic panel (CMP) will be obtained at baseline (medical visit prior to C1D1), 
between C1D8-C1D16, at the start of the second cycle  
 


37 
Version 3.6 – 9/28/2023 
 
 
 
 
 
 
Figure 1: Study Design 
 
 
Subjects will be asked to answer a questionnaire regarding adverse effects (Patient 
reported outcomes version of the common terminology criteria for AEs (PRO-CTCAE)) 
and medication adherence (PROMIS on medication adherence (Appendices 14.1 and 
14.2) when they present for the serial blood samples for the pharmacokinetics and 
pharmacogenomic studies. Additionally, food collection and drug accountability 
(Appendix 14.3) will be done for the first cycle, prior to pharmacokinetic studies).  
 
 
4.2 
Study Regimen  
 
This prospective, multicenter, cohort study will assess ribociclib pharmacokinetics and 
pharmacogenomics in female patients with HR+/HER2- metastatic breast cancer. 
Potential trial patients will be pre-identified at participating centers. 
 
Patients who have adequate hematologic, hepatic, and renal function will be screened 
for enrollment. Patients who ultimately meet the inclusion and exclusion criteria as 
detailed in Section 3, and desire participation, will be enrolled.  
 
4.3 
Patient Screening, Enrollment, Monitoring  
 


38 
Version 3.6 – 9/28/2023 
 
 
 
 
The screening and monitoring procedures include the following listed below. Details are 
provided in Table 14. 
 
4.3.1 Informed Consent  
 
Signed informed consent will be obtained from the patient before any study-specific 
procedures are undertaken.  Additionally, patient will receive COVID-19 related 
documentation per IRB and Georgetown university policy. 
 
4.3.2 Medical History  
 
The following information should be collected during the screening period: 
 
1. Complete medical history, including documentation of any clinically significant 
medical conditions  
2. Performance status (ECOG) 
3. Medication information, including over the counter medications and herbal 
supplements  
4. Smoking history will be documented  
5. Presence and severity of any symptoms/conditions associated with their advanced 
solid tumor malignancy 
6. Detailed oncology history, including: 
a) Primary tumor: date of diagnosis, histology/cytology, and location 
b) Metastasis information: date of diagnosis, histology/cytology, and location 
c) Surgical history 
d) Anti-cancer and radiation treatments administered (including dates and type 
of modality, and if therapy was in the neoadjuvant, adjuvant, or metastatic 
setting) 
 
4.3.3 Demographics  
 
Age, sex, and self-reported race/ethnicity will be recorded. 
 
4.3.4 Patient Eligibility Criteria  
 
Inclusion and exclusion criteria (per section 3.2 and 3.2, respectively) 
 
4.3.5 Review Concomitant Medications  
 
Permitted, not recommended and prohibited concomitant medications, per section 
appendices 14.4 and 14.5.  
 
4.3.6 Physical Exam and Assessment of Performance Status  
 
At screening, a physical examination, height, weight, blood pressure, and pulse rate is 
required. Symptom-directed physical examinations, blood pressure, weight, and pulse 
rate will be performed. All physical examinations and vital signs assessments should be 


39 
Version 3.6 – 9/28/2023 
 
 
 
 
performed by a physician or registered nurse or other qualified health care provider 
according to local regulations.  
 
4.3.7 CYP3A5 Phenotype Screening  
 
After informed consent is complete, participants will undergo CYP3A5 screening to 
ensure the necessary number of participants with each phenotype are enrolled. If 
sample size requirements (sections 3.3 and 9.1; at least 3 participants in AA or Black 
cohort who are CYP3A5 poor metabolizers; at least 3 participants in the NHW cohort 
who are CYP3A5 intermediate or normal metabolizers) are met, then CYP3A5 
phenotype screening may be bypassed per Principal Investigator discretion. 
 
A buccal sample will be collected from participants upon completion of informed consent. 
Upon collection, the sample and kit will be mailed to Kailos Genetics to perform targeted 
next-generation sequencing on CYP3A5. Samples will be processed in accordance with 
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory procedures. 
Similar to other pharmacogenetic results (PharmacoScanTM test discussed in section 
4.3.8), these results will not be returned to the participant. The test results will be 
provided to the study team through a secure electronic method (e.g., encrypted email, 
Box.com). 
 
Patients will be considered a screen failure if: 
• 
The participant is a CYP3A5 poor metabolizer AND identifies as non-Hispanic 
White AND the study has already enrolled 15 participants who meet these 
criteria. 
OR 
• 
2) The participant is a CYP3A5 intermediate or normal metabolizer AND 
identifies as African American AND the study has already enrolled 15 participants 
who meet these criteria. 
 
The standard turnaround time for CYP3A5 screening will be one week or less. The 
timing can be as quick as 48 hours if the participant’s situation requires a faster 
turnaround time. 
 
4.3.8 Laboratory Samples  
 
Laboratory samples for this study will be assessed using the certified laboratory at the 
Investigators’ institutions or at a clinical laboratory such as Quest or LabCorp and these 
data will be used for all data analysis. The Principal Investigator or sub-Investigator will 
review, initial, and date all laboratory results and electrocardiograms. Any laboratory 
value outside the reference range that is considered clinically significant by the 
Investigator will be followed as appropriate. Clinically significant laboratory values will be 
recorded as AEs if they meet the criteria as specified in Section 8.1.  
 
Hematology samples (complete blood count [CBC]) will be collected and assessed using 
a certified laboratory. The Investigator will review, initial, and date all laboratory results. 
Any laboratory value outside the reference range stated in the inclusion criteria will 


40 
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preclude the patient from study participation. Comprehensive metabolic panel (CMP) to 
include: albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen (BUN), 
creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin. Any laboratory value outside the reference range stated in the inclusion 
criteria will preclude the patient from study participation. The CBC and CMP are 
performed per standard clinical practice and are not drawn specifically for research 
purposes. 
 
Serial blood samples for pharmacokinetic and pharmacogenomic studies will be 
obtained during cycle one, between days 8 and 16 in the Georgetown University Clinical 
Research Unit, or locally at the enrolling site. Blood samples will be collected 
immediately prior to the ribociclib dose, and 0.5hr ± 5min, 1hr ± 5min, 2hr ± 15min, 4hr ± 
15min, 6hr ± 15min after the daily dose of ribociclib. Samples will be collected in the 
Georgetown University Clinical Research Unit, or at the local site and shipped to the 
National Institute of Health to process and analyze the data. 
 
Frozen whole blood will be used is isolate DNA via the Wizard® Genomic DNA 
Purification Kit (Promega). This assay is able to yield 250-500µg from 10mL of whole 
blood. The Tissue Culture and Biobanking Shared Resource (TCBSR) will perform DNA 
isolation in batches. Isolated DNA can then be used for pharmacogenomic testing. 
 
Pharmacogenomic testing will be performed by the National Cancer Institute on the 
PharmacoScanTM microarray (Thermo Fischer). PharmacoScanTM analyzes 4,627 
markers in 1,191 genes. These assay allows for the genotyping of multiple genes that 
have known pharmacogenetic value, including phase I and phase II enzymes, 
regulatory/modifier genes, drug target genes, and phase III/transporter genes. It includes 
51 variants in CYP3A4 and 22 in CYP3A5. In brief, the assay involves several steps, 
including amplifying DNA via multiplex polymerase chain reaction (PCR). The amplified 
DNA is then fragmented, precipitated, centrifuged and dried, and then resuspended and 
prepared for hybridization. Fragments then hybridize to the microarray and are 
processed by the GeneTitan™ Multi-Channel Instrument of PharmacoScanTM. 
 
Blood samples (3-4 mL for each timepoint) will also be used for serial pharmacokinetic 
studies. A liquid chromatography with tandem mass spectrometry (LC–MS/MS) method 
will be used to assess ribociclib concentrations in human plasma. An assay has been 
developed specifically for ribociclib (36). In brief, liquid chromatography separates 
compounds within, then an electrospray ionization and mass spectrometry are optimized 
to detect transitions between ribociclib and the internal standard [13C6] ribociclib. LC-
MS/MS consists of serial sampling (times mentioned above) that will allow for calculation 
of maximum concentration (Cmax), the time to reach Cmax (Tmax), AUC, clearance, volume 
of distribution(vd), elimination half-life, and mean residence time (MRT). The lower limit 
of quantitation is 0.5 nM of ribociclib in plasma. A backup blood sample will be obtained 
for each timepoint in the serial collection and for the pharmacogenetic test. A summary 
of the amount of blood collected from each patient is listed below: 
• 
10 mL – 1 sample (10 mL) for pharmacogenomics assay 
• 
10 mL – 1 backup sample (10 mL) for pharmacogenomics assay 
• 
18 mL – 6 samples (3 mL each) for serial PK 


41 
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• 
18 mL – 6 backup samples (3 mL each) for serial PK 
• 
Total: 56 mL 
 
4.3.9 Electrocardiogram  
 
Electrocardiograms will be obtained prior to the first cycle, middle of the first cycle 
(between C1D8-C1D16),  at prior to the initiation of the second cycle. During the study, 
electrocardiogram will be assessed by the treating physician. If there are grade 2-4 
cardiac toxicities the patient will be referred to cardio-oncology. At the end of the study 
cardio-oncology will review and tabulate results of  QTc interval  in all 
electrocardiograms (three per patient: one at baseline, cycle 1 day 8-16 and prior to 
initiation of cycle 2). 
 
4.3.10 Adverse Event Assessment  
 
Baseline symptoms at cycle 1 day 1 (prior to initiating therapy) should be detailed and 
graded. Once treatment has started, AEs will be assessed every 2 weeks during the first 
cycle. The individual Investigator should record any AE in detail including the date of 
onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and 
outcome, relationship of the AE to study drug, and any action(s) taken. AE grade (Based 
on the CTCAE 5.0)  and start date will be documented in the adverse event monitoring 
form (Appendix 14.6). Patients will be followed for one cycle.  
 
See section 8 for adverse event monitoring and reporting. The Principal Investigator or 
sub-Investigators will assess AEs, laboratory data, and vital signs throughout the study. 
AEs will be assessed by NCI CTCAE Version 5.0. AEs, whether in response to a query, 
observed by site personnel, or reported spontaneously by the patient will be recorded. 
All AEs will be followed to a satisfactory conclusion. 
 
4.3.11 Removal of Patients from Study  
 
Each patient has the right to withdraw from study treatment at any time. In addition, the 
Investigator may discontinue a patient from the study treatment at any time for any 
reason if the Investigator considers it necessary, including the occurrence of an AE or 
noncompliance with the protocol.  
 
