Clinical trial NCT02632045
Conditions: Metastatic Breast Cancer Breast Carcinoma
Keywords: Breast Neoplasms Breast Cancer Breast Carcinoma Breast tumors Cancer of the Breast
Sponsor: Melissa K Accordino
Start date: 2016-03-01; Completion date: 2022-01-04
Enrollment: 169 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized trial for patients with metastatic hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have progressed on an aromatase inhibitor plus a CDK4/6 inhibitor (either palbociclib or ribociclib) to either fulvestrant alone or fulvestrant with ribociclib (LEE-011). The purpose of the trial is to determine whether there is continued benefit for patients to remain on a CDK4/6 inhibitor at the time of switching anti-estrogen therapy. As ribociclib and palbociclib have a similar toxicity and drug profile and mechanism of action, the investigators feel that it is appropriate for patients to receive either drug with an aromatase inhibitor prior to randomization.

Detailed description:
Despite advances in early detection and therapeutic options, unresectable or metastatic breast cancer remains incurable and is one of the leading causes of cancer-related mortality. Breast cancer is a molecularly heterogeneous disease. This study will be evaluating estrogen receptor (ER) expression positivity and/or progesterone receptor (PgR) positivity of breast cancer with the absence of over-expression or amplification of HER2.

Inhibitors of the cyclin dependent kinases 4 and 6 (CDK4/6) have been developed and demonstrated impressive activity in patients with ER-positive HER2-negative breast cancer with marked improvements in progression free survival. This question is asking whether CDK 4/6 inhibition should be continued with hormone therapy in patients who will be switching their hormone therapy in the metastatic breast cancer setting.

Arms: arm 1: LEE-011 is administered orally, 600mg, daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks. arm 2: Placebo is administered orally, 600mg daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks.
Interventions: intervention 1: LEE-011 intervention 2: Fulvestrant intervention 3: Placebo
Intervention descriptions: intervention 1: 600 mg capsule (3x 200 mg capsules) intervention 2: 500 mg injection intervention 3: 600 mg capsule (3x 200 mg capsules)

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 113 
Local Protocol #:  AAAP9506 NCT02632045
TITLE:  A randoMized phAse II trIal of fulvestraNt or exemestane wiTh or without Ribociclib After 
progression on AntI-estrogeN therapy plus cyclin-dependent kinase 4/6 inhibition in patients with 
unresectable or metastatic hormone receptor positive, HER2 negative breast cancer (MAINTAIN Trial) 
Coordinating Center:  
Columbia University Medical Center 
Principal Investigator:   
Melissa Accordino, MD   
Site Principal Investigator and Contact Information: 
Columbia University Medical Center 
Melissa Accordino, MD    
161 Fort Washington Ave, NY, NY 10032 
Phone: 212-305-1945  
Email: mkg2134@cumc.columbia.edu 
Albert Einstein University / Montefiore Medical Center 
Sun Young Oh, MD 
1695 Eastchester Rd, Bronx, NY 10461 
Phone: 718 405-8404 
Email: suyoung@montefiore.org  
Weill Cornell Medicine 
Eleni Andreopoulou, MD 
425 East 61st Street-8th Floor. New York, NY 10065 
Phone: 212 821-0644 
Email: ela9082@med.cornell.edu 
Mount Sinai Medical Center 
Amy Tiersten, MD 
1 Gustave L. Levy Place, Box 1079, NY, NY 10029 
Phone: 212-241-3300 
Email: amy.tiersten@mssm.edu 
Laura and Isaac Perlmutter Cancer Center at NYU Langone 
Yelena Novik, MD 
160 E 34th St, 4th Floor New York, NY 10016 
Phone: 212 731-5350 
Email: Yelena.Novik@nyulangone.org 
University of Wisconsin School of Medicine 
Kari Wisinski, MD 
600 Highland Avenue  
K4/542 Clinical Science Center 
Madison, WI 53792  
Phone: 608-262-2876 
Email: kbwisinski@medicine.wisc.edu 
Northwestern Medical Hospital 
William Gradishar, MD 
NMH/Arkes Family Pavilion Suite 850 
676 N Saint Clair 
Chicago IL 60611 
Phone: 312-695-4541 
Email: w-gradishar@northwestern.edu 


 
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Vanderbilt-Ingham Cancer Center 
Sonya Reid, MD 
Division of Hematology/ Oncology 
Vanderbilt University Medical Center/ Vanderbilt-Ingram Cancer Center 
2220 Pierce Avenue, 777 Preston Research Building 
Nashville, TN 37232-6307 
Phone: 615-936-8422 
Email: sonya.reid@vumc.org 
University of Alabama at Birmingham (UAB) 
Clinical Protocols and Data Management Shared Facility, UAB Comprehensive Cancer Center 
Erica Stringer-Reasor, MD 
1720 2nd Ave South. NP2501 
Birmingham, Alabama 35294 
Phone: 205-975-2816 
Email: ereasor@uabmc.edu 
Stony Brook Cancer Center 
Lea Baer, MD 
3 Edmund D. Pellegrino Road 
Stony Brook, NY 11794 
Phone: 631-638-1000 
Email: Lea.Baer@stonybrookmedicine.edu 
Northwell Health/R.J. Zuckerberg Cancer Center 
Jane Carleton, MD 
450 Lakeville Road 
Lake Success, NY 11042 
Phone 516-734-8966 
Email: jcarleto@northwell.edu 
Northside Hospital, Inc.  
Amelia B. Zelnak, M.D., M.Sc. 
Address: 1000 Johnson Ferry Rd Atlanta, GA 30342 
Phone: 770-205-5292 
Email: azelnak@atlantacancercare.com 
The University of Kansas Cancer Center 
Anne P O'Dea, MD 
2330 Shawnee Mission Parkway, Ste 209 South 
Westwood, KS  66205 
Phone: 913-588-6029 
Email: aodea@kumc.edu 
Statistician: Codruta Chiuzan, PhD 
Mailman School of Public Health 
722 West 168th Street, 6th Floor 
New York, New York 10032 
Tel: 212-305-9107 
Email: cc3780@cumc.columbia.edu 
 
Medical Monitor:  
Kevin M. Kalinsky, MD 
1365 Clifton Road, NE 
Atlanta, GA 30322 
404-778-1900 
Email: kevin.michael.kalinsky@emory.edu 


 
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Novartis Supplied Agent(s):   1) Ribociclib (a.k.a. LEE011, NVP-LEE011) [the primary 
investigational drug.]  
2) Letrozole (a.k.a. Femara, C17H11N5).  [Standard of care.]    
Other Agent(s):   
1) Fulvestrant (a.k.a. Faslodex, C32H47F5O3S). [Standard of care.]    
2) Exemestane (a.k.a. Aromasin, 6-methylenandrosta-1,4-diene-
3,17-dione). [Standard of care) 
 
 
 
 
 
 
 
 
 
 


 
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Protocol Signature Page 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable federal, state, and local laws, rules, 
and regulations relating to the conduct of the protocol. I have read and understand the information 
in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks and potential 
benefits. I will promptly submit the protocol to the applicable IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modification made during the 
course of the study must first be approved by the IRB, prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. I certify that I, and the study 
staff, have received the requisite training to conduct this research protocol. I agree to maintain 
adequate and accurate records in accordance with Columbia University and Herbert Irving 
Comprehensive Cancer Center policies, Federal, state and local laws and regulations. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator                 Date 
 
 
 
_________________________________                 
Principal Investigator Name (Print) 
 
 
 
 
_________________________________                 
Name of Institution 
 
Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder.  


 
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Table of Contents 
Protocol Signature Page ............................................................................................................... 4 
1. 
SYNOPSIS ........................................................................................................................ 8 
1.1 
STUDY SCHEMA .................................................................................................. 9 
1.2 
OBJECTIVES ....................................................................................................... 10 
1.2.1 Primary Objectives: ................................................................................... 10 
1.2.2 Secondary/Exploratory Objectives: ........................................................... 10 
1.2.3 Summary Table of Objectives: .................................................................. 11 
2. 
BACKGROUND ............................................................................................................... 12 
2.1 
Overview: .............................................................................................................. 12 
2.2 
Targeting the Cell Cycle: ...................................................................................... 12 
2.3 
Clinical Trials Involving CDK4/6 inhibition in ER-positive Breast Cancer: ....... 14 
2.4 
Primary Investigational Drug Ribociclib (a.k.a. LEE011, NVP-LEE011): .......... 17 
2.5 
Fulvestrant (a.k.a. Faslodex, C32H47F5O3S)): ........................................................ 18 
2.6 
Rationale for the proposed study: .......................................................................... 19 
2.7 
Biomarker Studies: ................................................................................................ 21 
3. 
PATIENT SELECTION .................................................................................................... 22 
3.1 
Inclusion Criteria: .................................................................................................. 22 
3.2 
Exclusion Criteria: ................................................................................................. 23 
4. 
REGISTRATION PROCEDURES ................................................................................... 25 
5. 
PHARMACEUTICAL INFORMATION ............................................................................. 26 
5.1 
Ribociclib (Investigational agent, supplied by Novartis): ..................................... 27 
5.1.1 Overview: ..................................................................................................... 27 
5.1.2 Drug Product: (IB) ....................................................................................... 27 
5.1.3 Drug Storage: (IB) ........................................................................................ 27 
5.1.4 Pharmacodynamics: ..................................................................................... 27 
5.1.5 Safety/Toxicology (IB) ................................................................................ 29 
5.1.6 Pharmacokinetics and metabolism ............................................................... 30 
5.1.7 Agent Ordering ............................................................................................. 32 
5.2 
Fulvestrant (standard of care medication after randomization, not supplied by 
the study) ............................................................................................................... 32 
5.2.1 Overview: (Prescribing information, PI) ...................................................... 32 
5.2.2 Drug Product: (PI) ........................................................................................ 32 
5.2.3 Drug Storage: (PI) ........................................................................................ 33 
5.2.4 Pharmacokinetics: (PI) ................................................................................. 33 
5.2.5 Safety/Toxicology: (PI) ................................................................................ 33 
5.2.6 Agent Ordering: ............................................................................................ 34 
5.3 
Letrozole (Standard of care medication provided prior to randomization in 
patients registered under scenario #1, supplied by Novartis) ................................ 34 
5.3.1 Overview: (Prescribing information) ........................................................... 34 
5.3.2 Drug Product: (Prescribing Information) ..................................................... 35 
5.3.3 Drug Storage: (Prescribing Information) ..................................................... 35 
5.3.4 Pharmacokinetics: (Prescribing Information) .............................................. 35 


 
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5.3.5 Safety/Toxicology: (Prescribing Information, PI) ....................................... 36 
5.3.6 Agent Ordering: ............................................................................................ 38 
5.4 
Exemestane ............................................................................................................ 38 
5.4.1 Overview: (Prescribing information) ........................................................... 38 
5.4.2 Drug Storage: (Prescribing Information) ..................................................... 38 
5.4.3 Pharmacokinetics: (Prescribing Information) .............................................. 38 
5.4.4 Safety/Toxicology: (Prescribing Information, PI) ....................................... 38 
5.3.5 Agent Ordering: ............................................................................................ 39 
5.5 
Combining Fulvestrant with Ribociclib ................................................................ 39 
6. 
TREATMENT PLAN ........................................................................................................ 39 
6.1 
Study Design: ........................................................................................................ 39 
6.2 
Agent Administration ............................................................................................ 40 
6.3 
General Concomitant Medication and Supportive Care Guidelines ..................... 43 
Concomitant therapy requiring caution .................................................................. 45 
Drugs with QT prolongation ................................................................................. 45 
6.4 
Duration of Therapy .............................................................................................. 45 
6.5 
Duration of Follow up ........................................................................................... 46 
6.6 
Criteria for Removal .............................................................................................. 46 
7. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 46 
7.1 
Letrozole and Exemestane .................................................................................... 47 
7.2 
Fulvestrant ............................................................................................................. 47 
7.3 
Ribociclib / Placebo .............................................................................................. 47 
7.4 
Renal Impairment: ................................................................................................. 53 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS................................. 54 
8.1 
Synopsis of Common Adverse Events with the study drugs ................................ 54 
8.2 
Definitions and Reporting ..................................................................................... 58 
8.3 
Guidelines for Processing IND Safety Reports ..................................................... 65 
8.4 
Secondary Malignancy .......................................................................................... 65 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................. 65 
10. 
STUDY CALENDAR ........................................................................................................ 67 
10.1 
Table 1: Registered Prior to Receiving AI + CDK 4/6 Inhibitor (Scenario #1) .... 67 
Day 
67 
10.2 
Table 2: Registered After Progression on AI or tamoxifen or fulvestrant + 
CDK 4/6 Inhibitor (Scenario #2) ........................................................................... 68 
X 
68 
11. 
MEASUREMENT OF EFFECT ........................................................................................ 69 
11.1 
Antitumor Effect – Solid Tumors .......................................................................... 69 
11.2 
Safety Assessment ................................................................................................. 75 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ............................................... 75 
12.1 
Data Collection ...................................................................................................... 75 
12.2 
Data Reporting ...................................................................................................... 76 
12.3 
Data and Safety Monitoring Committee ............................................................... 76 