Each patient will be withdrawn from study treatment if any of the following occur: 
 
• 
The patient requires radiotherapy or alternate antineoplastic agents during the study 
period 
• 
The investigator believes it is in the best interest of the patient 
• 
Clinically significant deterioration of the patient's medical status as determined by the 
investigator 
• 
Any other medical reason that the study investigator deems appropriate 
 
4.3.12 Discontinuation of Individual Patients  
 


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When a patient discontinues the study treatment (without reaching a protocol-defined 
endpoint), the investigator will notify the Principal Investigator as soon as possible 
(provided, in each case, patient care and safety are not compromised). When a patient 
discontinues the study treatment, a final visit will be conducted, preferably prior to the 
initiation of another anticancer therapy. However, these procedures should not interfere 
with the initiation of any new treatments or therapeutic modalities that the investigator or 
patient’s treating physician feel is necessary to treat the patient's condition. Following 
discontinuation of the study drug, the patient will be treated in accordance with the 
investigator's/treating physician’s best clinical judgment.  
 
At the final visit, the reason(s) for the discontinuation from the study will be recorded and 
a physical examination, body weight, vital signs measurement, laboratory analyses, 
performance status, tumor assessment, and an assessment of AEs will be performed as 
soon as possible after discontinuation from the study treatment. If a patient is 
discontinued from the study with an ongoing AE or an unresolved clinically significant 
laboratory result, the site will attempt to provide follow up until a satisfactory clinical 
resolution of the laboratory result or AE is achieved.  
 
4.3.13 Patient Replacement Criteria  
 
If a patient is enrolled but is unable to tolerate ribociclib or to participate in laboratory 
workup and cardiac studies as well during cycle 1, she would be deemed non-evaluable. 
In the case of an unexpected trauma or death that is considered unrelated to the 
underlying solid tumor malignancy, patient would be deemed to be non-evaluable.  
 
4.3.14 Discontinuation of the Entire Study  
 
The Investigators may terminate this study provided that written notice is submitted at a 
reasonable time in advance of the intended termination. The following procedures for 
discontinuation will be followed:  
 
1. If the Investigators have decided to prematurely discontinue the study, the 
Investigators will promptly notify in writing the IRB of the decision and give detailed 
reasons for the discontinuation. 
2. The Principal Investigator must promptly notify the enrolled patients of the premature 
discontinuation and administer appropriate treatments such as replacement of 
protocol therapy, if applicable, by other appropriate regimens. 
 
4.3.15 Protocol Deviations  
 
The Investigator should not implement any deviation from the protocol without prior 
review and in accordance with the IRB and local regulations, except when necessary to 
eliminate an immediate hazard to study patients.  
 
5 Study Treatments  
 


43 
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5.1 
Allocation to Treatment  
 
Following full assessment and determination that the patient meets all eligibility criteria 
and has given informed consent for study participation; the investigator or designee will 
contact the study principal investigator (PI) or designee and request study enrollment. A 
patient identification number will be assigned, which must be used on all CRF pages and 
on all documentation and correspondence referencing that patient. 
 
5.2 
Compliance  
 
Drug accountability will be performed at every visit during the first cycle (Appendix iii). The 
number of remaining capsules (of ribociclib and letrozole) will be documented and 
recorded to assess compliance.  
 
The following paragraph is also discussed in the informed consent form. Patient’s or 
their insurance company will have to pay for the prescribed medications as they are part 
of standard care. However, the first 28-day cycle of their treatment with ribociclib will be 
paid for through a voucher. Neither the patient nor insurance company would be charged 
for the first 28-day cycle of ribociclib. This is expected to cover the cost of the ribociclib 
for the duration of the study. More details about the voucher  are available here: 
https://mprsetrial.mckesson.com/7426//#. If the patient and their physician choose to 
continue using ribociclib beyond the first cycle then it would lead to added costs for the 
patient and/or their insurance company. 
 
5.3 
Drugs  
 
The drugs used in the course of this trial will be ribociclib and letrozole or fulvestrant as 
well as a luteinizing hormone-releasing hormone (LHRH) agonist (i.e., goserelin, 
leuprolide) for premenopausal women. These drugs are commercially available drugs and 
will be prescribed by their oncologist.    
 
5.3.1 Ribociclib  
 
Commercially available Ribociclib 600 mg (3 x 200 mg tablets by mouth) QD on days 1 
to 21 of a 28-day  cycle, followed by 7 days off ribociclib (Days 22 to 28).  
 
5.3.2 Fulvestrant  
 
Commercially available fulvestrant will be used. Locally obtained commercial supplies of 
fulvestrant will be used in accordance with local regulations. 
 
 
5.3.3 Letrozole  


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Commercially available letrozole will be used. Locally obtained commercial supplies of 
fulvestrant will be used in accordance with local regulations. 
 
5.3.4 Luteinizing hormone-releasing hormone (LHRH) agonist (e.g., 
goserelin, leuprolide)  
 
Commercially available luteinizing hormone-releasing hormone (LHRH) agonist 
(goserelin or leuprolide) will be used. Locally obtained commercial supplies will be used 
in accordance with local regulations only for premenopausal women. 
 
5.4 
   Dose Modifications  
 
 
• 
The following dose modifications were developed from the FDA label and supplemented 
by additional participant-oriented modifications used in previous clinical trials. 
• 
Grading is according to CTCAE Version 5.0. 
• 
All treatment should be discontinued/delayed until the toxicity resolves to Grade 1 or 
lower, or to baseline if Grade 2 at the time of study entry 
• 
Patients may delay retreatment for up to 28 days to allow the toxicity to resolve. If the 
toxicity requiring dose interruption has not resolved completely or to CTCAE Grade 1 (or 
to baseline if Grade 2 at time of study entry) during the maximum 28-day dose 
interruption period, the patient must permanently discontinue treatment on study 
• 
Patients may restart therapy if toxicities resolve to Grade 1 or lower (or to baseline if 
Grade 2 at the time of study entry). 
• 
If a dose interruption is required at any point on the study because of hematologic toxicity, 
weekly blood draws for CBC will be monitored until the AE resolves, and weekly blood 
draws for CBC also will be required for an additional 4 weeks after the AE has been 
resolved to the specified levels. 
• 
The patient must be referred to a hematologist for further evaluation (1) if frequent transfusions 
are required or (2) if the treatment-related hematologic toxicities have not recovered to CTCAE 
Grade 1 or less after 28 days.  
• 
For major surgery while on treatment, up to 28 days of study treatment interruption is 
allowed.  
• 
All dose interruptions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded. 
 
Table 5: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis 
Interstitial Lung 
Disease/Pneumonitis 
Grade 1 
(asymptomatic) 
Grade 2 
(symptomatic) 
Grade 3 
(Severe 
symptomatic) or 
Grade 4 (life-
threatening) 
No dose 
interruption or 
adjustment is 
Dose interruption 
until recovery to 
Grade ≤ 1 then 
Discontinue 
ribociclib. 


45 
Version 3.6 – 9/28/2023 
 
 
 
 
required. Initiate 
appropriate 
medical therapy 
and monitor as 
clinically indicated 
consider resuming 
ribociclib at the 
next lower dose 
level*. 
If Grade 2 recurs, 
discontinue 
ribociclib. 
*An individualized benefit-risk assessment should be performed when considering 
resuming ribociclib. 
 
 
 


46 
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Table 6: Dose Modification and Management for cutaneous adverse reactions including 
SCARs 
Grade 1 
(< 10% body 
surface area 
(BSA) with 
active skin 
toxicity, no 
signs of 
systemic 
involvement) 
Grade 2 
(10-30% 
BSA with 
active skin 
toxicity, no 
signs of 
systemic 
involvement) 
Grade 3 
(severe rash not responsive 
to medical management; > 
30% BSA with active skin 
toxicity, signs of systemic 
involvement present; SJS*) 
Grade 4  
(any % BSA 
associated with 
extensive 
superinfection, with 
IV antibiotics 
indicated; life 
threatening 
consequences; 
TEN**) 
No dose adjustment is 
required. 
 
 
Initiate appropriate medical 
therapy and monitor as 
clinically indicated. 
Interrupt ribociclib until the 
etiology of the reaction has 
been determined. 
 
If the etiology is a SCAR, 
permanently discontinue 
ribociclib. 
If the etiology is not a SCAR, 
interrupt dose until recovery 
to Grade ≤ 1, then resume 
ribociclib at the same dose 
level. 
If the cutaneous adverse 
reaction still recurs at Grade 
3, resume ribociclib at the 
next lower dose level. 
Permanently 
discontinue 
ribociclib. 
Abbreviations: Severe Cutaneous Adverse Reactions (SCARs); Stevens-Johnson 
Syndrome (SJS); Toxic Epidermal Necrolysis (TEN) 
* SJS (Grade 3 and 4) is defined as skin sloughing covering <10% BSA and 10-30% 
BSA, respectively, with associated signs (e.g., erythema, purpura, epidermal 
detachment and mucous membrane detachment) 
** TEN (Grade 4) is defined as skin sloughing covering >=30% BSA with associated 
symptoms (e.g., erythema, purpura, epidermal detachment, and mucous membrane 
detachment). 
 
 
 


47 
Version 3.6 – 9/28/2023 
 
 
 
 
Table 7: Dose Modification and Management for QT Prolongation 
 
ECGs with QTcF* > 480 ms 
• 
Interrupt ribociclib treatment ms 
• 
If QTcF prolongation resolves to < 481 ms, resume 
treatment at the next lower dose 
• 
If QTcF ≥ 481 ms recurs, interrupt dose until QTcF 
resolves to < 481 ms; then resume ribociclib at 
next lower dose level. 
ECGs with QTcF* > 500 ms 
• 
Interrupt ribociclib treatment if QTcF greater than 
500 ms 
• 
If QTcF prolongation resolves to < 481 ms, resume 
treatment at the next lower dose level. 
Permanently discontinue ribociclib if QTcF interval 
prolongation is either greater than 500 ms or greater 
than 60 ms change from baseline AND associated with 
any of the following: Torsades de Pointes, polymorphic 
ventricular tachycardia, unexplained syncope, or 
signs/symptoms of serious arrhythmia. 
Electrocardiograms (ECGs) should be assessed prior to initiation of treatment. 
Repeat ECGs at approximately Day 14 of the first cycle and at the beginning of the 
second cycle, and as clinically indicated. 
*QTcF = QT interval corrected by Fridericia’s formula. 
 
 
 
 
 


48 
Version 3.6 – 9/28/2023 
 
 
 
 
Table 8: Dose Modification and Management for AST or ALT Elevations 
 
Grade 1 
(> ULN – 
3x ULN) 
Grade 2 
(> 3 to 5x ULN) 
Grade 3 
(>5 to 20x 
ULN) 
Grade 4  
(> 20x ULN) 
AST and/or 
ALT elevations 
from baseline*, 
WITHOUT total 
bilirubin 
increase above 
2x ULN 
No dose 
adjustment 
required 
Baseline* at < 
Grade 2: Dose 
interruption until 
recovery to ≤ 
baseline grade, 
then resume 
ribociclib at same 
dose level. If 
Grade 2 recurs, 
resume ribociclib at 
next lower dose 
level 
Baseline* at Grade 
2: No dose 
interruption 
Dose 
interruption 
until recovery 
to ≤ baseline* 
grade, then 
resume at 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 patients develop ALT and/or AST > 3 x ULN along with total 
bilirubin > 2 x ULN irrespective of baseline grade, discontinue 
ribociclib. 
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; 
ULN, upper limit of normal. 
*Baseline = prior to treatment initiation. 
 
 
 


49 
Version 3.6 – 9/28/2023 
 
 
 
 
Table 9: Dose Modification and Management for Blood bilirubin increased without 
AST/ALT increase  
 
Toxicity/Grade 
Recommendations  
Blood bilirubin increased without AST/ALT increase  
Grade 1: >ULN - 1.5 x (upper 
limit of normal) ULN if baseline 
was normal;  
> 1.0 - 1.5 x baseline if baseline 
was abnormal  
Maintain dose level with LFTs 
monitored bi- weekly.  
Grade 2:  
>1.5 - 3.0 x ULN if baseline was 
normal; 
>1.5 - 3.0 x baseline if baseline 
was abnormal  
Dose interruption of ribociclib. If resolved to ≤ 
grade 1 in ≤ 21 days, then maintain dose level. 
If resolved to ≤ grade 1 in > 21-28 days or 
toxicity recurs, then reduce 1 dose level. 
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption. If 
toxicity recurs after two dose reductions, or 
recovery to ≤ grade 1 is > 28 days, discontinue 
ribociclib.  
Grade 3: >3.0 - 10.0 x ULN if 
baseline was normal;  
>3.0 - 10.0 x baseline if baseline 
was abnormal  
Dose interruption of ribociclib, until resolved to 
≤ grade 1, then lower 1 dose level of ribociclib. 
Repeat liver enzyme and bilirubin tests twice 
weekly for 2 weeks after dose resumption. If 
resolved to ≤ grade 1 in > 28 days or toxicity 
recurs, discontinue ribociclib.  
Grade 4: >10.0 x ULN if baseline 
was normal;  
>10.0 x baseline if baseline was 
abnormal  
Discontinue ribociclib.  
 
 
 
 
 


50 
Version 3.6 – 9/28/2023 
 
 
 
 
Table 10: Dose Modification and Management for Neutropenia 
 
Grade 1 or 2 
(ANC 
1000/mm3 to 
LLN) 
Grade 3 
(ANC 500 to 1000/mm3) 
Grade 3 Febrile 
Neutropenia 
Grade 4  
(ANC < 500/mm3) 
No dose 
adjustment 
required 
Dose interruption until 
recovery to Grade ≤ 2. 
Resume ribociclib at the same 
dose level. 
If toxicity recurs at Grade 3, 
dose interruption until 
recovery, then resume 
ribociclib at the next lower 
dose level. 
Dose interruption 
until recovery of 
neutropenia to 
Grade ≤ 2. 
Resume ribociclib 
at the next lower 
dose level. 
Dose interruption 
until recovery to 
Grade ≤ 2. 
Resume ribociclib 
at the next lower 
dose level. 
Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal. 
*Grade 3 neutropenia with single episode of fever > 38.3°C (or) above 38°C for more than 
one hour and/or concurrent infection. 
 
Table 11. Dose modifications and Management for Thrombocytopenia and Anemia 
 
Toxicity/Grade 
Recommendations  
Thrombocytopenia (platelet count) 
Grade 1: <75,000 mm3 
No dose adjustment required  
Grade 2: 50-75 mm3 
Dose interruption until recovery to grade ≤1. 
Re- initiate ribociclib at the same dose.  
Grade 3: 25-50 mm3 
Dose interruption until recovery to grade ≤1. 
Re- initiate ribociclib at the same dose level. If 
toxicity recurs at grade 3: temporary dose 
interruption until recovery to grade ≤1 and 
reduces ribociclib to the next lower dose level.  
Grade 4: >25 mm3 
Dose interruption until recovery to grade ≤1. 
Re- initiate ribociclib at the next lower dose 
level. If toxicity recurs at grade 4: discontinue 
ribociclib.  
Anemia (hemoglobin) 
Grade 1: ≥10.0 – LLN g/dL 
No dose adjustment required.  
Grade 2: ≥8.0 – <10.0 g/dL 
No dose adjustment required.  
Grade 3: <8.0 - >4.9 g/dL, 
transfusion indicated  
Dose interruption until recovery to grade ≤2. 
Re- initiate ribociclib at the same dose.  
Grade 4: Life-threatening consequences; 
urgent intervention indicated  
Discontinue ribociclib.  
 
 
Table 12: Dose Modification and Management for Other Toxicities that are deemed 
related and clinically significant by the treating physician* 
Grade 1 or 2 
Grade 3 
 
Grade 4  


51 
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No dose adjustment is 
required. Initiate appropriate 
medical therapy and monitor 
as clinically indicated 
Dose interruption until recovery to 
Grade ≤ 1 then resume ribociclib at 
same dose level. 
If Grade 3 recurs, resume ribociclib at 
the next lower dose level. 
Discontinue 
ribociclib. 
*Excluding adverse reactions discussed in tables 5-11. 
 
 
Table 13. Dose Modifications for Toxicities Related to Ribociclib  
 
Starting dose 
600 mg 
First dose reduction  
400 mg 
Second dose reduction 
200 mg 
 
 
5.5       Drug Accountability  
 
Ribociclib and letrozole are oral medications, patients will bring the containers to the 
visits for pill accountability, per section 5.2. 
 
5.6 
Concomitant Medications  
 
Patients will be instructed to consult the Investigator or other appropriate study 
personnel before taking any new medications, supplements, or vaccines during the 
study prescribed by a provider or over the counter medications or supplements-. 
   
Concomitant medications taken within 30 days prior to baseline will be recorded. At each 
study visit, all concomitant medications taken since the previous visit, including 
prescription and non-prescription medications, vitamin and mineral supplements, herbal 
and naturopathic remedies, vaccines, and supportive therapies, will be recorded.   
 
5.6.1 Permitted Concomitant Medications  
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases, and 
supportive care agents, such as pain medications, antiemetics, and antidiarrheals are 
allowed. Potential drug interaction between ribociclib and concomitant medications 
should always be taken into consideration when prescribing such medications. 
Bisphosphonates and denosumab are allowed.  
 
Prophylactic use of WBC growth factors with ribociclib is not recommended.  
 
Antiemetic therapy can be used according to clinical guidelines for antineoplastic 
medications with low to minimal emetogenic potential for treatment and/or prevention of 
nausea and vomiting as a result of study treatment  


52 
Version 3.6 – 9/28/2023 
 
 
 
 
 
5.6.2 Medications Prohibited  
 
A full list of the medications that are prohibited during study treatment can be found in 
the appendix 14.4.  
 
Other investigational and anti-neoplastic therapies (including radiation) are prohibited.  
 
Systemic corticosteroid treatment should not be given during the study treatment with 
ribociclib, except for:  
a. Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive 
airways diseases), eye drops or local injections (e.g. intra-articular) 
b. A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-
inflammatory potency of 4 mg dexamethasone (e.g. for chronic obstructive 
pulmonary disease or as an antiemetic). 
 
 
 
5.6.3 Medications Not Recommended  
 
In appendix 14.5 there is a list of the medications are not recommended during study 
treatment and within 14 days prior to the first dose of study medication and for the 
duration of study treatment. These medications should be excluded if possible. If they 
must be given, then it will be based on the investigator’s judgment. 
 
6 Study Procedures  
 
6.1 
Schedule of Events  
 
Screening assessments are to be conducted within 28 days prior to initiating protocol 
therapy unless otherwise specified. CBC with differential and biochemical profile 
(sodium, potassium, calcium, chloride, bicarbonate, BUN, creatinine, AST, ALT, total 
bilirubin, albumin, alkaline phosphatase) assessments must be done within 28 days prior 
to initiating protocol therapy, between day 8-16 of cycle 1, and prior to initiation of cycle 
2.  
 
 
 


53 
Version 3.6 – 9/28/2023 
 
 
 
 
Table 14. Study Calendar: Patients will be followed for one cycle 
Study procedure/task 
Screening a 
Treatment cycle 
is 28 days 
End of study b 
Study day 
≤ 28 days prior 
to study entry 
Cycle 1 Day 8 - 
16 
 
Procedures 
 
 
 
Eligibility criteria c 
X 
 
 
Informed consent d 
X 
 
 
Clinical visits e 
X 
Per routine clinical practice 
Adverse Events  
 
X 
X 
CYP3A5 Screening f 
X 
 
 
Treatments g 
 
 
 
Ribociclib 
 
600 mg PO once daily for 21 days, 
followed by a 7-day rest period to 
complete a 28-day treatment cycle 
Fulvestrant 
 
500 mg IM  injection on days 1 and 
15 
Letrozole  
 
2.5 mg PO daily 
Goserelin  
 
3.6 mg SQ every 28 days  
or 
10.8 mg SQ every 12 weeks 
Leuprolide depot 
 
3.75 mg IM every 28 days 
or 
11.25 mg IM every 12 weeks 
Tests 
 
 
 
Blood draw for pharmacogenomic studies 
 
 
X 
 
Serial blood draws for pharmacokinetic 
studies 
• 
Immediately prior to the ribociclib 
dose, and 0.5hr ± 5min, 1hr ± 5min, 
2hr ± 15min, 4hr ± 15min, 6hr ± 
15min after the daily dose of 
ribociclib.  
 
X 
 
Electrocardiogram h 
X 
X 
X 
CBC with differential and CMP i 
X 
X 
X 
Pregnancy Test j 
X 
 
 
NCI CTCAE PRO questionnairek   
X 
X 
X 
Adverse event monitoring log  
X 
X 
X 
Medication adherence PROMIS 
questionnaire and drug accountability 
 
X 
X 
 
a Screening: All assessments should be performed within 28 days prior to study entry. 
Study entry will be defined by confirmation of eligibility.  