 
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12.4 
Quality Control and Quality Assurance ................................................................ 76 
12.5 
Confidentiality ....................................................................................................... 77 
12.6 
Source Documents ................................................................................................. 77 
12.7 
Reporting to Novartis Pharmaceuticals Corporation............................................. 77 
12.8 
Records Retention ................................................................................................. 78 
13. 
STATISTICAL CONSIDERATIONS ................................................................................ 78 
13.1 
Study Design/Primary Endpoint (Sample Size: N=120 Randomized evaluable 
patients) ................................................................................................................. 78 
13.2 
Accrual Rate .......................................................................................................... 80 
13.3 
Evaluation of Toxicity ........................................................................................... 80 
13.4 
Correlative Studies ................................................................................................ 80 
13.5 
Reporting and Exclusions ...................................................................................... 80 
13.6 
Unblinding Procedures .......................................................................................... 80 
14. 
PROTECTION OF HUMAN SUBJECTS ......................................................................... 81 
15. 
CONSENT: LEGAL AUTHORIZED REPRESENTATIVE IF PATIENT WITHOUT 
CAPACITY ....................................................................................................................... 82 
16. 
STUDY FINANCES ......................................................................................................... 82 
16.1 
Conflict of Interest: ............................................................................................... 82 
17. 
PUBLICATION PLAN ...................................................................................................... 82 
18. 
REFERENCES: ............................................................................................................... 82 
APPENDIX A: ECOG Performance Status Criteria ..................................................................... 87 
APPENDIX B: Strong CYP3A4 and CYP3A5 Inducers and Inhibitors ........................................ 88 
APPENDIX C: Serum AND PLASMA Biospecimen Collection ................................................... 93 
APPENDIX D: Whole Blood for ctDNA biomarkers ..................................................................... 96 
APPENDIX E: Archived Tissue and Biopsy Collection and Shipment ........................................ 98 
TUMORGRAFT (PDX) PROCESS ............................................................................... 103 
ASSESSMENT OF RESPONSE IN THE TUMORGRAFT ........................................................ 103 
APPENDIX F: GUIDELEINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES105 
APPENDIX G: DRUG ORDER FORM ...................................................................................... 110 
APPENDIX H: SKIN COLOR PHOTOGRAPHY ....................................................................... 112 
 
 
 
 
 
 


 
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1. 
SYNOPSIS 
Title: A randomized phase II trial of fulvestrant or exemestane with or without Ribociclib after progression 
on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or 
metastatic hormone receptor positive, HER2 negative breast cancer.  
Short Title: Study of efficacy of ribociclib plus fulvestrant or exemestane after progression on CDK4/6 
inhibition in patients with HR+ HER2- metastatic breast cancer.   
 
Patient Selection (Section 3 for complete inclusion and exclusion criteria details)  
1. Men or women at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of 
the breast with metastatic or unresectable disease. 
2. Hormone receptor positive (HR+) status, defined as either estrogen receptor positive (ER+), progesterone 
receptor positive (PgR+), or both, as defined by immunohistochemistry (IHC) ≥1% as per the ASCO-CAP 
guidelines.  
3. HER2/Erbb2 negative (HER2-) status as per ASCO-CAP  
4. Postmenopausal status or receiving ovarian suppression, including GnRH agonists (such as goserelin). 
5. Evidence of measurable or unmeasurable disease.   
6. Stable CNS disease allowed.   
7. Eastern Cooperative Group (ECOG) performance status of 0 or 1.  
8. No evidence of clinically significant congestive heart failure or other serious cardiac disease.  
9. Adequate renal, liver, and bone marrow function.  
10a. Written informed consent and HIPAA authorization obtained from the subject/legal representative prior to 
performing any protocol-related procedures; 
10b. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, 
and other requirements of the study 
 
Study Design: This is a phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate 
fulvestrant (or exemestane) +/- ribociclib in patients with HR+HER2- breast cancer who have previously progressed 
on aromatase inhibitor (AI: letrozole, arimidex, exemestane), selective estrogen receptor downregulator (SERD): 
tamoxifen), or fulvestrant plus CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Progression free survival 
is the primary endpoint. The trial will determine whether there is clinical benefit to continuing CDK4/6 inhibition 
beyond progression.    
 
Patients can be screened and registered at two different time points:  
Registration Scenario #1: Before receiving any CDK4/6 inhibitor or  
Scenario #2: At the time of disease progression while being treated with a CDK4/6 inhibitor (ribociclib or 
palbociclib or abemaciclib)+ AI, tamoxifen or fulvestrant 
In scenario #1, the study will provide patients with ribociclib + letrozole, but patients will not be randomized until 
they demonstrate objective evidence of disease progression on treatment. If the patient has previously received 
letrozole, an alternative AI can be prescribed but will not be provided by the study, i.e. administered as standard of 
care (ribociclib and letrozole will still be provided by the study). Patients are allowed to have received 4 consecutive 
weeks of an aromatase inhibitor prior to protocol registration for scenario 1. In scenario #2, patients will be 
randomized after registration.  
At randomization, patients will be assigned to one of the two arms in a 1:1 ratio: 1) Fulvestrant  (or exemestane) + 
ribociclib or 2) Fulvestrant (or exemestane) + placebo.  Fulvestrant will be given as a 500 mg dose intramuscularly 
(IM) every 2 weeks for 3 times (loading dose) and then every 4 weeks, as per standard of care. Exemestane will be 
given as 25 mg orally daily, as per standard of care. The investigational drug ribociclib will be given as 600 mg 
daily, 3 weeks on/1 week off. Placebo will be administered on the same schedule. For all patients, ribociclib/placebo 
will be supplied by the study.  Fulvestrant or exemestane will be given, as standard of care. 
If patient received prior fulvestrant, exemestane must be the hormone therapy backbone in the 
randomization. If patient received prior exemestane, fulvestrant must be the hormone therapy backbone in 
the randomization. If neither has been administered, selection of fulvestrant or exemestane in the 
randomization will be per investigator discretion. 
 


 
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Accrual Target: N= 120 randomized, evaluable patients. Patients will be accrued from 11 academic medical centers 
in the US, with a goal of completing accrual in two years.    
We will ensure that neither registration scenario contains > 60% (N=80) of total study accrual.  
 
Patients will receive treatment on study until disease progression, unacceptable toxicity, or death or withdrawal from 
study based on patient choice or treating physician’s discretion. Every effort will be made to follow patients for 
primary and secondary outcomes regardless of treatment discontinuation for any reason. Crossover is not built into 
the study. 
 
Evaluations 
Safety Assessment: 
History, physical exam, and routine blood work such as blood counts and comprehensive metabolic panel will be 
performed on day 1 of each treatment cycle, including prior to randomization in patients registered under scenario 
#1. (i.e. at least every 4 weeks- Section 10: Study Calendar.)  
 
Primary and Secondary Endpoint Evaluations:  
CT scans of the chest, abdomen, and pelvis and bone scan are to be performed prior to every third cycle of treatment 
(approximately every 12 weeks, depending on potential treatment delays), and prior to randomization in patients 
registered under scenario #1. PET scans can substitute for CT scans + bone scan, at the discretion of the onsite 
investigator.  Additional off-schedule scans may be performed if concern for interval disease progression or other 
disease/treatment related complications. Disease progression will be determined at the local institution, per RECIST 
1.1 criteria.  
 
Skin color photography (if skin lesions are present) is recommended every 12 weeks (+/- 1 week) to assess for 
disease progression or response, particularly in patients with no measurable disease by radiologic criteria. (Appendix 
I).  
 
Biomarker Assessment: 
1) Archived tissue from primary and/or metastatic tissue is required, unless not available. If patient is 
amenable and has accessible tumor, repeat biopsy is optional. These biopsies should be considered in 
patients with accessible disease. Biopsies can be within 7 days of the cycle (+/- 7 days). Optional biopsies 
for tissue biomarker assessment will be performed in consenting patients prior to study treatment, at time of 
initial progression in patients registered under scenario#1, and when the patient goes off study.  
2) Serum, plasma, and whole blood will be collected at multiple time points (Section 10: Study Calendar) and 
stored for future biomarker driven studies.   
 
 
1.1 
STUDY SCHEMA 
 
 
 
 
 
 
 
Randomization (1:1) 
Fulvestrant (or exemestane) 
+ placebo  
Fulvestrant (or exemestane) 
+ ribociclib 


 
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o Scenario #2 – Patient may progress on AI or tamoxifen or fulvestrant plus prior CDK4/6 
inhibitor. 
o Patient may receive fulvestrant OR exemestane in the randomization, if they have not 
received before 
1.2 
OBJECTIVES 
1.2.1 
Primary Objectives:  
1. To evaluate the progression-free survival (PFS) of fulvestrant or exemestane with or without 
ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibitor in 
patients with hormone receptor positive (HR+), HER2- breast cancer.  
• 
Endpoint: PFS. Defined as the interval from time of randomization until objective disease 
progression (local assessment) or death from any cause. Kaplan-Meier estimates will be used 
to calculate medians and 95% confidence intervals for PFS. A one-sided log-rank test will be 
used to test for a difference in PFS between the two arms. 
1.2.2 
Secondary/Exploratory Objectives: 
1. To assess the Overall Response Rate (ORR = complete + partial response rate) and Clinical 
Benefit Rate (CBR= ORR + stable disease rate at ≥ 24 weeks of follow up) in the study 
population in both arms of the trial, post-randomization. 
• 
Endpoints: ORR, CBR. Evaluation of disease will be made according to RECIST 
criteria (version 1.1) in patients with measurable disease. As this study will enroll 
patients with measureable and un-measurable disease as defined by RECIST v1.1, ORR 
will only be assessed in evaluable patients. CBR will also be determined. Patients with 
non-measurable disease only can be categorized as ‘complete response’, ‘non-complete 
response’, ‘non-progressive disease’, or ‘progressive disease’, but are sometimes not 
evaluable. (Section 11.1.4.2: Evaluation of Non-Target Lesions).   
• 
Duration of overall response:  The duration of overall response is measured as the time 
interval from when measurement criteria are met for complete or partial response 
(whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented 
 
2. For patients in registration scenario #1, to assess the PFS, ORR, CBR, and safety of ribociclib 
with an aromatase inhibitor in patients with metastatic or unresectable HR+ HER2- breast 
cancer. This analysis will be based on data collected in the pre-randomization component of the 
trial for patients registered under scenario #1. There is no comparator arm for this component of 
the trial, but it will add to the available clinical safety and efficacy data with ribociclib + AI in 
this population.  
3. To explore differences in clinical outcome (PFS, ORR, CBR) in patients receiving an aromatase 
inhibitor plus ribociclib vs. palbociclib vs. abemaciclib (scenario 1), both prior to randomization 
and then after continuation of CDK4/6 inhibition. In addition to potential differences between 
clinical outcomes based on the choice of CDK4/6 inhibitor for initial treatment, there might also 
be differential mechanisms of resistance that could impact outcomes when CDK4/6 inhibition is 
continued beyond progression along with fulvestrant or exemestane.  Patterns of resistance, 
including location of resistance, and any differences in tissue-based markers will be explored. 
• 
Endpoints: PFS, ORR, CBR, Site of Recurrence. This is exploratory. Given the fact that 
patients with HR+ metastatic breast cancer have an improved PFS when adding CDK 4/6 
inhibition to hormone therapy and given the small sample size of this study, there will not be 
enough patients to power this trial to evaluate the difference between CDK 4/6 inhibitors in 
those who register in scenario #1.  Patients who received abemaciclib (LY2835219) are 
eligible for this trial (scenario #1). 


 
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4. To evaluate the rates of adverse events and tolerability of the combination of fulvestrant or 
exemestane with and without ribociclib.  
• 
Endpoint: Adverse Events. The frequency of subjects experiencing toxicities will be 
tabulated based upon the CTEP Active Version of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0. 
5. To explore potential predictive tumor and blood-based predictive biomarkers.  
• 
Biomarkers: Exploratory tumor tissue biomarkers that will be examined include 
overexpression or amplification of Cyclin D1 and Cyclin E, phospho-Rb expression, Rb1 
loss, p16INK4A loss, and TK1 and TOP2A expression (as measures of E2F1 transcriptional 
activity). Serum and plasma will be collected and stored for potential future exploratory 
analyses.  Differences in resistance between those who received ribociclib vs. palbociclib vs. 
abemaciclib will be explored. 
6. To assess the impact of the combination therapy vs. fulvestrant or exemestane alone on patient 
reported global health assessment and quality of life.  
• 
Survey Instruments. Patient reported outcomes will be assessed using validated 
questionnaires (PROMIS Global Health and PROMIS 29; EQ 5D 3L)87,88.  
 