54 
Version 3.6 – 9/28/2023 
 
 
 
 
b This visit will occur prior to initiation of cycle 2 (e.g., 29th day of the study, plus or minus 
3 days) 
c Eligibility Criteria Evaluation: Patients must meet all of the eligibility criteria reported in 
the protocol  
d Informed Consent: Must be obtained prior to undergoing any study-specific procedures. 
e Clinical Visits: clinical visits will include medical history, vital signs and physical exam 
and will be conducted as per local practice and as clinically indicated. Physical 
Examination includes a general clinical examination of major body systems. 
f To be performed after informed consent and used for screening according to sections 
3.6 and 4.3.7. CYP3A5 Screening may be bypassed per Principal Investigator discretion 
if the  necessary number of participants with each phenotype are enrolled (cohort of AA 
or Black participants - at least 3 poor metabolizers; cohort of NHW participants - at least 
3 intermediate or normal metabolizers). If CYP3A5 is already performed it does not need 
to be repeated within the window of < 28 days. 
g All patients will receive ribociclib plus physician choice endocrine therapy with 
fulvestrant or letrozole. Luteinizing hormone-releasing hormone (LHRH) agonist 
(goserelin or leuprolide) will be required for premenopausal women. 
h To be performed at these times per routine clinical practice and the treating physician: 
prior to treatment initiation; repeat on day 8-16 of cycle 1, and prior to initiation of cycle 2 
i To be performed at these times per routine clinical practice and the treating physician: 
baseline, repeat on day 8-16 of cycle 1, and prior to initiation of cycle 2  
j To be performed at these times per routine clinical practice and the treating physician: 
Pregnancy test (serum or urine), required for women of childbearing potential 
k Questionnaires to be completed within 28 days of C1D1 
 
6.2 
Patient Withdrawal  
 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator for safety or behavioral reasons, 
or the inability of the patient to comply with the protocol required schedule of study visits 
or procedures at a given study site.  
 
Reasons why patients may discontinue or be withdrawn from the protocol may be due to 
the following:  
- AEs  
- Intercurrent illness  
- Disease progression  
- Patient is non-compliant  
- Patient is lost to follow-up  
- Withdrawal of consent  
 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient. In any circumstance, every effort should be made to document patient 
outcomes, if possible. The investigator should inquire about the reason for withdrawal, 
request the patient to return all unused investigational product, request the patient to 


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return for a final visit, if applicable, and follow up with the patient regarding any unresolved 
AEs. 
 
 
 
7 Assessments  
 
7.1 
Safety Assessments  
 
Safety assessment will consist of monitoring of all AEs, including serious adverse events 
(SAEs) at every clinical visit and monitoring of hematology to be performed to check the 
patient’s eligibility at the time of screening, on day 8-16 of cycle 1, and prior to initiation 
of cycle 2 
 
Other procedures as necessary according to standard of care and in accordance with 
each site’s institutional guidelines will be assessed to monitor for AEs related to the 
underlying disease, treatment with ribociclib, other endocrine therapy, or supportive 
therapies. 
 
7.1.1 Physical Examination 
 
A full physical examination of all major body systems will be required at screening. 
Symptom directed physical examinations will be performed as per routine clinical practice 
during the study.  Only physical examination at screening will be recorded on the case 
report form (CRF).  
  
7.1.2 Safety Assessments  
 
Blood tests will include the following:  
 
1) Hematology panel: complete blood count with differential  
2) Blood chemistry panel: ALT, ASL, alkaline phosphatase, total bilirubin, serum creatinine  
 
Blood tests will be drawn at the time points described in the study calendar table and 
analyzed at local laboratories.  
  
A hematology panel (includes complete blood count with differential) will be performed to 
verify the patient’s eligibility at screening, repeat on day 8-16 of cycle 1, and prior to 
initiation of cycle 2. Laboratory data will be recorded on the CRF.  
  
Blood Chemistry will be performed to verify the patient’s eligibility at screening, repeat on 
day 8-16 of cycle 1, and prior to initiation of cycle 2. Laboratory (blood chemistry and 


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hematology panels) data will be recorded on the CRF. In the case a laboratory abnormality 
meets the definition of AE, as determined by the investigator and according to AE 
reporting, this must be captured on an AE CRF page.  
 
Electrocardiograms will be performed to verify the patient’s eligibility at screening, repeat 
on day 8-16 of cycle 1, and prior to initiation of cycle 2 of treatment with ribociclib. 
Data will be recorded on the CRF. In the case an electrocardiogram abnormality meets 
the definition of AE, as determined by the investigator and according to AE reporting, this 
must be captured on an AE CRF page. 
8 Adverse Event Reporting  
 
8.1 
Adverse Events  
 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
 
8.2 
Reporting Period  
 
For SAEs, the active reporting period to the principal investigator begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s participation 
in the study, through the completion of cycle 1.  
  
AEs (serious and non-serious) should be recorded on the CRF from the time the patient 
has taken at least one dose of ribociclib through the last patient visit.  
  
Death must be reported if it occurs during the SAE reporting period after the last dose of 
ribociclib, irrespective of any intervening treatment.  
 
8.3 
Definition of Adverse Events  
 
An AE is any untoward medical occurrence in a clinical investigation patient administered 
a product or medical device; the event need not necessarily have a causal relationship 
with the treatment or usage.  Examples of AEs include but are not limited to:  
 
- Abnormal test findings  
- Clinically significant symptoms and signs  
- Changes in physical examination findings  
- Hypersensitivity  
- Drug abuse  
- Drug dependency  


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 Additionally, 
they 
may 
include 
the 
signs 
and 
symptoms 
resulting 
from:  
 
- Drug overdose  
- Drug withdrawal  
- Drug misuse  
- Drug interactions  
- Medication error  
- Occupation exposure  
- Worsening of signs and symptoms of the malignancy under study should be reported as 
AEs in the appropriate section in the CRF  
  
Disease progression assessed by measurement of malignant lesions on radiographs or 
other methods should not be reported as AEs.  
 
8.3.1 Medication Errors 
 
Medication errors may result from the administration or consumption of the wrong drug, 
by the wrong patient, at the wrong time, or at the wrong dosage strength.  
  
Such medication errors occurring to a study participant are to be captured on the 
medication error CRF which is a specific version of the AE page, and on the SAE form 
when appropriate.  
  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:  
 
- Medication errors involving patient exposure to the investigational product  
- Potential medication errors or uses outside of what is foreseen in the protocol that does 
or does not involve the participating patient.  
 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of 
the AE page and, if applicable, any associated AE(s) are captured on an AE CRF page.  
 
8.4 
Abnormal Test Findings  
 
The criteria for determining whether an abnormal objective test finding should be reported 
as an AE are as follows:  
 
- Test result is associated with accompanying symptoms; and/or  
- Test result requires additional diagnostic testing or medical/surgical intervention; and/or  


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- Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy; and/or  
 
- Test result is considered to be an AE by the investigator. 
  
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE.  
 
8.5 
Serious Adverse Events 
 
An SAE is any untoward medical occurrence at any dose that:  
- Results in death 
- Is life-threatening (immediate risk of death) 
- Requires inpatient hospitalization or prolongation of existing hospitalization  
- Results in persistent or significant disability/incapacity (substantial disruption of the ability 
to conduct normal life functions);  
- Results in congenital anomaly/birth defect  
  
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE. If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE and 
as an SAE with CTC Grade 5 (see Section on Severity Assessment).  
  
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization. However, if it is determined that the 
event may jeopardize the patient or may require intervention to prevent one of the other 
AE outcomes, the important medical event should be reported as serious. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
 
If an AE meets any of the following criteria, it is to be reported to the DSMC as an SAE:  
 
1) Death of Patient An event that results in the death of a patient. 
2) Life-Threatening An event that, in the opinion of the Investigator, would have resulted in 
immediate fatality if the medical intervention had not been taken. This does not include 
an event that would have been fatal if it had occurred in a more severe form. 


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3) Hospitalization (unless planned for observation, protocol compliance, elective 
procedures, social reasons) or 
4) Prolongation of Hospitalization An event that results in an admission to the hospital 
for any length of time or prolongs the patient's hospital stay. This does not include an 
emergency room visit or admission to an outpatient facility. 
5) Congenital Anomaly An anomaly detected at or after birth, or any anomaly that results 
in fetal loss.  
6) Persistent or Significant Disability/Incapacity An event that results in a condition that 
substantially interferes with the activities of daily living of a study patient. Disability is not 
intended to include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle). 
7) Important Medical Event Requiring Medical or Surgical Intervention to Prevent 
Serious Outcome An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or surgical intervention to prevent any of 
the outcomes listed above (i.e., death of patient, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
Dose-limiting toxicities are defined as AEs that are possibly, probably, or definitely 
related to the therapy (any part of the combination) and would require treatment 
discontinuation.  
 
8.6 
Hospitalization 
 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital 
or equivalent healthcare facility or any prolongation to an existing admission. Admission 
also includes transfer within the hospital to an acute/intensive care unit (e.g., from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological 
floor to a tuberculosis unit).  An emergency room visit does not necessarily constitute a 
hospitalization; however, the event leading to the emergency room visit should be 
assessed for medical importance.  
  
Hospitalization does not include the following:  
- Rehabilitation facilities  
- Hospice facilities  
- Respite care (i.e. caregiver relive)  
- Skilled nursing facilities  
- Nursing homes  
- Same-day surgeries  
 


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not an SAE. Examples include:  
- Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (e.g., for work-up of persistent 
pre-treatment lab abnormality);  
- Social admission (e.g., patient has no place to sleep);  
- Administrative admission (e.g., for yearly physical examination);  
- Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol);  
- Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery);  
- Hospitalization for observation without a medical AE;  
- Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;  
- Admission exclusively for the administration of blood products  
  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE, and 
the resulting appendectomy should be recorded as treatment of the AE.  
 
8.7 
Severity Assessment  
 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria (NCI CTC), (Version 5.0).  Note the distinction between the severity and the 
seriousness of an AE.  A severe event is not necessarily an SAE. For example, a 
headache may be severe (interferes significantly with the patient's usual function) but 
would not be classified as serious unless it met one of the criteria for SAEs, listed above.  
 
The study Investigator will rate the severity of each AE according to the NCI CTCAE 
Version 5.0. For AEs not captured by the NCI CTCAE Version 5.0, the following should 
be used: 
1) Grade 1 (Mild) The AE is transient and easily tolerated by the patient. No dose 
adjustment recommended.  
2) Grade 2 (Moderate) The AE causes the patient discomfort and interrupts the patient's 
usual activities. Interrupt therapy until grade <1, reinitiate ribociclib at the same dose, if 
AE reoccurs at grade 2, hold until grade <1, and restart at the next lower dose level. 
3) Grade 3 (Severe): The AE causes considerable interference with the patient's usual 
activities. Interrupt therapy until grade <1, reinitiate ribociclib at the same dose, if AE 
reoccurs at grade 2, hold until grade <1, and restart at the next lower dose level. If 
toxicity reoccurs grade 3 discontinue permanently. 


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4) Grade 4 (Life Threatening) The AE causes considerable interference with the patient's 
usual activities and maybe incapacitating or life-threatening. Discontinue ribociclib.  
5) Grade 5 (Severe, Resulting in Death) The AE resulted in the death of the patient. 
 
 
 
8.8 
Causality Assessment  
 
The investigator’s assessment of causality must be provided for all AEs (serious and non- 
serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an AE; generally, the facts (evidence) or arguments to suggest a causal 
relationship should be provided. If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” If the investigator's causality assessment is “unknown but not 
related to investigational product”, this should be clearly documented on study records.  
 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.  
 