1.2.3 
Summary Table of Objectives: 
 
Objective 
Endpoint 
Primary 
To evaluate the progression free survival 
(PFS) of fulvestrant (or exemestane) +/- 
ribociclib after progression on anti-
estrogen therapy plus cyclin-dependent 
kinase 4/6 inhibitor. 
PFS 
Secondary / 
Exploratory 
To compare the ORR and the CBR in the 
fulvestrant (or exemestane) /placebo vs. 
fulvestrant (or exemestane) /ribociclib 
arms. 
Complete and Partial Response Rate, and 
Stable Disease Rate by RECIST criteria in 
patients with measurable disease.  
Duration of Response (in responders). 
For patients in registration scenario #1, to 
assess the efficacy and safety of ribociclib 
with anti-estrogen therapy 
PFS, ORR, CBR, Adverse event rates.  
To explore the efficacy and patterns of 
resistance of ribociclib vs. palbociclib vs. 
abemaciclib in combination with anti-
estrogen therapy 
PFS, Response Rates, Location of Distant 
Metastasis:  This is exploratory, as the study 
is not adequately powered to detect a 
difference.   
To evaluate the rates of adverse events and 
tolerability of fulvestrant (or exemestane) 
+/- ribociclib 
Adverse Events: Events will be tabulated 
based upon the CTEP Active Version of the 
CTCAE v4.0. 
To explore potential predictive biomarkers, 
including exploring differences in tissue-
based biomarkers in those who progressed 
on ribociclib vs. palbociclib vs. 
abemaciclib 
 
 
 
 
Tissue Biomarkers: Overexpression or 
amplification of cyclin D1 and cyclin E, 
phospho-Rb expression, Rb1 loss, p16 loss, 
and TK1 and TOP2A expression.  
 
Serum and plasma will be collected and 
stored for potential future exploratory 
analyses. 
 
To assess impact on patient reported global 
Validated Survey Instruments. PROMIS 


 
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health assessment / Q.O.L.  
(Global Health and PROMIS-29) and EQ-
5D-3L will be used.   
 
2. 
BACKGROUND 
2.1 
Overview: 
Despite advances in early detection and therapeutic options, unresectable or metastatic breast cancer remains 
incurable and is one of the leading causes of cancer-related mortality.1 Breast cancer is a molecularly 
heterogeneous disease, with three distinct molecular subtypes.2 The first group is characterized by estrogen 
receptor (ER) expression positivity and/or progesterone receptor (PgR) positivity with the absence of over-
expression or amplification of HER2. The second group is characterized by over-expression or amplification 
of HER2, with more than half of these tumors also positive for expression of ER/PgR. The third group lacks 
expression of ER, PgR, and HER2, and is thus referred to as triple negative breast cancer. Approximately 
65% of newly diagnosed breast cancers are ER/PgR-positive and HER2-negative (sometimes referred to as 
luminal tumors), while an additional 20% of newly diagnosed cases are HER2-positive. Hormonally targeted 
drugs, specifically drugs that antagonize estrogen binding to the ER (tamoxifen), drugs that block estrogen 
biosynthesis (non-steroidal and steroidal aromatase inhibitors- only effective in postmenopausal patients), 
and drugs that antagonize and down-regulate the ER (fulvestrant), have been the mainstay of systemic 
treatment for patients with both localized and metastatic ER/PgR-positive breast cancers.3 Fulvestrant is the 
most recent addition to the armamentarium of hormonal therapies available to treat these patients. However, 
acquired resistance (and occasionally primary resistance) to anti-estrogen therapy universally develops in 
patients with metastatic breast cancer.4 Interestingly, even after acquired resistance develops, breast cancer 
cells appear to still depend on low-level ER activity in addition to signaling through newly acquired aberrant 
signaling pathways.5 In addition, in patients initially diagnosed with ER/PgR positive localized breast cancer 
who later recur, tumors usually demonstrate some degree of resistance to anti-estrogen therapy at the time of 
recurrence.6  
 
Traditionally, chemotherapy with minimal activity and significant toxicity has been the only option to treat 
patients with anti-estrogen resistance. This changed in 2012 with the approval of the molecularly targeted 
mTOR inhibitor everolimus to be used in combination with the steroidal aromatase inhibitor exemestane in 
patients with metastatic ER-positive HER2-negative breast cancer who have progressed on a non-steroidal 
aromatase inhibitor. Everolimus appears to at least temporarily restore sensitivity to anti-estrogen therapy 
and results in a progression free survival benefit.7 More recently, inhibitors of the cyclin dependent kinases 4 
and 6 (CDK4/6) have been developed and demonstrated impressive activity in patients with ER-positive 
HER2-negative breast cancer with marked improvements in progression free survival.8,83 Identifying well 
tolerated targeted therapies that obviate the need for systemic chemotherapy, delay disease progression, and, 
ideally, prolong survival, as well as characterizing their optimal usage, remains a primary objective in breast 
cancer research. 
 
2.2 
Targeting the Cell Cycle: 
The cell cycle is a tightly regulated series of events that allow the cell to replicate its genetic material and 
proliferate.9 The cell cycle progresses from a G1 growth phase during which the cell grows and accumulates 
nutrients, to the S-phase during which replicated DNA is synthesized, to the G2 growth phase marked by 
further cell growth, mitochondrial division, and a final check on the fidelity of DNA replication, and finally 
to the M phase during which mitosis and cytokinesis occur resulting in two daughter cells.9 Multiple 
checkpoints within the cell cycle ensure that only cells with appropriate growth factor stimulus, adequate 
nutrients, and without significant DNA damage are allowed to divide.10 Cells that do not meet these criteria 
are either forced into a quiescent state, an arrest phase pending repair of DNA damage, or to undergo 
apoptosis/cell death. Most healthy cells spend the majority of their lifespan in the quiescent G0 phase, which 
is entered shortly after the completion of M-phase. Sustained proliferation in the absence of appropriate 
growth factor stimulus, in the absence of adequate nutrient supply, and in the presence of DNA damage is 
one of the hallmarks of cancer, and thus disruption of the cell cycle is an almost universal feature of 
malignancy.11 Many cancers achieve this disruption through disabling one or more checkpoints in the cell 


 
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cycle, either through mutations, epigenetic silencing, or post-translational modification.12  
 
The cyclin dependent kinases (CDKs), a family of evolutionarily conserved serine-threonine kinases, are 
critical effector proteins of the cell cycle machinery, which when activated, allow for progression from one 
phase of the cell cycle to the next.9,13 Expression and activation of the CDKs are positively and negatively 
regulated by a diverse set of proteins. They are regulated positively by the cyclins, a family of proteins that 
bind to CDKs to form a functional holoenzyme. The CDKs are regulated negatively by a large number of 
endogenous inhibitor proteins, including p16, p19, and p21, many of which are able to sense DNA damage 
and then bind to the cyclin-binding domain of CDKs and thus inhibit the activation of CDKs.13 (see figure 1).  
 
 
CDK4 and CDK6 are a pair of highly homologous proteins with largely redundant biological function that 
interact with D-type cyclins (either the D1, D2, or D3 subunit), and regulate the so called restriction 
checkpoint that occurs during G1 phase.15 Cells at the restriction point can either progress to S phase and 
thus commit to another cycle of cell division or can withdraw to the quiescent G0 phase.15 A variety of pro- 
and anti-growth signals from the extracellular and intracellular environment determine this fate.15 Growth 
factor signaling frequently leads to increased downstream transcription and expression of cyclin D. Anti-
proliferative signals are communicated through the tumor suppressor retinoblastoma protein (Rb1, also 
known as Rb and p110) as well as Rb-related proteins p107 and p130. Hypophosphorylated Rb represents its 
activated form and is able to sequester the elongation factor 2 (E2F) family of transcription factors, and thus 
leads to decreased expression of genes involved in cell cycle progression.15 Alternatively, 
hyperphosphorylation of Rb by CDK4/6 in complex with cyclin D, and subsequently by CDK2 in complex 
with cyclin E in late G1 phase, results in the inactivation of Rb and allows increased synthesis of genes 
involved in DNA replication including thymidylate synthase and dihydrofolate reductase.15  
 
Endogenous inhibition of CDKs is normally mediated through the Cip-Kip family of pan-CDK inhibitors, 
including p21, p27, and p57, and by the INK4 family of CDK4/6-specific inhibitors, including p16INK4a, p15 
INK4b, p18 INK4c, and p19.16 Tumors increase cyclin D dependent activity through a number of different 
mechanisms including CDK4 amplification, CDK4/6 mutations resulting in decreased binding to p16INK4a, 
cyclin D over-expression or amplification of its encoding gene CCND1, and p16INK4a inactivation by deletion 
or epigenetic silencing.17 CCND1 amplification is a commonly occurring event in breast cancer, with 
approximately 30% of luminal A, 60% of luminal B and 40% of HER2 expressing tumors demonstrating 
amplification.18,19 In addition, CDK4 over-expression or amplification is seen in approximately 25% of 
luminal and HER2-positive tumors. Alternatively, approximately 75% of basal-like breast cancers 
demonstrate loss of heterozygosity for the Rb alleles combined with markedly decreased expression of Rb, a 
downstream event that allows for progression through the cell cycle at the restriction point even in the 
absence of CDK4/6-cyclin D activity.19 (see table 1 based on data from The Cancer Genome Atlas).  
 
 
Fig 1 Simplified 
diagram of the cell 
cycle checkpoints and 
their regulation by 
CDK/cyclin complexes 
and their endogenous 
inhibitors. 14 
Table 1: RB Pathway Alterations by Breast Cancer Subytpe 


 
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The functional significance of CDK4 and cyclin D1 to oncogenesis has been investigated in murine models 
of breast cancer.20,21 In both CDK4 and cyclin D1 knockout mice, implanted breast cancers demonstrate 
significant reduction in tumor growth. In particular, breast cancer models driven by HER2 signaling and by 
hormone receptor signaling appear to be dependent on CDK4/6-cyclin D1 activity. There is also some 
evidence that cyclin D1 has additional non-CDK dependent functions that may drive oncogenesis, including 
induction of chromosome instability by transcriptional regulation of chromosome instability related genes, 
induction of cellular migration and invasiveness, and pro-angiogenic effects.22 In addition, CDK6 has 
recently been found to have kinase-independent function in promoting angiogenesis.23 This latter effect is 
likely not inhibited by the currently available CDK4/6-inhibitors that all target the kinase domain.  
 
Preclinical models suggest a particular role for CDK4/6 inhibition in ER-positive breast cancer cells, 
including both cells that remain sensitive to estrogen inhibition and cells that have developed acquired 
resistance to estrogen inhibition.24 The ER regulates the transcription of cyclin D1, with estrogen mediated 
ER signaling resulting in increased expression of cyclin D1 on the RNA and protein level, accompanied by 
hyperphosphorylation of Rb and progression through the cell cycle. In ER-positive breast cancer cell lines 
that are sensitive, treatment with anti-estrogens results in growth arrest and marked reduction in cyclin D1 
expression.25 Cyclin D1 also appears to function in the recruitment of SRC family co-activator of ER, and 
thus augments ER mediated transcriptional activity, forming a feed forward loop.26 The development of 
resistance to anti-estrogens in ER-positive breast cancer models is associated with persistent cyclin D1 
expression and hyperphosphorylation of Rb. 27 
   
Targeting the cell cycle has been challenging due to the difficulty of developing specific inhibitors to the 
cyclins and CDKs.28 However, in recent years, CDK4/6 specific inhibitors have been developed and 
demonstrated significant clinical activity in metastatic hormone-responsive breast cancer and in well-
differentiated and de-differentiated liposarcoma (a disease marked by minimal responsiveness to traditional 
chemotherapy and in which CDK4 amplification occurs in >90% of cases).29,30 In fact, inhibitors of CDK1, 
CDK2, CDK4/6, CDK7 and CDK9 as well as pan-CDK inhibitors have been developed and are entering into 
early and late phase clinical trials in a large number of oncologic settings.31 The various CDK inhibitors 
induce cell cycle arrest at different points of the cell cycle and inhibiting certain CDKs (CDK7 and 9) also 
significantly impacts transcriptional activity.31 In February 2015, the CDK4/6 inhibitor palbociclib gained 
accelerated US approval by the FDA for the first line treatment of patients with ER-positive HER2-negative 
metastatic breast cancer. 
 