8.9 
Withdrawal Due to Adverse Events 
 
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. When a patient withdraws because of an SAE, the SAE must be reported in 
accordance with the reporting requirements defined below.  
 
8.10 Eliciting Adverse Event Information 
 
The investigator is to report all directly observed AEs and all AEs spontaneously reported 
by the patient. In addition, each study patient will be questioned about AEs.  
 
 
8.11 Reporting Requirements  
 
8.11.1 Serious Adverse Events  
 
In the event of an SAE, whether related to study drugs, study procedures or even if not 
directly related to any study intervention, the study team will notify the Principal 


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Investigator and Co-Principal Investigators, via email and cc: LCCC-Multicenter-
IITs@georgetown.edu within 24 hours of being made aware of the SAE. SAEs should be 
reported on the FDA Medwatch form.  
 
SAEs should be reported to the IRB, per local IRB guidelines, and to the DSMC, per 
DSMC reporting guidelines. 
 
8.11.2 Non-Serious Adverse Events   
 
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for 
the collection of SAE information is not the same as the AE CRF. Where the same data 
are collected, the forms must be completed in a consistent manner. For example, the 
same AE term should be used in both forms. AEs should be reported using concise 
medical terminology on the CRFs as well as on the form for the collection of SAE 
information.  
 
9 Data Analysis and Statistical Methods  
 
9.1 
Sample Size, Accrual and, Study Duration  
 
This study is powered to assess the primary outcome (ribociclib in CYP3A5 poor 
metabolizers vs. CYP3A5 intermediate or normal metabolizers) independently within 
each race-based cohort. The pharmacokinetic study used to inform the FDA’s decision 
to suggest alternative dosing for patients prescribed a strong CYP3A inhibitor (ritonavir) 
exhibited a 3.2-fold increase in AUC (15). Genotype may have a lower effect, but the 
extent of the effect is unclear. We will aim to detect a minimum clinically meaningful 
change: 2-fold change in AUC, which is less than the fold changes seen in the ritonavir 
CYP3A drug interaction pharmacokinetic study. In the meantime, data from the same 
pharmacokinetic study showed the standard deviation of AUC fold change (in log2 scale) 
was 0.56. Given that the groups in our study are considered similar, to be conservative, 
we used the standard deviation of 0.75 in our calculation. 
 
Allelic frequencies for CYP3A5 are provided from CPIC and PharmGKB and translated 
to phenotypes via the Hardy-Weinberg equation (32). Based on these frequencies 
(normal metabolism: 35%; intermediate metabolism: 48%; poor metabolism: 16%), a 
sample size of 18 would provide 80% power at an α=0.05 to detect a 2-fold change in 
AUC between CYP3A5 poor metabolizers vs. CYP3A5 expressors (i.e., CYP3A5 
intermediate or normal metabolism) in African Americans/Blacks.  Based on the allelic 
frequencies for Non-Hispanic Whites (normal metabolism: 0.6%; intermediate 
metabolism: 14.7%; poor metabolism: 84.6%), a sample size of 18 would also provide 
80% power at an α=0.05 to detect a 2-fold change in AUC between CYP3A5 poor 
metabolizers vs. CYP3A5 expressors (i.e., CYP3A5 intermediate or normal metabolism). 


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Thus, an overall sample size of 36 would provide adequate power to independently test 
the primary outcome in the two race-based cohorts.  
 
9.2 
Statistical Analysis Plan  
 
Primary analyses will be performed as follows. Within each race-based cohort, the 
ribociclib exposure which measured by ribociclib AUC will be summarized by median 
[Interquartile range, IQR], and two-sample t-test if normality holds or Wilcoxon-Mann-
Whitney test will be used to compare AUC between CYP3A5 poor metabolizers and 
CYP3A5 intermediate or normal metabolizer in each independent race-based cohort.   
Secondary analyses will be performed as follows. Descriptive statistics will be used to 
characterize the data profile, frequency and percentages for categorical variables, and 
mean (SD) or median [IQR] for continuous variables based on the data normalization. 
Multiple regression will be used to identify variables associated with ribociclib AUC. To 
best account for any factor that may affect ribociclib exposure, covariates to be 
assessed include CYP3A5 metabolism status, renal function, liver function, age, race, 
weight, sex, among others. Any covariates with P < 0.2 on univariate analysis will enter 
the stepwise multiple linear regression model, with P < 0.05 considered statistically 
significant. This methodology will also be used to assess a change in absolute neutrophil 
count and QTc as the outcome variable. Depending on data distribution, a two-sample t-
test or Wilcoxon-Mann-Whitney test will be used for 1) a change (baseline and C1D8-
C1D16) in continuous variables (e.g., QTc, absolute neutrophil count) between CYP3A5 
poor metabolizers and CYP3A5 intermediate or normal metabolizers, 2) to check the 
association between a continuous variables and categorical risk factors. Pearson 
correlation coefficient or Spearman correlation coefficient will be calculated to measure 
the association between two continuous variables. Fisher’s exact test will be used for 
checking the association between two categorical variables. AEs will be assessed with 
descriptive statistics and univariate logistic regression will assess the occurrence of 
specific AEs with pharmacokinetic properties (e.g., AUC, Cmax). The approach from the 
linear regressions will be adapted to logistic regression to identify covariates associated 
with the occurrence of grade III or IV neutropenia.  
 
Descriptive analysis of the PRO-CTCAE adverse event log to determine frequency of 
adverse events by race and by CYP3A5 genotype.  
Descriptive statistics will be used to describe the patients reported outcomes in the 
survey (see Appendices). As an exploratory analysis, multiple regressions will be used 
to assess the relationship between patients reported outcomes and other covariates 
(mentioned above) with ribociclib AUC.  
 
9.3 
Correlative Studies 
 


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The PharmacoScanTM microarray provides data on 4627 markers for each patient. 
These data serve as a rich opportunity for hypothesis-generating correlative studies with 
pharmacokinetic properties or AEs. Study designs for exploratory pharmacogenomics 
are usually conducted as either candidate gene studies or a genome-wide association 
study (GWAS) (37). This work will be conducted as a candidate gene analysis as the 
sample size (n = 36) is too limited to attempt a study similar to a GWAS. 
 
Candidate genes will be selected based on biological plausibility. For example, although 
data around CYP3A4 are limited (section 1.4), it is a prime candidate gene given 
overlapping substrate specificity with CYP3A5 and the significant sequence homology 
(approximately 84%) between CYP3A4 and CYP3A5. Additional candidate genes will be 
identified based on metabolic pathways, signaling pathways, ribociclib mechanism of 
action. 
 
A list of genes will be created through a primary literature review and information from 
the FDA review. Given the pace of discovery work in this field, the list will be generated 
at or near the completion of the data collection. Prior to the analysis, genes will be 
ranked so that the stronger candidates are tested with a given outcome first. For 
example, CYP3A4 will likely be the first gene assessed for an association with ribociclib 
AUC with statistical analysis as described in section 9.3 and those similar to other work 
(38).  
 
Another example of a candidate gene is the ABCB1 gene which is included in the 
PharmacoScanTM assay and single nucleotide variations were recently associated with 
persistent chemotherapy induced alopecia (39). A recent study in our institution showed 
that the use of scalp cooling in African American/Black women with early stage breast 
cancer receiving chemotherapy was not effective preventing alopecia; alopecia was 
prevented in 0/11 patients while previous studies in White populations have reported 50-
80% success (40). For this exploratory analysis we aim to assess if this difference could 
be related to genetic variations and this could potentially be studied in the future with 
cytotoxic agents associated to alopecia. Depending on how many genes are in the list, 
we will provide the q-value as well to control the false discovery rate and we may also 
attempt a learning algorithm such as LASSO or a variant of it to further screen the 
associated markers 
9.4 
Safety Analysis  
 
Safety data will be summarized for all patients who received one cycle of ribociclib. 
 
9.5 
Data Safety Monitoring Committee  
 
As this study is an investigator-initiated study utilizing FDA approved agents it is 
considered a moderate risk study that requires real-time monitoring by the PI and study 


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team and semiannual reviews by the LCCC Data and Safety Monitoring Committee 
(DSMC).  
 
The Principal Investigator and with other investigators (when available) and research 
staff will review the accrual, toxicities, and other protocol issues at weekly protocol 
meetings and on monthly network disease group teleconferences.  
  
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data 
and Safety Monitoring Committee every 6 months from the time the first patient is enrolled 
in the study. Results of the DSMC meetings will be forwarded to the IRB. E-mail notification 
from the PI will be sent to the DSMC Chair any time there is a major event or issue with 
the trial affecting patient safety or conduct of the trial. The DSMC Chair has the discretion 
to have the study reviewed by the DSMC sooner more frequently than every 6 months 
based on information received.  
 
All SAEs, which are considered unanticipated problems, are required to be reported to the 
IRB. In addition, all SAEs will be submitted to the DSMC, per DSMC requirements. Based 
on SAEs, the IRB retains the authority to close the study to further accrual pending more 
detailed reporting and/or modifications to further reduce risk and maximize the safety of 
participating patients.  
 
DSMC recommendations should be based not only on results for the trial being monitored 
as well as on data available to the DSMC from other studies. It is the responsibility of the 
PI to ensure that the DSMC is kept apprised of non-confidential results from related studies 
that become available. It is the responsibility of the DSMC to determine the extent to which 
this information is relevant to its decisions related to the specific trial being monitored.   
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB. If 
the DSMC recommends a study change for patient safety or efficacy reasons the trial PI 
must act to implement the change as expeditiously as possible. In the unlikely event that 
the trial PI does not concur with the DSMC, then the Lombardi Cancer Center Associate 
Director of Clinical Research must be informed of the reason for the disagreement. The 
trial PI, DSMC Chair, and the Lombardi Cancer Center ADCR will be responsible for 
reaching a mutually acceptable decision about the study. Confidentiality must be 
preserved during these discussions. However, in some cases, relevant data may be 
shared with other selected trial investigators and staff to seek advice to assist in reaching 
a mutually acceptable decision.  
 
If a recommendation is made to change a trial for reasons other than patient safety or 
efficacy the DSMC will provide an adequate rationale for its decision.  
 


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The rights and privacy of people who participate in a clinical research will be protected at 
all times. In the event that data are to be used for broader research, it will be de-
identified and would not permit linkages to individual research participants and variables 
that could lead to deductive disclosure of the identity of individual patients. No efforts will 
be made to identify individual cases, and any shared archive data will not be linked to 
other identifiable data. The following de-identification and security procedures will be 
followed to share information with collaborators part of the study: 
 
1) Deletion of 18 HIPAA identifiers 
a. Non-identifiable unique patient ID will be generated  
2) Secure netID-based single sign-on (netID is Georgetown’s LDAP based secure login 
system) 
3) Users will have to authenticate themselves prior to accessing controlled data 
4) Furthermore, based on their roles, users will require authorization to see specific studies 
5) Auditing and security assessments will be performed on a quarterly basis to ensure 
appropriate de-identification procedures and use of data. 
For future studies involving new data types that are not covered in the descriptions 
above, NIH policy on data sharing will be followed where applicable. For example, 
Genome Wide Association Studies, if conducted, will comply with NIH Guidelines NOT-
OD-07-088 (http://grants.nih.gov/grants/gwas/) for data release. Following these 
guidelines, GWAS data will be submitted to NCBI’s dbGAP 
(http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other tools as the NIH’s policy on 
GWAS evolves. 
 