2.3 
Clinical Trials Involving CDK4/6 inhibition in ER-positive Breast Cancer: 
Flavopiridol was the first CDK inhibitor to be investigated in clinical trials.32 Flavopiridol is a non-selective 
inhibitor that targets CDK1, 2, 4/6, and 7. In preclinical studies, flavopiridol induces G0 and G1 arrest in a 
variety of tumor cells as monotherapy. The effects of flavopiridol synergizes with chemotherapy, which 
typically induces an S-phase delay as the result of DNA damage. Flavopiridol demonstrated minimal clinical 
activity when used as a single agent.33 While there was some activity seen in solid tumors including breast 
cancer in early phase clinical trials when combined with cytotoxic chemotherapy, there was also substantial 


 
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dose limiting toxicity seen with these combination regimens, most notably neutropenia and diarrhea.34 
Moreover, because these regimens required precise timing of flavopiridol, usually administered a few hours 
after chemotherapy, they were impractical for implementing in larger clinical trials. There is in vitro 
evidence that if the timing of administration is not properly synced, that CDK-inhibitors can reduce the 
efficacy of cytotoxic chemotherapy due to the reduction of tumor cells actively entering the cell cycle, on 
which the latter depends.35 There is also a theoretical concern that because CDKs are involved in DNA repair 
mechanisms, that the combination of CDK-inhibition with cytotoxic chemotherapy or radiation therapy may 
increase the adverse effects on healthy tissue as well as increase the mutational burden in cancer cells.35  
 
Three selective CDK4/6 inhibitors, palbociclib, abemaciclib and ribociclib have all entered advanced phase 
clinical trials in breast cancer, and are described in detail below. All three drugs competitively bind to the 
ATP-binding pocket of the CDK4/6 kinase domain.36  
 
Palbociclib (PD0332991): 
Given the biological interplay between cyclin D1 and the ER, discussed above, highly selective CDK4/6-
specific inhibitors were evaluated in breast cancer. In vitro studies with palbociclib, a pyridopyrimidine 
compound, demonstrated selective growth inhibition in luminal type breast cancer cell lines, including anti-
estrogen resistant cell lines, and demonstrated minimal activity in basal-like cell lines. It demonstrated 
marked G1-phase arrest in the MDA-MB-435 luminal breast cancer cell line.37 Activity was also observed in 
most HER2-positive breast cancer cell lines, in particular those that were also ER-positive.37 There was 
synergy when palbociclib was combined with tamoxifen in ER-positive cell lines including those with 
tamoxifen resistance and there was also synergy when palbociclib was combined with trastuzumab in HER2-
positive cell lines.37 There was minimal activity in cell lines with Rb deleted. As a single agent, palbociclib 
demonstrated significant tumor regression in some xenograft models.38  
 
Palbociclib was first investigated in humans in an open label phase I dose-finding study open to patients with 
Rb-intact solid tumors or lymphomas.39 The drug was administered orally on a 2-week on, 1-week off 
schedule, with the 200 mg dose of palbociclib being established as the maximum tolerated dose. Neutropenia 
was the only dose limiting toxicity observed. This myelosuppressive effect was consistent with the expected 
effects of CDK inhibition on rapidly dividing cells such as hematopoietic progenitor cells. A separate phase I 
trial investigated a 3-week on/1-week off schedule of palbociclib in 41 patients with Rb-intact solid tumors 
and lymphoma.40 In this study, neutropenia was again the only dose limiting toxicity, and a dose of 125 mg 
daily on a 3 week on/1 week off schedule was established as the recommended dose for phase II studies. 
Common non-dose limiting toxicities included fatigue, low-grade diarrhea, nausea, and constipation.   
 
In a phase II study of 28 heavily pretreated patients with Rb-intact metastatic breast cancer, palbociclib 125 
mg daily was administered on a 3 week on / 1 week off schedule as monotherapy.41 Only two of the 28 
patients (7%) were noted to have a partial response, while an additional four patients (14%) were noted to 
have stable disease beyond six months. None of the patients with ER-negative breast cancer demonstrated a 
partial response or stable disease at six months. As several of the patients in this study had received several 
prior lines of chemotherapy, it was felt that there might be acquired cross-resistance between chemotherapy 
and palbociclib. Thus, further clinical trials with palbociclib focused mainly on minimally pre-treated 
patients with ER-positive breast cancer, and in combination with anti-estrogens. The only grade III/IV 
toxicities observed in this trial were neutropenia (50%) and thrombocytopenia (21%), with one patient 
developing febrile neutropenia requiring hospitalization after cycle 1. The relative infrequency of febrile 
episodes in neutropenic patients has led some investigators to hypothesize that CDK4/6 inhibition leads to a 
temporary cytostatic but not cytotoxic effect on bone marrow progenitor cells, which is different than the 
cytotoxic effects of traditional chemotherapy.42 In addition, the infrequency of severe GI mucositis 
accompanying the neutropenia seen with these drugs likely contributes to decreased infection risk.42  
 
The multicenter randomized phase I/II PALOMA-1 study evaluated the combination of palbociclib 125 mg 
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vs. letrozole alone in patients with previously untreated metastatic ER-positive/HER2-negative breast 
cancer.43 The phase I component of the study established the safety of this combination. The phase II 
component of the study accrued 165 patients and was divided into two parts, with the first part open to all 
participants in the study and a second part open only to patients selected for CCND1 amplification or p16 
loss (N=99). After exploratory analysis failed to demonstrate that CCND1 amplification or p16 loss 
predicted response to palbociclib, the two parts were combined for a final efficacy analysis. Compared to 
letrozole alone, the combination of palbociclib and letrozole provided a very impressive increase in 
progression free survival, the predefined primary outcome, from 10.2 months to 20.2 months (Hazard Ratio 
(HR)=0.37; p=0.0004). A statistically significant difference in overall survival has not yet been achieved, but 
the majority of patients in both arms of the study were still alive at the time of the most recent analysis. The 
combination treatment arm tolerated treatment well for the most part, with grade III/IV neutropenia (54% vs. 
1%), grade II-IV anemia (35% vs. 6%), grade II-IV thrombocytopenia (16% vs. 1%), and fatigue (40% vs. 
23%) being the most commonly reported serious events. There was also a slight increase in the incidence of 
pulmonary embolism and grade III/IV infections in the combination arm compared to letrozole alone (5% vs. 
0% for each). Based on these results, in February 2015 the FDA granted accelerated approval for the use of 
palbociclib and letrozole in the first line treatment of patients with metastatic ER-positive HER2-negative 
breast cancer. The confirmatory phase III randomized PALOMA-2 study accrued 450 patients and has been 
completed.44  
 
The double blind phase III PALOMA-3 trial is investigating the combination of hormonal therapy and 
palbociclib in pre- and post-menopausal patients with metastatic ER-positive/HER2-negative breast cancer, 
with disease relapse or progression after at least one line of hormonal therapy and at most one line of 
chemotherapy.45 (All patients were naïve to CDK4/6 inhibition.) Postmenopausal patients received the ER 
downregulator fulvestrant with or without palbociclib 125 mg daily 3 weeks on/1 week off, while 
premenopausal and peri-menopausal women also received the LHRH analog goserelin to shut down the 
pituitary-ovarian axis. The primary endpoint was investigator determined progression-free survival, with 
secondary endpoints of overall survival, response rate, patient reported outcomes and safety analysis. The 
interim analysis of PALOMA-3 was presented at ASCO 2015.46,83 A total of 521 patients were randomized in 
a 2:1 ratio to the combination (N=347) and hormonal therapy alone (N=174) arms. The median age at 
enrollment was 57 years, with the majority of patients postmenopausal (79%), with visceral metastatic 
disease (60%), and with previously demonstrated sensitivity to anti-estrogen therapy prior to disease 
progression (79%). 33% of patients in this trial had previously received one line of chemotherapy, while the 
majority of patients had not been pretreated with chemotherapy. The PFS at time of interim analysis was 9.2 
months in the combination arm vs. 3.8 months for fulvestrant alone. (HR=0.42; p<0.000001). Benefit was 
seen with the addition of palbociclib in both pre- and post-menopausal patients. The most commonly seen 
adverse events in the combination arm were neutropenia (78% vs. 4%), leukopenia (45% vs. 4%), and 
fatigue (38% vs. 27%). In spite of the very high occurrence of neutropenia, only 0.6% of patients developed 
febrile neutropenia in the combination arm and only 2% of patients required treatment discontinuation due to 
adverse events.  
 
There are ongoing clinical trials investigating the role of palbociclib in combination with HER2-targeted 
therapies in metastatic HER2-positive breast cancers as well as studies investigated the role of palbociclib in 
the adjuvant or neoadjuvant setting, in particular in patients with residual disease after neoadjuvant therapy.   
 
Abemaciclib (LY2835219): 
Abemaciclib is another selective CDK4/6-specific inhibitor that is being evaluated in early phase clinical 
trials. In preclinical in vitro testing, it results in G1 phase arrest and inhibits the formation of phosphorylated 
Rb.47 In the dose escalation phase of a monotherapy study (N=55), grade III fatigue was the main dose 
limiting toxicity, and a dose of 200 mg twice daily was established as the maximum tolerated dose49. The 
largest cohort in the phase I study were patients with heavily pretreated metastatic breast cancer (N=47), 36 
of whom had ER-positive disease. As monotherapy, abemaciclib resulted in partial responses in 9 of these 47 
patients (19%), all of whom had ER-positive disease, and stable disease in 24 patients (51%). Common 


 
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adverse events included diarrhea, nausea, vomiting, and fatigue, with neutropenia the only common grade 
III/IV toxicity, seen in 11% of patients.  In other early-phase studies in metastatic breast cancer, there 
appears to be a significantly higher rate of diarrhea with abemaciclib compared with palbociclib and 
ribociclib.51 Ongoing phase II/III studies are evaluating abemaciclib as monotherapy or in combination with 
anti-estrogen therapies in patients with ER-positive breast cancer in a variety of clinical settings. 50-52  
 
2.4 
Primary Investigational Drug Ribociclib (a.k.a. LEE011, NVP-LEE011): 
Ribociclib is a small molecule inhibitor of CDK4/6 that is highly specific for the CDK4-Cyclin D1 and 
CDK6-Cyclin D3 complexes (Section 5: additional pharmaceutical information).53 It demonstrates superior 
selectivity compared to palbociclib and abemaciclib for CDK4/6 in in vitro studies, and thus may potentially 
be better tolerated at higher/more pharmacodynamically active doses. In preclinical in vitro and in vivo 
testing, ribociclib at concentrations in the nanomolar range results in dose dependent anti-tumor activity that 
correlates well with reduction of phospho-Rb.53 In murine models, ribociclib demonstrates growth inhibition 
and occasional tumor regression, similar to palbociclib, and has activity against both ER-positive as well as 
HER2-positive breast cancer.53 It has also demonstrated activity in BRAF-positive and NRAS-positive 
melanoma models, suggesting that the drug has activity in tumors driven by downstream signaling from the 
epidermal growth factors.53 Preclinical pharmacockinetic studies indicate that ribociclib is metabolized and 
eliminated by the cytochrome p450 system, with drug levels potentially affected by drugs that inhibit or 
induce CYP3A3,54 CYP3A4 inhibitors include HIV protease inhibitors and several anti-bacterials and to a 
lesser extent anti-emetic medications, while CYP3A4 inducers include anticonvulsants, some diabetic 
medications such as pioglitazone, and HIV NNRTIs.53,54 Several chemotherapeutic medications are also 
substrates for CYP3A4 and the co-administration of ribociclib with these medications could potentially affect 
their levels.53,54    
 
In the first in human phase I trial, 132 patients with multiple tumor types were treated with ribociclib 
monotherapy, with doses ranging from 50 mg to 1200 mg daily on a 3 weeks on / 1 week off schedule.55 The 
majority of reported adverse events were grade I/II, including neutropenia, leukopenia, nausea, and fatigue. 
Asymptomatic QTc prolongation was observed with increasing frequency at doses above 600 mg daily; no 
adverse cardiac events occurred. Based on this concern, the recommended phase II dosing for ribociclib was 
established as 600 mg daily on a 3 weeks on / 1 week off schedule.  
 
Ongoing phase I, II and III trials are evaluating ribociclib in ER-positive breast cancer, BRAF-mutant 
melanoma, as well as other solid tumors such as liposarcoma, neuroblastoma, and head and neck cancers.56 A 
phase Ib/II open label trial is evaluating the combination of letrozole, the PI3Kα–specific inhibitor BYL719 
and ribociclib in patients with newly diagnosed metastatic ER-positive breast cancer.57 The initial phase of 
this trial evaluated the doublet combinations of BYL719/ribociclib and letrozole/ribociclib in seven patients, 
with both arms demonstrating acceptable safety. Another phase Ib/II study is evaluating the combination of 
the steroidal aromatase inhibitor exemestane, the mTOR inhibitor everolimus and ribociclib in patients with 
ER-positive breast cancer.58 These combinations were conceived as the result of preclinical testing that 
suggests that CDK4/6 inhibition can overcome primary or acquired resistance to inhibition of the PI3K-Akt-
mTOR pathway.53,54 Given these findings, evaluating ribociclib in combination with other targeted therapies 
and in the context of heavily pretreated cancers with acquired resistance to standard treatments has been a 
major focus of clinical trial development compared to the other CDK4/6 inhibitors. Preliminary data from 16 
patients enrolled in the exemestane/everolimus/ribociclib study suggests that the combination is safe and 
feasible.58 A planned phase II study will evaluate the safety and efficacy of this triplet combination compared 
to the doublets exemestane/everolimus and exemestane/ribociclib. In BRAF or NRAS-mutant metastatic 
melanomas, ribociclib is being evaluated in combination with BRAF and MEK inhibitors.   
 
Additional studies in breast cancer are ongoing.  The large randomized, placebo-controlled, double blind 
phase III MONALEESA-2 trial is evaluating the combination of ribociclib and letrozole vs. letrozole alone 
in patients with previously untreated ER-positive HER2-negative metastatic breast cancer. A smaller open 
label phase II trial (MONALEESA-1) is a pre-surgical pharmacodynamics study evaluating ribociclib in the 


 
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neoadjuvant setting, and has completed accrual.  
 
2.5 
Fulvestrant (a.k.a. Faslodex, C32H47F5O3S)): 
Fulvestrant is currently a standard of care hormonal therapy option in patients with ER-positive breast 
cancer.59 As described above, fulvestrant has been evaluated in combination with the CDK4/6 inhibitor 
palbociclib in the phase III PALOMA 3 trial (N=521), and is currently being evaluated in the large phase III 
MONARCH-2 trial in combination with abemaciclib. No major safety concerns have been raised in these 
trials, and thus the combination of fulvestrant with CDK4/6 inhibition appears to be feasible.  
 
Fulvestrant is a selective estrogen receptor downregulator (antagonist) used in the treatment of ER-positive 
breast cancer that has demonstrated activity in both untreated patients as well as those previously treated with 
hormonal therapy. It competitively binds to the ER with an affinity 100 times greater than that of 
tamoxifen.60 Fulvestrant is able to markedly inhibit ER mediated transcriptional activity in a dose-dependent 
manner by impairing ER dimerization, preventing ER localization to the nucleus and by increasing ER 
degradation.61 Unlike tamoxifen, fulvestrant does not have ER agonist activity and unlike any of the other 
available anti-estrogen therapies, it also results in a consistent reduction in PgR levels in breast cancer cells.61 
In preclinical studies, fulvestrant demonstrates anti-proliferative effects and induces apoptosis in ER-positive 
breast cancer cell lines, including those that are resistant to tamoxifen. 61 There appears to be minimal in vitro 
cross-resistance between fulvestrant and tamoxifen or non-steroidal aromatase inhibitors such as anastrozole 
or letrozole.62 Cells and murine models treated with fulvestrant eventually acquire resistance to the drug, 
with resistance thought to be partially conferred by an over-expression of the micro-RNAs 221 and 222.63 
Interestingly, miR-221/222 over-expression results in decreased levels of the endogenous pan-CDK 
inhibitors p27kip1 and p57kip1, thus increasing progression through the cell cycle at the G1 restriction point and 
at the S->G2 transition point.64 Combining fulvestrant with a CDK 4/6 inhibitor could potentially prevent 
this mechanism of resistance.  
 
Initial studies with lower dose fulvestrant 250 mg intramuscular monthly were disappointing, as they 
demonstrated minimal improvement over previously available anti-estrogen therapies. Two phase III non-
inferiority trials compared fulvestrant 250 mg intramuscular once monthly with anastrozole 1 mg daily in a 
total of 851 post-menopausal patients who had previously progressed on anti-estrogen therapy, with the 
majority having previously received tamoxifen.65,66 (A previous study had established anastrozole as a 
modestly effective second line hormonal therapy compared to megestrol acetate in patients who had 
progressed on tamoxifen.67) The time to progression on fulvestrant was 5.5 months vs. 4.1 months for 
anastrozole (HR=0.95; p=0.48) and the overall response rate was 19.2% vs. 16.5% (p=0.32), with a median 
duration of response of 16.7 mo vs. 13.7 mo. Subsequently, a phase III randomized trial compared fulvestrant 
250 mg intramuscular once monthly to tamoxifen 20 mg daily as the initial anti-estrogen therapy in 587 
postmenopausal patients with newly diagnosed or recurrent metastatic breast cancer.68 In the 78% of patients 
who were ER-positive or PgR-positive, the two treatments were essentially equivalent in the first line setting, 
with an overall response rate of 31.6% vs. 33.9%.  
 
The EFECT trial was a randomized phase III, double blind, placebo controlled trial comparing fulvestrant vs. 
the steroidal aromatase inhibitor exemestane 25 mg daily in 693 post-menopausal patients with ER or PgR-
positive metastatic breast cancer who had disease progression on a non-steroidal aromatase inhibitor 
(anastrozole or letrozole)69. Fulvestrant was administered with a loading dose of 500 mg intramuscular on 
day 0, followed by 250 mg doses on days 14 and 28, followed by 250 mg doses every four weeks. The 
median time to progression in both arms was equivalent (3.7 mo) and the overall response rate was 7.4% on 
fulvestrant vs. 6.7% on exemestane. (p=0.736). There was a trend towards more durable responses in patients 
who were treated with fulvestrant (13.5 mo vs. 9.8 mo).  
 
More recent clinical studies have established that higher dose fulvestrant 500 mg intramuscular monthly is 
more effective than 250 mg and equally well tolerated and safe. Pre-surgical biomarker studies of fulvestrant 
indicate that PgR expression specifically is only decreased at higher doses of fulvestrant.70-72 In the phase II 


 
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open-label FIRST trial, 205 postmenopausal patients with hormone receptor positive metastatic breast cancer 
were randomized to receive either fulvestrant 500 mg intramuscular monthly (with an additional 500 mg 
loading dose on day 14) vs. anastrozole 1 mg daily.73 There was no difference in the primary outcome of 
clinical benefit rate (overall response rate plus stable disease) at 24 weeks, but the secondary outcome of 
time to progression was significantly prolonged in the fulvestrant arm (23.4 mo vs. 13.1 mo; HR-0.66; 
p=0.01). Updated results from FIRST were presented at the 2014 San Antonio Breast Cancer Symposium.74 
There was a surprising and impressive improvement in overall survival in the fulvestrant arm (54.1 mo vs. 
48.4 mo; p=0.041). Overall survival was not a predefined outcome in the study but was added as an 
amendment to the protocol after interim analysis. The phase III, double-blind randomized FALCON trial 
comparing fulvestrant 500 mg intramuscular monthly to anastrozole 1 mg daily in postmenopausal women 
with hormone receptor positive locally advanced or metastatic breast cancer who had not previously been 
treated with any hormonal therapy has completed accrual.  
The phase III double-blind CONFIRM trial directly compared fulvestrant 500 mg monthly (with an 
additional dose on day 14) with the fulvestrant 250 mg monthly dose in 736 postmenopausal patients with 
metastatic recurrent breast cancer who had progressed on prior anti-estrogen therapy.75 There was a 
statistically significant improvement in the primary outcome of progression free survival on the higher dose 
of fulvestrant (6.5 mo vs. 5.5 mo; HR=0.80; p=0.006). On long term follow up, there was also an 
improvement in overall survival with the higher dose (26.4 mo vs. 22.3 mo; p=0.016), although this was not 
a predefined outcome measure. Both doses were well tolerated, with 20% of patients in each arm 
complaining of mild gastrointestinal disturbances, 19% reporting joint aches and pain, and 13% in each arm 
reporting injection site pain or reaction. There was a slight increase in hot flashes reported in the higher dose 
group (8% vs. 6%) and there were very rare serious events reported only in the higher dose arm of bronchitis 
(2 patients) and dyspnea (3 patients), which were not felt to be treatment related.  
 
Fulvestrant offers one additional benefit compared to other anti-estrogens. It has been estimated that 
approximately 20% of patients receiving oral endocrine therapy do not take their medication regularly.76 As 
fulvestrant is a parenteral agent administered once monthly in the clinic, it has the potential to improve 
adherence.  
2.6 
Rationale for the proposed study: 
The optimal CDK4/6 inhibitor and the optimal hormonal therapy to combine it with is yet to be determined, 
as there have been several ongoing clinical trials in ER-positive breast cancer that have been running in 
parallel over the past several years. Each of the available CDK4/6 inhibitors has different side effect profiles 
and slight differences in biological effects based on preclinical studies. Moreover, the optimal sequencing of 
CDK4/6 inhibition in the treatment of breast cancer is open to investigation. The majority of clinical trials to 
date have investigated the effects of CDK inhibition in patients with metastatic breast cancer with minimal 
pre-treatment with hormonal, targeted, or cytotoxic therapies, primarily due to the concern that there might 
be acquired cross-resistance between these other agents and CDK inhibitors.  
 
However, in spite of these concerns, there is clearly a role for continuing targeted therapies in patients with 
breast cancer, even beyond the point of disease progression. Fulvestrant has demonstrated impressive clinical 
activity and possibly prolongs survival in patients previously treated with one or more lines of anti-estrogen 
therapy, as described in Section 2.5, establishing a role for continuing ER targeted therapy beyond the point 
of disease progression. Everolimus appears to restore sensitivity to anti-estrogens by inhibiting resistance 
mediated by the PI3K/Akt/mTOR pathway. In patients with HER2-positive breast cancer, it has become 
standard practice to continue HER2-targeted therapies beyond progression on HER2-targeted therapy. The 
BIG 03-05 and EMILIA trials demonstrated that continuing HER2 targeted therapies in patients with HER2-
positive breast cancer who have had progression of disease on trastuzumab improves response rates and 
survival on the order of several months.77,84   
 
Ribociclib has been shown to inhibit growth in several breast cancer cell lines and has anti-tumor activity in 
patient-derived xenograft models.53,54 As described above, early phase clinical trials with ribociclib have 
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addition, all three of the available CDK4/6 inhibitors have been combined with fulvestrant in clinical trials, 
and the combination appears to be well tolerated and quite feasible. Given the similar preclinical profile and 
mechanism of action to palbociclib, it is anticipated that ongoing phase II/III studies of ribociclib will 
demonstrate clinical benefit when used in patients with ER-positive HER2-negative breast cancer.  
 
Considering how well tolerated these medications are, a very important remaining question is whether there 
is a role for continuing CDK4/6 inhibition beyond progression, similar to what is seen with the continuation 
of hormonal therapy and the continuation of HER2-targeted therapies in HER2-positive breast cancers. A 
second important question is whether there is enough of a difference between the available CDK4/6 selective 
inhibitors that patients may derive benefit from switching agents after disease progression on one of them, as 
is seen with the multiple bcr-abl targeted tyrosine kinase inhibitors used to treat chronic myeloid leukemia. In 
vitro work suggests that acquired resistance to CDK4/6 inhibition is related to either functional loss of Rb or 
through the activation of alternative signaling pathways;78 the former likely would not benefit from 
continuation of CDK4/6 inhibition or switching medications, but the latter might as compensatory activation 
of alternative pathways may be suboptimal for tumor growth. In addition, little is known about in vivo 
acquired resistance to CDK4/6 inhibition, which may potentially be related to various complex 
pharmacokinetic and pharmacodynamics factors that cannot be studied or predicted from in vitro studies. 
Moreover, as all of the first line trials with CDK4/6 inhibitors have combined the drug with an aromatase 
inhibitor, it is not always clear if disease progression occurs due to the development of resistance to CDK4/6 
inhibition or due to resistance to first line anti-estrogen therapy. Thirdly, it will be important to determine if 
the large proportion of patients who have received cytotoxic chemotherapy or multiple lines of anti-estrogen 
therapy as the initial therapy for metastatic breast cancer may still benefit from the addition of CDK4/6 
inhibition later in the sequence of treatment.  
 
Preclinical data suggests that patients may indeed benefit from treatment with CDK4/6 inhibition and 
fulvestrant after progression on a CDK4/6 inhibitor. There is evidence that resistance to hormonal therapy, 
mTOR inhibition, and cytotoxic chemotherapy is at least in part mediated by upregulation of CDK4/6-cyclin 
D activity in breast cancer, suggesting that there might be a role for CDK4/6 inhibition in patients who have 
progressed on these therapies. There is also growing preclinical evidence that persistent inhibition of 
CDK4/6 may be beneficial even after resistance develops to CDK4/6 inhibitors.  
 