10  Quality Control and Quality Assurance  
 
The study site may be subject to review by the IRB or to inspection by appropriate 
regulatory authorities. It is important that the investigator(s) and their relevant personnel 
are available during the monitoring visits and possible audits or inspections and that 
sufficient time is devoted to the process. 
11 Data Handling and Record Keeping 
 
11.1 Case Report Forms and Electronic Data Record  
 
As used in this protocol, the term CRF should be understood to refer to an electronic 
data record. A CRF is required and should be completed for each included patient.  
Patient data will be entered into the online accessible database. This database is 
housed at Lombardi-Georgetown but is accessible anywhere there is internet access.  
The data manager and research coordinator at each site will attend an online training 
session so that they may learn how to enroll data into the database. All screening data 


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should be entered prior to starting therapy, and all ongoing patient data should be 
entered within 10 business days of each patient visit. The investigator has ultimate 
responsibility for the collection and reporting of all clinical, safety, and laboratory data 
entered on the CRFs and any other data collection forms (source documents) and 
ensuring that they are accurate, authentic/original, attributable, complete, consistent, 
legible, timely (contemporaneous), enduring and available when required. Blood 
chemistry laboratory data during the treatment period, electrocardiograms, and 
concomitant medications will be collected on the CRF. Any corrections to entries made 
in the CRFs or source documents must be dated, initialed, and explained (if necessary) 
and should not obscure the original entry.  
 
In most cases, the source documents are the hospital's or the physician's patient chart. In 
these cases, data collected on the CRFs must match the data in those charts. In some 
cases, the CRF, or part of the CRF, may also serve as source documents. In these cases, 
a document should be available at the investigator’s site clearly identify those data that 
will be recorded in the CRF, and for which the CRF will stand as the source document.  
 
 
11.2 Record Retention  
 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to 
link records, e.g., CRFs and hospital records), all original signed informed consent 
documents, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence 
(e.g., letters, meeting minutes, telephone calls reports).  The records should be retained 
by the investigator according to International Conference on Harmonization (ICH), local 
regulations, or as specified in the Clinical Study Agreement (CSA), whichever is longer.  
 
If the investigator becomes unable for any reason to continue to retain study records for 
the required period (e.g., retirement, relocation), the study records must be transferred to 
a designee, such as another investigator, or another institution. Investigator records 
must be kept for a minimum of 2 years after completion or discontinuation of the study or 
for longer if required by applicable local regulations.  
 
11.3 Collaboration with the National Cancer Institute 
 
As described in sections 4.1 and 4.3.7, the NCI is collaborating with GLCCC and MWHC 
by providing pharmacogenomics and PK testing for the study. The NCI will receive 
biological samples (e.g., plasma, isolated DNA) in order to perform these assays. In 
addition, the NCI may receive de-identified data (e.g., age, height, weight, concomitant 
medications) to assist with the PK and pharmacogenomics analyses. Deidentified data 
will be encrypted and sent electronically to NCI investigators listed on this protocol.   


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12 Ethics  
 
12.1 Institutional Review Board (IRB) 
 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB.  All correspondence with the 
IRB/EC should be retained in the Investigator File.  
 
The only circumstance in which an amendment may be initiated prior to IRB approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  
In that event, the investigator must notify the IRB in writing immediately after the 
implementation.  
 
12.2 Ethical Conduct of the Study  
 
This protocol will be conducted in accordance with legal and regulatory requirements, as 
well as the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008).   
 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.  
 
12.3 Patient Information and Consent  
 
All parties will ensure the protection of patient personal data and will not include patient 
names or other identifiable data in any reports, publications, or other disclosures, except 
where required by laws.  
 
The study site will maintain a confidential list of subjects who participated in the study 
linking their numerical code to the subject’s actual identity. The informed consent/assent 
document must be in compliance with ICH GCP, local regulatory requirements, and legal 
requirements, including applicable privacy laws.  
 
The investigator must ensure that each study patient is fully informed about the nature 
and objectives of the study and possible risks associated with participation.  
 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed, unless a waiver 
of informed consent has been granted by the IRB.  The investigator will retain the original 


69 
Version 3.6 – 9/28/2023 
 
 
 
 
of each patient's signed consent/assent document.   
 
Participants are compensated for their time, transportation costs, and parking through a 
flat compensation of $150. This compensation will be available upon completion of the 
study visit between C1D8-C1D16. For subjects that are seen at the Georgetown CRU, the 
CRU will provide lunch for the participants during their visit, which is also paid for by the 
study. At other local sites, the participants will be provided a $10 stipend for a meal.   
 
12.4 Risk/Benefit Assessment 
 
12.4.1 Risks 
 
All risks have been described in the consent form. Based on the assessments of the risk-
to-benefit ratio, the risk level associated with participation in this study is low. 
 
Participants will undergo blood draws in this study. These blood draws will be performed 
by trained personnel who use appropriate hygiene practices to reduce the risk of infection. 
Minor discomfort and bruising related to needle insertion are common. 
 
There are risks secondary to study participation related to genetic testing, such as risks 
related to confidentiality surrounding the genetic information and the chance that the 
genetic information could in some way expose the study subject to increased risk 
regarding employment discrimination or that future life, health, disability or long term care 
insurance providers could potentially use this genetic information to modify the availability 
or pricing of insurance coverage. These concerns have arisen mainly in regard genetic 
testing results that are associated with susceptibility to disease risk and are generally less 
of a concern with pharmacogenomic testing such as that in the proposed study. Moreover, 
these genetic results are not meant for clinical use and will not be uploaded to the 
electronic health record or delivered to patients. The consent process will ensure patients 
are aware that they will not receive genetic results and that the genetic results are intended 
for research purposes only. Patients who would like to undergo genetic testing are free to 
do so outside of this research study. 
 
However, in the event this information is inadvertently or mistakenly released, the Genetic 
Information Nondiscrimination Act (GINA) indicates 1) health insurers may not use 
individual genetic information to make decisions about eligibility or to set premium 
amounts, and 2) employers with 15 or more employees may not use genetic information 
for decisions about hiring, promotion, or employment termination. They may not use 
individual genetic information when setting the terms of employment.    
 
12.4.2 Protections Against Risks 
 


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We will prevent or minimize risk through several actions. First, we collect study subject 
identifying information only when absolutely necessary. Second, participation is always 
completely voluntary with the right to withdraw at any time. Third, as described in section 
11, we have a very rigorous data storage and security plan that minimizes any chances of 
a data breach.   
 
12.4.3 Benefits 
 
There is no direct clinical benefit to patients for participating in this study. In the absence 
of a direct benefit, the study may advance the fields by provided an increased 
understanding of ribociclib metabolism, pharmacokinetics, and pharmacogenomics in the 
treatment of advanced breast cancer.   
 
 
12.5 Reporting of Safety Issues  
 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the 
principal investigator should be informed immediately.  
 
In addition, the principal investigator will be notified of any urgent safety measures taken 
by any investigator to protect the study patients against any immediate hazard, and of any 
serious breaches of this protocol or ICH GCP that the investigator becomes aware of. 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.    
 
a. Emergency Modifications: Investigators may implement a deviation from, or a 
change of, the protocol to eliminate an immediate hazard(s) to trial subjects without 
prior IRB approval. For any such emergency modification implemented, an IRB 
modification form must be completed within five (5) business days of making the 
change.    
 
b. Single Patient/Subject Exceptions: Any request to enroll a single subject who does 
not meet all the eligibility criteria of this study requires the approval of the Principal 
Investigator and the IRB.   
 
c. Other Protocol Deviations/Violations: All other planned deviations from the protocol 
must have prior approval by the Principal Investigator and the IRB.  
 
According to the IRB, a protocol deviation is any unplanned variance from an IRB 


71 
Version 3.6 – 9/28/2023 
 
 
 
 
approved protocol that:   
• Is generally noted or recognized after it occurs  
• Has no substantive effect on the risks to research participants  
• Has no substantive effect on the scientific integrity of the research plan or the value of 
the data   collected   
• Did not result from willful or knowing misconduct on the part of the investigator(s).   
 
 An unplanned protocol variance is considered a violation of the variance:  
• Has harmed or increased the risk of harm to one or more research participants.  
• Has damaged the scientific integrity of the data collected for the study.  
• Results from willful or knowing misconduct on the part of the investigator(s).  
• Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or   University policies.  
 
If a deviation or violation occurs without prior approval from the Principal Investigator, 
please follow the guidelines below:  
a. Protocol Deviations: Personnel will report to any data and safety monitoring 
committee in accordance with their policies. Minor deviations should be summarized 
and reported to the IRB at the time of continuing review. Major deviations should be 
summarized and reported to the Regulatory Affairs Coordinator who will submit to 
the IRB as soon as possible, but not more than 10 calendar days after acquiring 
information reasonably suggesting that a reportable (major) deviation has occurred.  
 
b. Protocol Violations: Violations should be reported by study personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.    
 
12.6 Amendments to the Protocol  
 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.    
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.    
 
 
 
 
 


72 
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13 References  
 
1. 
Robinson BN, Newman AF, Tefera E, Herbolsheimer P, Nunes R, Gallagher C, et al. Video 
intervention increases participation of black breast cancer patients in therapeutic trials. NPJ Breast 
Cancer. 2017;3:36. 
2. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. 
3. 
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of 
human breast tumours. Nature. 2000;406(6797):747-52. 
4. 
Institute NC. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) 
SEER*Stat Database: Mortality - All COD, Aggregated With State, Total U.S. (1969-2017) <Katrina/Rita 
Population Adjustment December 2019 [Available from: www.cdc.gov/nchs. 
5. 
Early Breast Cancer Trialists' Collaborative G. Effects of chemotherapy and hormonal therapy for 
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 
2005;365(9472):1687-717. 
6. 
Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R, et al. Combined 
tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in 
premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 
2001;19(2):343-53. 
7. 
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. 
Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal 
women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin 
Oncol. 2000;18(22):3748-57. 
8. 
Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, et al. Fulvestrant 
500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an 
international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997-3005. 
9. 
Leung BS, Potter AH. Mode of estrogen action on cell proliferative kinetics in CAMA-1 cells. I. 
Effect of serum and estrogen. Cancer Invest. 1987;5(3):187-94. 
10. 
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 
2009;9(3):153-66. 
11. 
Nadia Harbeck FdrP-L, Javier Cortes, Michael Gnant5 Nehmat Houssami, Philip Poortmans, 
Kathryn Ruddy, Janice Tsang and Fatima Cardoso. Breast cancer. Nature Reviews. 2019;5(66). 
12. 
Tripathy D, Bardia A, Sellers WR. Ribociclib (LEE011): Mechanism of Action and Clinical Impact of 
This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors. Clin Cancer Res. 
2017;23(13):3251-62. 
13. 
Neil A. O'Brien EDT, Raul Ayala, Luo Tong, Shawnt Issakhanian, Ronald Linnartz, Richard S. Finn, 
Samit Hirawat and Dennis J. Slamon. Abstract 4756: In vivo efficacy of combined targeting of CDK4/6, ER 
and PI3K signaling in ER+ breast cancer. Cancer research. 2014;74(19). 