In the MCF-7 luminal breast cancer cell line, acquired fulvestrant resistance is associated with CDK6 over-
expression, as demonstrated by both qt-PCR and western blot.79 When these cells are treated with the 
combination of fulvestrant and a CDK4/6 inhibitor, growth is significantly attenuated. In an MCF-7 
xenograft mouse model, fulvestrant and CDK4/6 inhibition results in estrogen-independent growth reduction 
while decreasing phospho-Rb and p107, and downregulating E2F1 and E2F2.5 In a separate pre-clinical 
study, the downstream effects of CDK4/6 inhibition were reported as being relatively rapid but transient, 
with phosphorylation of Rb at amino acids Ser780 and Ser795 being reduced within 4 hours of drug 
administration and reversal of this effect within 2 hours of removal of the drug.38 By 16 hours after removal, 
the cells were proliferating again, suggesting that benefit from treatment with CDK4/6 inhibitors does not 
persist for long after discontinuation of the drug. This finding was recapitulated in Colo-205 (colonic 
carcinoma cell line) xenograft mouse models that demonstrated significant tumor regression (>90% tumor 
growth inhibition) after initial treatment with an oral CDK4/6 inhibitor for 14 days.38 Tumors began to grow 
again approximately 50 days after drug withdrawal. At the time of regrowth, tumors were harvested and 
reimplanted into naïve mice. With doses and a schedule identical to the originally treated mice, the tumors 
regressed with equal sensitivity to drug. Similar findings were seen in a breast cancer MDA-MB-435 
xenograft model.38 (see figure below.)  
 
Ribociclib plus fulvestrant in ER+ breast cancer xenograft models 


 
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Thus, our proposal is to randomize patients with metastatic HR-positive HER2-negative breast cancer who 
have progressed on anti-estrogen therapy plus a CDK4/6 inhibitor (either palbociclib or ribociclib or 
abemaciclib) to either fulvestrant alone or fulvestrant with ribociclib. The purpose of the trial is to determine 
whether there is continued benefit for patients to remain on a CDK4/6 inhibitor at the time of switching anti-
estrogen therapy.. As ribociclib, abemaciclib, and palbociclib have a similar mechanism of action, we feel 
that it is appropriate for patients to receive any of these CDK 4/6 inhibitors with anti-estrogen therapy prior 
to randomization.  
 
Patients will be potentially eligible and registered for the trial at 2 time periods: either a) no prior CDK4/6 
plus an aromatase inhibitor - or – b) patients who have progressed on palbociclib or ribociclib or abemaciclib 
plus an aromatase inhibitor or tamoxifen or fulvestrant. Patients not previously treated with a CDK4/6 
inhibitor will be provided with ribociclib with letrozole by the study supplier (Novartis), after registration. If 
and when these patients demonstrate evidence of disease progression on this combination, and if they 
continue to meet the other eligibility criteria, they will be randomized to receive either fulvestrant (or 
exemestane) with ribociclib or fulvestrant (or exemestane) with placebo. Eligible patients who register after 
disease progression on ribociclib or palbociclib or abemaciclib (received either as part of a clinical trial or as 
standard of care) will be immediately randomized to receive fulvestrant with ribociclib or placebo.  
 
2.7 
Biomarker Studies: 
While most patients with ER-positive, HER2-negative metastatic breast cancer do appear to obtain a clinical 
benefit from CDK4/6 inhibition (either partial response or prolonged stable disease), validated biomarkers to 
predict which patients would benefit the most from CDK4/6 inhibition and to predict the small group of 
patients who may not benefit at all from CDK4/6 inhibition have not yet been identified. We propose to 
evaluate tissue biomarkers on archived formalin-fixed paraffin-embedded (FFPE) tissue, available from 
diagnostic biopsy procedures, and to perform optional biopsies prior to treatment, at time of disease 
progression (in the case of patients registered under scenario # 1), and at progression on fulvestrant (or 
exemestane)  + ribociclib/placebo. We also plan to collect peripheral blood specimens (serum and plasma) 
for the purposes of future blood based biomarker studies.  This serum and plasma will be stored and 
processed at the local institution and then requested to be shipped to CUMC when requested. Further details 
are available in the biomarkers section of this protocol (Section 9).  
 
In addition to the serum and plasma above, we will analyze plasma ctDNA biomarkers (ESR-1 and PI3K) 
isolated from whole blood samples. As per Section 10, whole blood samples (2x10mL fresh peripheral whole 
blood) will be collected using the Biocept sample collection tubes provided in the Biocept Sample Kit. 
Samples will be inverted multiple times and shipped for analysis in the CAP-accredited CLIA-certified 
Biocept laboratory using the shipment materials provided. Study specific Requisitions provided by Biocept 
will be submitted with the samples. Plasma will be processed for ctDNA biomarker studies using the 
SELECTOR technology (Appendix D) 
 


 
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3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria: 
A subject must meet all of the following criteria to be eligible for the study: 
 
• 
Men or women at least 18 years of age with histologically or cytologically confirmed 
adenocarcinoma of the breast with unresectable or metastatic disease.  
 
• 
Most recent tumor biopsy or surgical resection specimen must be either ER positive, PgR positive, or 
both, as defined by immunohistochemistry (IHC) ≥1% (as per the ASCO-CAP guidelines).85 
 
• 
HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 
1+. If IHC is 2+ (i.e. indeterminate), a negative in situ hybridization (FISH, CISH, or SISH) test is 
required by local laboratory testing. (as per the ASCO-CAP guidelines). 86 
 
• 
Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as goserelin.  
Postmenopausal status is defined by any one of the following criteria: 
➢ Prior bilateral oophorectomy.  
➢ Age ≥60 years.  
➢ Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, 
toremifen, or ovarian suppression) and FSH, LH, and estradiol in the postmenopausal range per 
local normal.   
If the patient does not meet criteria for postmenopausal status but is receiving ovarian ablation 
therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin, the patient is 
eligible for this study, provided that the GnRH agonist is started at least 2 weeks prior to C1D1 of 
anti-estrogen therapy. 
  
• 
Have evidence of measurable or unmeasurable disease.   
 
• 
Eastern Cooperative Group (ECOG) performance status of 0 or 1. (Appendix A)  
 
• 
Scenario 1: No prior cdk 4/6 inhibitor (Closed to Accrual).  If patient has not previously received 
letrozole, letrozole will be supplied by Novartis.  If previously progressed on letrozole, another 
aromatase inhibitor that the patient has not previoulsy received is allowed, per standard of care 
(anastrazole or exemestane, not supplied by study).  Ribociclib will be supplied by Novartis.  If 
patient has previously received letrozole, anastrazole, and exemestane, (s)he is not eligible.  For 
scenario 1, patients are allowed to have started the aromatase inhibitor within 4 consecutive weeks 
prior to protocol registration. For instance, it is acceptable for patient who will be treated with 
letrozole in scenario #1, to have started letrozole within 4 consecutive weeks prior to protocol 
registration. No prior fulvestrant allowed. 
 
• 
Scenario 2: the patient must have received an aromatase inhibitor (letrozole, arimidex, exemestane) 
or tamoxifen or fulvestrant plus palbociclib as standard of care or received a CDK4/6 inhibitor 
(palbociclib or ribociclib or abemaciclib), and demonstrated evidence of disease progression. If the 
patient was enrolled in a randomized clinical trial involving ribociclib or abemaciclib or palbociclib 
(such as the MONALEESA or PALOMA series of trials), then it must be known after study 
discontinuation and unblinding that the patient received the investigational drug and not placebo. 
Ribociclib or abemaciclib or palbociclib can also be given as standard of care.  Documentation of 
progression and duration of response on aromatase inhibitor or tamoxifen plus CDK 4/6 inhibitor 
should be provided whenever possible. If patient received prior fulvestrant, exemestane must be the 
hormone therapy backbone in the randomization. If patient received prior exemestane, fulvestrant 


 
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must be the hormone therapy backbone in the randomization. If neither has been administered, 
selection of fulvestrant or exemestane in the randomization will be per investigator discretion. 
 
• 
Adequate baseline laboratory studies (hematologic and chemistry), including the following 
parameters:  
➢ Absolute neutrophil count ≥ 1500 per microliter, Platelets ≥ 75,000 per microliter, Hemoglobin 
level ≥ 8.0 gm/dL on screening complete blood count  
➢ Potassium and total calcium (corrected only in the case of hypoalbuminemia) within normal 
limits of the local laboratory (Screening values can be rechecked after electrolyte repletion and 
before the first dose of study medication, if necessary.)  
➢ Serum creatinine level ≤ 1.5 mg/dL or estimated glomerular filtration rate > 50 mL/min.  
➢ In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) should be below 2.5 × the upper limit of normal (ULN). If the patient has liver 
metastases, ALT and AST should be < 5 × ULN. 
➢ Total bilirubin ≤ 1.5 x ULN. (In patients with well documented Gilbert’s Syndrome, total 
bilirubin ≤ 3 × ULN with direct bilirubin within normal range.) 
➢ INR ≤ 1.5 
 
• 
 (a) Written informed consent and HIPAA authorization obtained from the subject/legal 
representative prior to performing any protocol-related procedures; 
 
(b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory 
testing, and other requirements of the study 
 
• 
Must be able to swallow ribociclib and oral aromatase inhibitor, such as letrozole or exemestane. 
 
3.2 
Exclusion Criteria: 
A subject who meets any of the following criteria is ineligible for the study: 
 
1. Patient has a known hypersensitivity to any of the excipients of ribociclib, aromatase inhibitors (such 
as letrozole) or fulvestrant. 
 
2. Active central nervous system (CNS) disease. History of CNS metastases or cord compression is 
allowable if the patient has been clinically stable for at least 4 weeks since completion of definitive 
treatment and is off systemic steroids.  In the case of brain metastases, the patient must have stable or 
improved imaging at least 4 weeks after completion of definitive treatment. If there is evidence of 
active leptomeningeal disease, the patient is ineligible. 
  
3. Identified as having visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral 
crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as 
assessed by symptoms and signs, laboratory studies, and rapid progression of the disease. 
 
4. Received more than 1 prior systemic chemotherapy in the unresectable or metastatic setting. If the 
patient received 1 prior systemic chemotherapy, the patient is eligible. Having received prior 
therapies for breast cancer (such as everolimus or experimental agents) does not affect eligibility for 
this study.     
 
5. Completion of major surgery, chemotherapy, targeted therapy (such as everolimus or experimental 
agents_ or radiation within 14 days prior to starting investigational drug or has not recovered from 
major side effects. There is no required washout period from completion of prior anti-estrogen therapy (either 
scenario) or prior CDK 4/6 inhibitor (if scenario 2) to initiation of ribociclib/placebo and anti-estrogen on trial. 


 
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6. Residual acute toxic effects of prior anti-cancer therapy that have not resolved to CTCAE v.4 Grade ≤1. 
Exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea 
or other toxicities not considered a safety risk for the patient as per investigator’s discretion, are allowed to enter 
the study. 
 
7. Presence of a concurrent malignancy or malignancy diagnosed within 5 years of randomization, with 
the exception of basal or squamous cell carcinoma, non-melanomatous skin cancer, curatively 
resected cervical cancer, localized prostate cancer treated with curative intent, and stage I colorectal 
cancer treated with curative resection.  
 
8. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection). 
 
9. Patient has a known history of HIV infection (testing not mandatory) 
 
10. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including 
any of the following: 
 
• 
History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary 
artery bypass graft (CABG) within 6 months prior to study entry 
• 
Documented cardiomyopathy 
• 
Patient has a known Left Ventricular Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO). 
• 
Long QT syndrome or family history of long QT syndrome or family history of idiopathic 
sudden death or congenital long QT syndrome, or any of the following: 
i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, 
hypokalemia or hypomagnesaemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
ii. Concomitant medications(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by safe 
alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug) 
iii. Inability to determine the QTc interval 
• 
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third 
degree AV block) 
• 
Systolic Blood Pressure (SPB) >160 or <90 mmHg 
 
11. Corrected QT interval (QTcF) > 450 msec (QT interval using Fridericia’s correction) on screening 
electrocardiogram. If QTc prolongation is felt to be related to electrolyte imbalance, an EKG can be 
repeated after correction of electrolytes. Mean resting heart rate 50-100 bpm (determined from 
ECG). 
 
12. The presence of any other concurrent severe and/or uncontrolled medical condition that would, in the 
investigator or treating physician’s judgment, cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol. This includes 
uncontrolled infections that could potentially be exacerbated by anti-neoplastic treatment, active 
untreated or uncontrolled fungal bacterial or viral infections, etc. 
 


 
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13. Currently receiving treatment, including medications and herbal preparations, with known strong 
inducers or inhibitors of cytochrome p450 enzymes CYP3A4/5 medications that have a narrow 
therapeutic window and are predominately metabolized through CYP3A4/5 or herbal 
preparations/medications, dietary supplements, which cannot be discontinued prior to receiving 
investigational drug. Anti-retrovirals, anti-microbials, and anti-arrhythmics are the most common 
medications that interact with these enzyme. Please refer to Section 5: Pharmaceutical Information 
and Appendix B for more information and a list of drugs that should not be used concurrently with 
ribociclib.   
 