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14. 
KISQALI. KISQALI (ribociclib) package insert 2017. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf. Accessed 9/2/2020 [ 
15. 
Samant TS, Huth F, Umehara K, Schiller H, Dhuria SV, Elmeliegy M, et al. Ribociclib Drug-Drug 
Interactions: Clinical Evaluations and Physiologically-Based Pharmacokinetic Modeling to Guide Drug 
Labeling. Clin Pharmacol Ther. 2020. 
16. 
Aditya Bardia  SM, Mariana Chavez-Mac Gregor , Muaiad Kittaneh , Alyssa J. Marino , Alessandro 
MatanoSuraj Bhansali , Becker Hewes , Javier Cortes. Phase Ib/II study of LEE011, everolimus, and 
exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer. JCO. 2017;32. 
17. 
Dejan Juric EH, Laura Garcia Estévez, Richard H De Boer, Ingrid Mayer, Mario Campone, Shizuka 
Asano, Suraj Bhansali, Vickie Zhang, Becker Hewes and Pamela Munster. Abstract P5-19-24: Phase Ib/II 
study of LEE011 and BYL719 and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and 
molecular analysis. Cancer research. 2015;75(9). 
18. 
SM Tolaney AF-T, V Boni, T Bachelot, Y-S Lu, M Maur, A Fasolo, M Motta, C Pan, J Dobson, B 
Hewes and S Chin Lee. Abstract P4-22-12: Ribociclib + fulvestrant in postmenopausal women with HR+, 
HER2– advanced breast cancer (ABC). Cancer Research. 2017;77(4). 
19. 
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as 
First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18):1738-48. 
20. 
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated 
results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus 
letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 
2018;29(7):1541-7. 
21. 
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III Randomized 
Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor 
Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-72. 
22. 
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Overall Survival with 
Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382(6):514-24. 
23. 
Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine 
therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer 
(MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-15. 
24. 
Medicine NUNLo. clinicaltrials.gov 2020 [Available from: 
https://clinicaltrials.gov/ct2/results?cond=&term=CTLA4&cntry=&state=&city=&dist=. 
25. 
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus 
palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative 
metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of 
the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-39. 
26. 
Filipa Lynce RZ, Matthew Blackburn, Christopher Gallagher, Olwen Hahn, Maysa Abu-Khalaf, 
Mahsa Mohebtash, Tianmin Wu, Paula Pohlmann, Asma Dilawari, Shruti Tiwari, Ami Chitalia, Robert 
Warren, Ming Tan, Ayesha Shajahan-Haq and Claudine Isaacs. Abstract P1-19-20: Safety of palbociclib in 
African American women with hormone receptor positive HER2 negative advanced breast cancer and 
benign ethnic neutropenia: PALINA study. Cancer Res. 2020;80. 
27. 
FDA. NDA/BLA Multi-disciplinary Review and Evaluation, KISQALI (ribociclib). 2017. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209092Orig1s000MultidisciplineR.pdf. 
Accesed 9/2/2020. 


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28. 
NIH. NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical 
Research 2017. https://grants.nih.gov/policy/inclusion/women-and-minorities/guidelines.htm. Accessed 
9/2/2020 [ 
29. 
Al Hadidi S, Mims M, Miller-Chism CN, Kamble R. Participation of African American Persons in 
Clinical Trials Supporting U.S. Food and Drug Administration Approval of Cancer Drugs. Ann Intern Med. 
2020. 
30. 
Gonzalez FJ CM, Tukey RH. Drug Metabolism. In: Brunton LL, Hilal-Dandan R, Knollmann BC. 
Goodman & Gilman's: The Pharmacological Basis of Therapeutics. McGraw-Hill N, editor. NY2020. 
31. 
Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-
mediated metabolism. Adv Drug Deliv Rev. 2002;54(10):1271-94. 
32. 
Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, et al. Clinical 
Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus 
Dosing. Clin Pharmacol Ther. 2015;98(1):19-24. 
33. 
Seibert SR, Schladt DP, Wu B, Guan W, Dorr C, Remmel RP, et al. Tacrolimus trough and dose 
intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European 
American and African American kidney transplant recipients. Clin Transplant. 2018;32(12):e13424. 
34. 
Flockhart D. Drug interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine 2007.  "https://drug-interactions.medicine.iu.edu" Accessed 09/02/2020. [ 
35. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN 
Guidelines) Breast Cancer. V 8.2021 ed. Accessed 10/11/2019. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. 
36. 
Bao X, Wu J, Sanai N, Li J. Determination of total and unbound ribociclib in human plasma and 
brain tumor tissues using liquid chromatography coupled with tandem mass spectrometry. J Pharm 
Biomed Anal. 2019;166:197-204. 
37. 
Walgren RA, Meucci MA, McLeod HL. Pharmacogenomic discovery approaches: will the real 
genes please stand up? J Clin Oncol. 2005;23(29):7342-9. 
38. 
Iyer L, Hall D, Das S, Mortell MA, Ramirez J, Kim S, et al. Phenotype-genotype correlation of in 
vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with 
UGT1A1 promoter polymorphism. Clin Pharmacol Ther. 1999;65(5):576-82. 
39. 
Nunez-Torres R, Martin M, Garcia-Saenz JA, Rodrigo-Faus M, Del Monte-Millan M, Tejera-Perez 
H, et al. Association Between ABCB1 Genetic Variants and Persistent Chemotherapy-Induced Alopecia in 
Women With Breast Cancer. JAMA Dermatol. 2020. 
40. 
Asma Ali Dilawari PA, Richard Paxman, Ami Chitalia, Christopher Gallagher, Shruti Rakesh Tiwari, 
Chiranjeev Dash, Lucile L. Adams-Campbell. Scalp cooling to prevent chemotherapy induced alopecia 
(CIA) in black patients: Differences in efficacy? JCO. 2020;38. 
 
 
 
 
 
 
 
 
 


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14. Appendices  
 
14.1. PROMIS Medication Adherence  
 
Medication Adherence 
 
I’d like you to answer the following questions about your breast cancer medicine. Your 
medication might be called ribociclib or Kisqali. What breast cancer medication will you 
have in mind as you are answering these questions? 
 
________________________ 
 
I’ll read the responses for these questions, so you won’t need a response card. 
 
1. How many times per day are you supposed to take this medicine?  Would you say... 
Less than once per day……………, 1  
Once per day.………………………….,2  
Twice per day…………………………, 
3  
Three or more per day?…………. 
4  
 
To what extent do you agree with the following statements?   
2. You know how to take this medication as recommended.  Would you say you... 
Strongly disagree……….……………, 1  
Disagree……….………………………….,2  
Neither agree nor disagree…….., 
3  
Agree………………………………………,4 
Strongly agree?……………………….,5  
3. You understand why you need to take this medicine.  Would you say you... 
Strongly disagree……….……………, 1  
Disagree……….………………………….,2  
Neither agree nor disagree…….., 
3  
Agree………………………………………,4 
Strongly agree?……………………….,5  
4. You believe it is important to take this medication.  Would you say you... 
Strongly disagree……….……………, 1  
Disagree……….………………………….,2  
Neither agree nor disagree…….., 
3  


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Agree………………………………………,4 
Strongly agree?……………………….,5  
5. You believe the medicine is working.  Would you say you... 
 
Strongly disagree……….……………, 1  
Disagree……….………………………….,2  
Neither agree nor disagree…….., 
3  
Agree………………………………………,4 
Strongly agree?……………………….,5  
6. In the past 7 days, you took this medication as recommended.  Would you say... 
Never……….……………………………., 
1  
Rarely……….……………………….…….,2  
Sometimes………………………………, 
3  
Almost always…………………………,4 
Always?……………….………………….,5  
7. In the past 7 days, you remembered to take this medication.  Would you say... 
Never……….……………………………., 
1  
Rarely……….……………………….…….,2  
Sometimes………………………………, 
3  
Almost always…………………………,4 
Always?……………….………………….,5  
8. In the past 7 days, you did not take this medicine because it caused side effects that 
bothered you.  Would you say... 
Never……….……………………………., 
1  
Rarely……….……………………….…….,2  
Sometimes………………………………, 
3  
Almost always…………………………,4 
Always?……………….………………….,5  
Please say “Not at all” if you have no side effects. 
9. In the past 7 days, you stopped taking this medication because you thought you did not 
need it.  Would you say... 
Never……….……………………………., 
1  
Rarely……….……………………….…….,2  
Sometimes………………………………, 
3  
Almost always…………………………,4 
Always?……………….………………….,5  
10. In the past 7 days, you did not take this medication because of the cost.  Would you 
say... 
 