14. Patients who are receiving any other investigational agents concurrently or have received 
investigational agents within 14 days or 5 half-lives of the compound or active metabolites, 
whichever is longer before the first dose of the study treatment 
 
15. Patient is concurrently using hormone replacement therapy.  
 
16. Subject is pregnant or nursing. Serum or urine Beta-HCG must be checked in all non-
postmenopausal patients or patients of childbearing potential. (Fulvestrant is pregnancy category D 
and CDK4/6 inhibitors have demonstrated teratogenicity/fetotoxicity in animal studies.)  
 
 
4. 
REGISTRATION PROCEDURES 
*** Please see Appendix F for Guidelines for Affiliate Institutions for Registration and Data Reporting 
Requirements.  
 
CUMC Research Participant Registration (CUMC Subjects ONLY) 
Confirm eligibility as defined in Section 3. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent Procedures, 
along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this protocol 
will participate in the consenting process. Furthermore, properly delegated/trained Physician Investigators 
(i.e., MD, MD PhD) are required to sign/verify a protocol specific Eligibility Checklist for each subject 
enrolled on the study, in addition to providing the relevant source documentation to confirm subject 
eligibility. 
 
All participants must be centrally registered through the Central Registration Office within Herbert 
Irving Comprehensive Cancer Center at CUMC prior to initiation of study treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding holidays 
and weekends). Same day patient registrations (and after hour registrations) will be accommodated on a case-
by-case basis provided that the study team has expressed all time sensitive registration concerns/cases in a 
timely manner to the Central Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed IRB approved 
informed consent HIPAA form, and demographics forms must be submitted to the CPDM Central 
Registration Office via an email to CPDMRegistration@cumc.columbia.edu or fax to 212-304-6330, with 
the subject line “[PROTOCOL# AAAP9506 Pending Subject Registration Request (PHI)”.  Upon 
receipt, applicable subject information as well as a “pending eligibility” status will be entered into HICCC’s 


 
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institutional database.  This status will remain until further source documentation is made available to 
confirm overall patient eligibility. Required materials for all pending registration submissions are as follows: 
 
• 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional study ICFs 
(i.e. tissue, DNA, etc.) as applicable 
• 
The completed/signed IRB approved HIPAA Authorization form 
• 
Completed/signed CPDM ICF checklist 
• 
Completed/signed HICCC personal census form 
• 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (i.e., study specific Clinical Research 
Coordinator/Research Nurse, etc.) must submit the following documentation to the Central Registration 
Office via email or fax: 
 
• 
The completed/signed study specific Eligibility Checklist  (signed by a Physician level Investigator) 
• 
Copies of source documentation necessary for each item to be verified on the CUMC specific 
Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, serum chemistry, 
pregnancy test when applicable, and pertinent radiology reports such as CT/bone scans, 
PET/CT scans, MRI reports, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc) 
o Protocol deviation/waiver approvals (if applicable) 
• 
Please note: subject line of email or fax should include the following: “PROTOCOL# AAAP9506 
Complete Subject Registration Request (PHI).” 
Upon Receipt of the above-mentioned documentation, participant eligibility information will be verified by a 
qualified Central Registration Registrar. If any questions arise during the review process, queries in the form 
of emails will be addressed to the applicable study team personnel for clarification prior to enrollment.  All 
applicable finalized registration/eligibility information will then be entered into HICCC’s institutional 
database by the Central Registration Registrar.  Upon completion, an official subject registration notification 
email will be sent to the PI/research team, which will include eligibility/enrollment status, as well as subject 
ID information.  Protocol therapy may not be initiated prior to receipt of this notification from the Central 
Registration Office. 
 
All screen fail/ineligible subjects, as well as subjects who withdraw consent prior to enrollment/initiation of 
protocol therapy must be submitted to the Central Registration office in a manner analogous to the 
procedures noted above. Applicable source documentation will be required within the corresponding 
submissions. 
 
*** Please see Appendix F for Guidelines for Affiliate Institutions for Registration and Data Reporting 
Requirements.  
 
5. 
PHARMACEUTICAL INFORMATION 
This is a randomized study that will evaluate the efficacy of the combination of the ER downregulator 
fulvestrant (or exemestane) with the CDK4/6 inhibitor ribociclib vs. fulvestrant (or exemestane) with 
placebo, administered in patients with metastatic breast cancer who have previously had disease progression 
on the combination of CDK4/6 inhibition with an AI. For patients registered prior to having ever received a 


 
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CDK4/6 inhibitor with an AI (scenario # 1), the combination of ribociclib and letrozole will be provided by 
the study supplier (Novartis).  If the patient has received letrozole previously, another aromatase inhibitor 
may be used that the patient has not previously received (anastrazole, exemestane) – this will be given as 
standard of care and not supplied by the study (ribociclib will be supplied). Following disease progression, 
these patients will be randomized and switched to the combination of fulvestrant (or exemestane) +/- 
ribociclib.  (Section 6 for full treatment plan).  
 
A list of the adverse events and potential risks associated with the investigational agent ribociclib, as well as 
a brief review of the adverse events associated with the two standard of care agents letrozole, exemestane, 
and fulvestrant can be found in Section 8. 
 
5.1 
Ribociclib (Investigational agent, supplied by Novartis): 
5.1.1 Overview:  
Ribociclib is an orally bioavailable and highly selective small molecule inhibitor of the CDK4/cyclin-D1 and 
CDK6/cyclin-D3 enzyme complexes with IC50’s of 0.01 and 0.039 µM in biochemical assays, respectively. 
(Investigator’s Brochure = IB)  
 
5.1.2 Drug Product: (IB) 
The drug product is for oral administration. The available clinical forms are 50 mg and 200 mg hard gelatin 
capsules/tablets. The capsules/tablets only contain the drug substance; there are no excipients.  
 
5.1.3 Drug Storage: (IB) 
The shelf life of the drug product is established based on ongoing stability studies and may be extended 
during the clinical study. Capsules/tablets should not be stored at temperatures above 25 °C and should be 
protected from moisture and light.  
 
5.1.4 Pharmacodynamics: 
Enzymatic Studies (IB)  
The potency and selectivity of ribociclib as a CDK4/6 inhibitor were testing using biochemical assays. 
Isolated enzyme complexes were used to determine the compound’s IC50 against cyclin D bound CDK4 and 
CDK6 as well as additional kinases including other CDK family members. An enzymatic assay in TR-FRET 
format was established to monitor CDK4/cyclin D1 kinase activity following the phosphorylation of Ser780 
and p-Rb152 (the C-terminus fragment of phospho-Rb containing avi-tag.) In the presence of CDK 
inhibitors, the reduction in the TR-FRET signal was monitored and IC50 concentrations were determined. A 
similar assay was developed to examine the inhibition of the CDK6/cyclin D1 complex and the CDK6/cyclin 
D3 complex. In order to profile the compound’s selectivity for CDK4 and CDK6 complexes, four additional 
CDK complexes (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, and CDK9/cyclin T1) and six non-CDK 
serine/threonine kinase assays were developed using surrogate peptide substrates in an IMAP format. 
Ribociclib was profiled in these assays and the resulting IC50 values are summarized in the table below. The 
results demonstrated that ribociclib inhibited CDK4/cyclin D1 and CDK6/cyclin D3 with IC50s of 0.01 μM 
and 0.039 μM, respectively, while demonstrating poor inhibition (high μM IC50s) against other CDK family 
members. This demonstrated that ribociclib was a selective inhibitor of CDK4/6 kinases. The detailed assay 
protocols are available from Novartis upon request. Extended profiling was also carried out against the NIBR 
internal kinase selectivity panel, which covers 38 different serine/threonine kinases and tyrosine kinases. 
Ribociclib was inactive (IC50 > 10 μM) against the vast majority of kinases (35 of 38) in the panel, and 
demonstrated weak inhibition of the remaining three kinases (Aurora A, HER1, and LCK). This further 
demonstrated ribociclib’s strong selectivity for CDK4/6 with relative inactivity against all other kinases 
tested.  
 


 
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(Table courtesy of IB.) 
 
Kinase selectivity in transduced BaF3 cell line (IB) 
The cellular kinase selectivity of ribociclib was assessed using the BaF3 signaling pathway selectivity panel. 
This panel consists of a series of BaF3 murine pro-B-cell sublines whose proliferation and survival has been 
rendered IL-3-independent by stable transduction with individual constitutively activated tyrosine kinases 
(either by mutation or fusion with a dimerization-promoting protein domain.) Ribociclib-mediated 
suppression of BaF3 cell proliferation and viability was assessed after 48 hours by the AlamarBlue assay. 
Concentrations up to 10μM were tested; ribociclib did not reach half-maximal proliferative inhibition in 8 of 
the 11 transduced BaF3 panel models, nor in the parental wild type cells grown in the presence of IL-3. 
Ribociclib only marginally inhibited the proliferation of the other three models (Tel-IGF1R, FLT3-ITD and 
Tel-PDGFRβ models), displaying IC50s in the 5-10 μM range. In summary, ribociclib can be considered to 
be devoid of relevant inhibitory activity against the respective kinases as assessed in the BaF3 model context. 
 
In vitro studies with ribociclib (IB) 
CDK4/6-cyclin D complexes phosphorylate Rb at specific serine residues located at codons 780, 795 and 
807/811.80 Phosphorylation at these sites is a prerequisite for subsequent phosphorylation of Rb at other 
residues by the CDK2-cyclin E complex, which occurs late in G1 phase.   
 
A panel of human breast cancer cell lines was treated with titrated doses of ribociclib and dose-dependent 
inhibition of proliferation was observed across the panel with enhanced activity against ER+ breast cancer 
cell lines. An IC50 < 1µM was observed for most ER-positive breast cancer lines. (IB / Novartis internal 
data). Ribociclib as a single agent has been shown to have activity in preclinical models of ER+ breast 
cancer.   
 
In the Jeko-1 mantle cell lymphoma cell line that overexpress cyclin D1 as a result of the chromosomal 
translocation t(11;14), ribociclib inhibits the phosphorylation of Rb at CDK4/6-specific sites with an average 
IC50 of 0.060 µM. Ribociclib also inhibits the growth of many other tumor cell types in vitro, including 
liposarcoma, melanoma, malignant rhabdoid, and esophageal, breast, lung and pancreatic carcinomas.  
 
The ability of ribociclib to inhibit cell proliferation was assessed using the BrdU uptake assay and by cell 
cycle analysis using flow cytometry. Ribociclib inhibited BrdU uptake with an average IC50 of 0.1 μM in 
Jeko-1 cells. Alternatively, in H2009 cells that lack functional Rb, a greater than10 μM IC50 was observed, 
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of ribociclib’s anti-proliferative effects in Jeko-1 cells was G1-phase arrest (with a full G1-phase arrest 
observed at a concentration of <1 µM), whereas H2009 cells did not demonstrate this effect. Regardless of 
the various genetic aberrations that may be present in the cancer cells, the anti-tumor activity of ribociclib 
requires the presence of functional Rb. As discussed in Section 2, the vast majority of ER-positive breast 
cancer has Rb intact, while a high percentage of triple negative breast cancers demonstrate Rb loss. 
 
In vivo studies with ribociclib (IB) 
In early in vivo studies in mice and rats, ribociclib was well tolerated, with body weight loss not exceeding 
12.5% at treatment doses as high as 250 mg/kg per os daily and 150 mg/kg daily, respectively. No significant 
changes in blood chemistry tests were observed after 28 days of consecutive dosing. However, 
myelosuppression was observed and tightly correlated with phospho-Rb target inhibition. Treatment with 
ribociclib resulted in significant tumor regression in the Jeko-1 mantle cell lymphoma xenograft model (in 
SCID immunodeficient mice) at doses greater than or equal to 75 mg/kg daily. In vivo 
pharmacokinetic/pharmacodynamics and efficacy studies demonstrated that plasma levels corresponding to 
approximately 0.5 - 4 μM over a 24 hour dose interval are required to obtain near complete target inhibition 
and complete regression in the Jeko-1 MCL xenograft model. Continuous dosing over at least 3 days was 
required to achieve optimal target inhibition in this model. Moreover, near complete (>80%) target inhibition 
over the entire 24 hour dosing interval appeared requisite to achieve tumor regression.  
 
Ribociclib also showed significant anti-tumor activity in a panel of patient-derived tumor xenograft models 
when dosed at 250 mg/kg daily. Ribociclib efficacy was only observed in tumors that demonstrate phosphor-
Rb expression at baseline, and all Rb-null tumors showed no effect, consistent with the known mechanism of 
action of CDK4/6 inhibition. Tumor types where anti-tumor activity corresponding to near stasis of tumor 
growth included breast, pancreas, and melanoma. 
 