Never……….……………………………., 
1  
Rarely……….……………………….…….,2  
Sometimes………………………………, 
3  
Almost always…………………………,4 
Always?……………….………………….,5  
11. In the past 7 days, you are bothered by the side effects of treatment.  Would you say... 
Not at all….……………………………., 
1  
A little bit…………………………..…….,2  
Somewhat………………………………, 
3  


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Quite a bit…….…………………………,4 
Very much?…………………………….,5  
Please say “Not at all” if you have no side effects. 
12. In the past 7 days, the cost of your medicine has been a financial hardship to you and 
your family.  Would you say... 
Not at all….……………………………., 
1  
A little bit…………………………….…….,2  
Somewhat………………………………, 
3  
Quite a bit…….…………………………,4 
Very much?…………………………….,5  
 
14.2 Patient Reported Outcomes of CTCAE 
 
NCI PRO-CTCAE ™ ITEMS 
Item Library Version 1.0 
English 
Form Created on 05 August 2020 
As individuals go through treatment for their cancer, they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days… 
 
1a.  In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT 
SORES at their WORST? 
Ο None 
Ο Mild 
Ο 
Moderate 
Ο 
Severe 
Ο Very 
severe 
1b.  In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE 
with your usual or daily activities? 
Ο Not at 
all 
Ο A little 
bit 
Ο 
Somewhat 
Ο Quite 
a bit 
Ο Very 
much 
 
2a.  In the last 7 days, how OFTEN did you have NAUSEA? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
2b.  In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
 
3a.  In the last 7 days, how OFTEN did you have VOMITING? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
3b.  In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
 


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4a.  In the last 7 days, how OFTEN did you have BLOATING OF THE ABDOMEN 
(BELLY)? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
4b.  In the last 7 days, what was the SEVERITY of your BLOATING OF THE 
ABDOMEN (BELLY) at its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
 
5a.  In the last 7 days, what was the SEVERITY of your CONSTIPATION at its 
WORST? 
Ο None 
Ο Mild 
Ο 
Moderate 
Ο Severe 
Ο Very 
severe 
 
6a.  In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA/DIARRHOEA)? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
 
7a.  In the last 7 days, how OFTEN did you have ARM OR LEG SWELLING? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
7b.  In the last 7 days, what was the SEVERITY of your ARM OR LEG SWELLING at 
its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
7c.  In the last 7 days, how much did ARM OR LEG SWELLING INTERFERE with 
your usual or daily activities? 
Ο Not 
at all 
Ο A 
little bit 
Ο 
Somewhat 
Ο Quite a 
bit 
Ο Very 
much 
 
8a.  In the last 7 days, how OFTEN did you feel a POUNDING OR RACING 
HEARTBEAT (PALPITATIONS)? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
8b. In the last 7 days, what was the SEVERITY of your POUNDING OR RACING 
HEARTBEAT (PALPITATIONS) at its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
 
9a.  In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
 
10a.  In the last 7 days, did you have any HAIR LOSS? 


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Ο Not at 
all 
Ο A little 
bit 
Ο 
Somewhat 
Ο Quite 
a bit 
Ο Very 
much 
 
11a.  In the last 7 days, how OFTEN did you have a HEADACHE? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
11b.  In the last 7 days, what was the SEVERITY of your HEADACHE at its WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
11c.  In the last 7 days, how much did your HEADACHE INTERFERE with your usual 
or daily activities? 
Ο Not 
at all 
Ο A 
little bit 
Ο 
Somewhat 
Ο Quite a 
bit 
Ο Very 
much 
 
12a.  In the last 7 days, how OFTEN did you have ACHING MUSCLES? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
12b.  In the last 7 days, what was the SEVERITY of your ACHING MUSCLES at their 
WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
12c.  In the last 7 days, how much did ACHING MUSCLES INTERFERE with your 
usual or daily activities? 
Ο Not 
at all 
Ο A 
little bit 
Ο 
Somewhat 
Ο Quite a 
bit 
Ο Very 
much 
 
13a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS 
ELBOWS, KNEES, SHOULDERS)? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
13b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS 
ELBOWS, KNEES, SHOULDERS) at their WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
13c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS) INTERFERE with your usual or daily activities? 
Ο Not 
at all 
Ο A 
little bit 
Ο 
Somewhat 
Ο Quite a 
bit 
Ο Very 
much 
 
14a.  In the last 7 days, what was the SEVERITY of your VAGINAL DRYNESS at its 
WORST? 
Ο None 
Ο Mild 
Ο 
Moderate 
Ο Severe 
Ο Very 
severe 
 


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15a.  In the last 7 days, how OFTEN did you have HOT FLASHES/FLUSHES? 
Ο 
Never 
Ο 
Rarely 
Ο 
Occasionally 
Ο 
Frequently 
Ο Almost 
constantly 
15b.  In the last 7 days, what was the SEVERITY of your HOT FLASHES/FLUSHES 
at their WORST? 
Ο 
None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very 
severe 
 
 
14.3 Medication Diary  


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14.4 Prohibited medications 
 


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Version 3.6 – 9/28/2023 
 
 
 
 
Prohibited Medications* 
Category 
Drug name 
Strong inhibitors of 
CYP3A4/5 
Boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, saquinavir/ritonavir, 
telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole  
Strong inducers of 
CYP3A4/5 
Avasimibe, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin) , St. John's wort 
(hypericum perforatum)  
Substrates of CYP3A4/5 
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, 
astemizole, cisapride, cyclosporine, diergotamine, 
dihydroergotamine, ergotamine, fentanyl, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, 
simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine  
Medications with a known 
risk or possible for QT 
prolongation and/or 
Torsades de Pointe (TdP) 
Amiodarone, anagrelide, arsenic trioxide, astemizole, 
azithromycin, bepridil, chloroquine, chlorpromazine, 
cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, 
donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomethadyl, 
mesoridazine, methadone, moxifloxacin, ondansetron (i.v. 
only), pentamidine, pimozide, probucol, procainamide, 
propofol, quinidine, sevoflurane, sotalol, sparfloxacin, 
sulpiride, terfenadine, thioridazine, vandetanib, venlafaxine  
Herbal 
medications/preparations or 
dietary supplements that are 
strong inhibitors or inducers 
of CYP3A4/5 or those with a 
known risk of QT 
prolongation 
Herbal preparations/medications 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, black cohosh, and ginseng. Patients should 
stop using these medications 7 days prior to the first dose 
of study drug.  
 
*List applies to formulations of medications that are absorbed systemically 
 
 
 
 
 


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14.5 Medications not Recommended 
 
Medications Not Recommended*  
Category 
Drug name 
Moderate CYP3A4/5 inhibitors  
Amprenavir, atazanavir, casopitant, cimetidine, 
darunavir, diltiazem, fosamprenavir, lomitapide, 
netupitant, tofisopam, verapamil  
Moderate CYP3A4/5 inducers  
Bosentan, efavirenz, etravirine, genistein, 
lersivirine, modafinil, nafcillin, talviraline  
Sensitive CYP3A4/5 substrates 
Alpha-dihydroergocryptine, almorexant, alpaviroc, 
apixaban (doses < 2.5 mg only), atazanavir, 
atorvastatin, avanafil, bosutinib, brecanavir, 
brotizolam, budesonide, buspirone, capravirine, 
casopitant, darifenacin, darunavir, ebastine, 
eletriptan, eplerenone, felodipine, fluticasone, 
ivacaftor, lomitapide, lumefantrine, lurasidone, 
maraviroc, midazolam, perospirone, quetiapine, 
ridaforolimus, sildenafil, ticagrelor, tilidine, 
tolvaptan, triazolam, vardenafil, vicriviroc, 
voclosporin  
Strong BSEP inhibitors  
Bosentan, fusidate, glibenclamide, , sulindac, 
troglitazone (TGZ-sulfate)  
MATE1 and OCT2 substrates  
Acyclovir, amantadine, amiloride, cephalexin, 
cephradine, cimetidine, famotidine, fexofenadine, 
memantine, metformin (also a substrate for OCT1, 
MATE1, and MATE2K), pindolol, procainamide, 
ranitidine, varencicline  
BCRP substrates  
Rosuvastatin and sulfasalazine  
Medications that carry a possible 
risk for QT prolongation  
Alfuzosin, apomorphine, aripiprazole, atazanavir, 
atomoxetine, bedaquiline, clozapine, 
dexmedetomidine, dolasetron, eribulin, famotidine, 
felbamate, fingolimod, foscarnet, gatifloxacin, 
gemifloxacin, granisetron, iloperidone, isradipine, 
lithium, mirabegron, mirtazapine, moexipril, 
norfloxacin, ofloxacin, olanzapine, ondansetron 
(p.o. only at 4 mg or 8 mg), oxytocin, paliperidone, 
pasireotide, pipamperone, promethazine, 
quetiapine, ranolazine, rilpivirine, risperidone, 
roxithromycin, sertindole, telavancin, tetrabenazine, 
tizanidine, tolterodine, vardenafil, ziprasidone  
 
 
*List applies to formulations of medications that are absorbed systemically 


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14.6 Adverse event monitoring log (CTCAE 5.0): 
 
Adverse event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Baseline 
Mid-cycle  
visit 
End of 
study 
 
Mark N/A or grade for each visit 
AND date of onset  
Rash 
<10% BSA 
10-30% BSA 
Severe rash, 
>30%, SJS 
Any %, 
requiring 
antibiotics, TEN 
 
 
 
Interstitial Lung 
Disease/ 
Pneumonitis 
Asymptomatic 
Symptomatic 
Severe 
Symptomatic 
Life threatening  
 
 
 
Nausea 
Loss of 
appetite without 
alteration of 
eating habits 
Oral intake 
decreased 
without weight 
loss, 
dehydration, 
malnutrition 
Inadequate oral 
intake, 
hospitalization 
indicated 
N/A 
 
 
 
Vomiting  
Intervention not 
indicated 
Outpatient IV 
hydration 
Tube feeding, 
TPN, 
hospitalization 
Life threatening  
 
 
 
Diarrhea 
Increase of <4 
stools per day 
Increase of 4-
6 stools per 
day 
>7 stools per 
day over 
baseline 
Life threatening 
 
 
 
Constipation 
Occasional or 
intermittent 
symptoms; 
occasional use 
of stool 
softeners, 
laxatives, 
dietary 
modification, or 
enema  
Persistent 
symptoms 
with regular 
use of 
laxatives or 
enemas  
 
Obstipation 
with manual 
evacuation 
indicated; 
limiting self-
care ADL  
 
Life threatening 
 
 
 
Fatigue 
Relived by rest 
Not relieved 
by rest, 
limiting basic 
activities of 
daily living 
Limiting self-
care 
N/A 
 
 
 
Anorexia 
Loss of 
appetite without 
alteration in 
eating habits  
 
Oral intake 
altered without 
significant 
weight loss or 
malnutrition; 
oral nutritional 
supplements 
indicated  
Associated with 
significant 
weight loss or 
malnutrition 
(e.g., 
inadequate oral 
caloric and/or 
fluid intake); 
tube feeding or 
TPN indicated  
Life-threatening 
consequences; 
urgent 
intervention 
indicated  
 
 
 
 


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Alopecia 
<50% of 
normal, only 
obvious to 
close 
inspection 
>50% of 
normal, a wig 
or hair piece is 
necessary; 
psychosocial 
impact  
N/A 
N/A 
 
 
 
Arthralgia  
Mild pain 
Moderate 
pain, limiting 
activities of 
daily living  
Severe pain, 
limiting self- 
care 
N/A 
 
 
 
Headache 
Mild pain 
Moderate 
pain, limiting 
activities of 
daily living  
Severe pain, 
limiting self- 
care 
N/A 
 
 
 
Hot flush * 
Mild 
Moderate, 
limiting 
activities of 
daily living 
Severe 
N/A 
 
 
 
Other  
 
 
 
 
 
Other 
 
 
 
 
 
Other 
 
 
 
 
 
Abbreviations: LLN: lower limit of normal; ULN: upper limit of normal; BSA: body surface area  
*No CTCAE 
 
Baseline visit → Completed by ____________ Date: ____________ 
Mid-cycle 1 visit → Completed by ____________ Date: ____________ 
End of study visit → Completed by ____________ Date: ____________