5.1.5 Safety/Toxicology (IB)  
Ribociclib was assessed for off-target activity on 147 G-protein couple receptors, transporters, ion channels, 
nuclear receptors, and enzymes, using in vitro biochemical assays. Greater than 50% inhibition at 
concentrations as high as 10 μM was found only against three targets: phosphodiesterase 4d (PDE4d) at an 
IC50 of 0.39 μM, apelin receptor at an IC50 of 10 μM, and the orexin-2 receptor at an IC50 of 10 μM. There 
was minimal binding and essentially no activity against the remaining 144 targets at the concentrations 
assessed.  
 
In vivo rat safety studies did not reveal any effects on the central nervous system or on respiratory function. 
Cardiac safety studies did demonstrate a signal for prolongation of the QT interval with the potential to 
induce rare premature ventricular contractions at higher exposure levels. (More serious ventricular 
arrhythmias were not observed in rats.)  
 
The effects of ribociclib on the bone marrow (myelosuppression), lymphoid system (lymphoid depletion), 
intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) and testes (atrophy) in rats and 
dogs is considered to be on-target off-tumor effects of CDK4/6 inhibition resulting in impaired cell 
proliferation in these normally proliferative healthy tissues. An increased number of ovarian corpora lutea 
were observed in a single female dog at the highest dose tested (20 mg/kg/day) and this effect could also be 
related to the pharmacology of ribociclib (arrest of estrous cycle). The hepatobiliary system was also affected 
in dogs treated with ribociclib, with toxic effects including proliferative changes, cholestasis, sand-like 
gallbladder calculi, and inspissated bile in the extrahepatic bile ducts. These were felt to be off-target effects 
of unclear etiology. Inflammatory changes in the lungs of dogs’ were considered secondary to aspiration of 
the investigational agent and are indicative of the irritant potential of the formulation if directly inhaled.  
 
Correlating hematologic and/or biochemical changes were seen for the effects described on the bone marrow, 
lymphoid system and liver. In rats, the changes seen in the bone marrow demonstrated a clear tendency 
towards reversibility, and all other findings fully reversed shortly following drug withdrawal. In dogs, the 


 
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changes seen in the testes and lungs demonstrated a clear trend towards reversibility and all other changes 
were full reversed shortly after drug withdrawal.  
 
Based upon these findings, hematologic and hepatobiliary parameters have been closely followed in early 
phase clinical trials with ribociclib, and gastrointestinal effects have been monitored. In vitro, mutagenic and 
phototoxic potential have not been demonstrated with ribociclib. In addition, given the in vivo QT 
prolongation, QTc will be closely monitored during the trial. 
 
Safety assessment in clinical studies:  
Section 8.1: Synopsis of common adverse events with the study drugs.  
 
5.1.6 Pharmacokinetics and metabolism  
The pharmacokinetic profile of ribociclib has been investigated in vivo in mice, rats, dogs, and cynomolgus 
monkeys. The plasma profiles of ribociclib following oral administration in mice, rats, and monkeys are 
characterized by moderate terminal half-lives (2 to 7 hours in duration), as compared to longer terminal half-
lives in dogs of approximately 18 hours.  
 
The bioavailability of ribociclib was evaluating using a radiolabeled formulation. In adult male rats, 48-84% 
of the dose was absorbed, consistent with moderate absorption. The final bioavailability is low to moderate 
in rats (10-65%) and in cynomolgus monkeys (10-23%), while it is moderate in mice (65%) and dogs (64%). 
Following oral administration, peak ribociclib plasma concentrations occurs within 2 to 4 hours in all species 
tested.  
 
Gender dependent toxicokinetics were identified in rats, with higher exposure to ribociclib in males as 
compared to females (3.2 to 7 fold difference in area under the curve (AUC)) and with higher exposure to its 
metabolite LEQ803 (6.2 to 17.8 fold difference in AUC during the 24 hours post administration).   
 
Distribution: 
Plasma protein binding was moderate and showed no major concentration dependency across all species 
tested, with unbound fractions in plasma for humans of 30±2% and animals ranging from 20±1% to 32±6%. 
Extensive distribution of ribociclib and its metabolites to rat tissues was seen following a 10 mg/kg oral dose, 
but there was no uptake into the central nervous system. The highest concentrations were found in glandular 
tissues such as the thyroid gland (following oral or intravenous administration), the pineal body 
(intravenous), the pituitary gland (oral), Harderian gland (oral), preputial gland (oral) and adrenal medulla 
(intravenous). The highest concentrations were seen in the thyroid gland. In addition to glandular tissues, 
kidney (intravenous), liver (oral) and spleen (oral and intravenous) tissues demonstrated high concentrations 
of the investigational drug and its metabolites. Distribution was also observed in the melanin-containing 
structures of pigmented male rats, such as the choroids, ciliary body, and meninges. In body tissues, 
clearance of radioactively labeled drug and metabolites occurs with half-lives on the range of less than 10 
hours across all species, with nearly complete clearance within one week (with <0.04% retention in animals 
harvested at that time point.)   
 
Metabolism: 
In all species, N-demethylation is the most common metabolic reaction, resulting in the production of the 
drug metabolite LEQ803. Traces of two potential unique human metabolites were detected in hepatocytes. In 
mice, rats, monkey and humans, glutathione adducts were found which were detected but could not be seen 
in plasma or excreta (urine, bile, feces) in the rat pharmacokinetic studies. In male rats, unchanged NVP 
LEE-011 (45.5%) and its N-demethylated and N-acetylated metabolite M11 (15.3%) are the major 
components in plasma. The pharmacologic activity of M11, a rat specific metabolite is not known. In 
hepatocyte incubations with ribociclib, LEQ803 is the major metabolite observed in human, rat and monkey, 
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In male rats, ribociclib is eliminated mainly by hepatic metabolism. The major metabolism pathway seems to 
be the direct sulfation of ribociclib to M8 and excretion in the bile. Considering the recovery of ribociclib in 
urine, bile, and feces of bile duct-cannulated rats, the clearance of direct ribociclib excretion amounted to 
18.2% of the total plasma clearance.  
 
Excretion: 
Results from pharmacokinetics studies in male rats demonstrated that 3H-components (including ribociclib 
and its major metabolites) were predominantly excreted with bile (61.4±8.22% of dose), with urine excretion 
representing a minor percentage (5.44±2.36% of dose after oral administration and 10.1±2.09% after 
intravenous administration.) The majority of the administered dose (87.3%) was excreted within 24 hours via 
bile, feces (direct enteric secretion), and urine. Recovery was good, indicating little retention in the body.  
 
Drug-drug interactions: 
Oxidative metabolism of ribociclib is predominantly by CYP3A4 with a minor contribution of approximately 
20% by FMO3. Uptake of ribociclib in Caco-2 cells and hepatocytes occurs by moderate to high passive 
permeation modulated by some active transport. Ribociclib is a substrate of P-glycoprotein (MDR1) and 
likely also of an unidentified uptake transporter in hepatocytes.   
 
Ribociclib is a time-dependent CYP3A4 inhibitor (Ki= 5 μM, kinact = 0.0245 / min) and demonstrated 
reversible inhibition of CYP1A2 (Ki = 16 μM). No pregnane X receptor (PXR)-mediated CYP3A4 induction 
was observed with the drug. Ribociclib was found to inhibit P-glycoprotein (IC50 of 143 μM), MXR 
transporter (IC50 of 24 μM) and human bile salt export pump (BSEP) (IC50 of 4.7 μM). The elimination of 
ribociclib may potentially be affected by co-administration of drugs that inhibit or induce CYP3A4 or drugs 
that are strong inhibitors of P-glycoprotein. (Appendix B). In addition, depending on the therapeutic dose, 
ribociclib may inhibit CYP3A4 and to a lesser extent CYP1A2, BSEP, and MXR, and thus levels of 
medications that are metabolized by these enzymes may be affected by co-administration.  
 
Pharmacokinetics in Human Studies: (IB)  
As of March 2014, pharmacokinetic data were available from 128 patients from the first-in- human study of 
ribociclib (CLEE011X2101.) Following oral dosing, ribociclib was rapidly absorbed with median Tmax 
ranging from 1 to 5 hours. Ribociclib plasma exposure exhibited slightly over-proportional increases in 
exposure across the dose range tested (50 to 1200 mg), with no clear evidence of time-dependent auto-
inhibition of its clearance mediated by CYP3A4. Steady state was generally reached by day 8 and the mean 
effective T1/2 based on the accumulation ratio ranged from 15.9 to 32.6 hours across the dose range tested. 
The accumulation ratio based on AUC obtained in a dosing interval across the studied doses ranged from 
1.55 to 2.52. The maximum tolerated dose and recommended dose for expansion from this study were 
declared as 900 mg daily and 600 mg daily on a 3 weeks on/1 week off schedule, respectively. 
 
A food effect study conducted in healthy subjects indicated that ribociclib administered as drug-in-capsule 
can be taken without regard to meals. A drug-drug interaction study with ritonavir (a strong CYP3A4 
inhibitor) and rifampicin (a strong CYP3A4 inducer) conducted in healthy subjects (CLEE011A2101) 
indicated that concurrent use of strong CYP3A4 inhibitors or strong CYP3A4 inducers may markedly affect 
ribociclib exposure and should be avoided.  
 
A different drug-drug interaction cocktail study with midazolam (a sensitive CYP3A4 substrate) and caffeine 
(a sensitive CYP1A2 substrate) was conducted in healthy subjects (CLEE011A2106). Preliminary PK data 
indicate that ribociclib (400 mg) is a moderate inhibitor of CYP3A4, but did not have a substantial effect on 
CYP1A2 substrates in humans. Concurrent use of sensitive CYP3A4 substrates with a narrow therapeutic 
index should be avoided. Concurrent use of CYP1A2 substrates is not expected to lead to clinically important 
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5.1.7 Agent Ordering 
Ribociclib is an investigational agent supplied to investigators by Novartis Pharmaceuticals Corporation. 
Ribociclib supplied for this protocol is intended for clinical trial use only and is not commercially available. 
Ribociclib is shipped directly from the company to the participating institution (Appendix H for Drug Order 
Form). For further details on molecule characterization, see the ribociclib Investigator’s Brochure. 
 
5.2 
Fulvestrant (standard of care medication after randomization, not supplied by the study)  
5.2.1 Overview: (Prescribing information, PI)  
Fulvestrant is a selective estrogen receptor downregulator (SERD). It is an antagonist of the ER, and 
competitively binds to receptors on tumors and other tissue that expresses the ER. Binding of fulvestrant to 
the ER produces a nuclear complex that causes a dose-related down-regulation of estrogen receptors and 
inhibits tumor growth. Fulvestrant was FDA approved in 2002 for the treatment of postmenopausal women 
with metastatic breast cancer whose disease progressed on first line anti-estrogen therapy with tamoxifen or 
an AI.  
 
Fulvestrant is contraindicated during pregnancy. In animal studies, fulvestrant causes fetal loss or fetal 
abnormalities at or below doses in the range of those approved for prescription in humans. It is listed as 
pregnancy category D. 
  
In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant as 
well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant 
delayed the establishment of tumors from xenografts of MCF-7 cells in nude mice. Fulvestrant inhibited the 
growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts.  
 
Fulvestrant showed no agonistic effect in in vivo uterotropic assays in immature or ovariectomized mice and 
rats. In immature rats and overiectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. 
In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to 
fulvestrant treatment suggests no peripheral steroidal effects.  
 
5.2.2 Drug Product: (PI) 
The active ingredient of fulvestrant is (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl) sulfinyl]nonyl}estra-
1,3,5(10)-triene-3,17-diol. Fulvestrant is prepared as a solution for intramuscular injection only, under the 
brand name of Faslodex. The solution contains alcohol, usp, benzyl alcohol, and benzyl benzoate, in addition 
to the active ingredient fulvestrant. It is available in 250 mg in 5 mL prefilled syringes.   
 
Because fulvestrant is administered intramuscularly, caution should be exercised prior to administering to 
patients with bleeding diatheses, thrombocytopenia, or who are on anticoagulant therapy. 
 
The proper method for intramuscular administration of fulvestrant is described below:  
1) Remove glass syringe barrel from tray and check that it is not damaged.  
2) Remove perforated patient record label from syringe.  
3) Peel open the safety needle outer packaging.  
4) Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the 
attached rubber tip cap.  
5) Twist to lock the needle to the luer connector.  
6) Remove needle sheath.  
7) Remove excess gas from the syringe. (A small gas bubble may remain.)  
8) Administer intramuscularly in the buttock, slowly. (20-60 seconds.)   
9) Immediately activate needle protection device upon withdrawal from patient by pushing lever arm 
completely forward until needle tip is covered. 
10) Repeat steps 1->9 for second syringe.  


 
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5.2.3 Drug Storage: (PI) 
Fulvestrant is typically packaged as two 5 mL clear neutral glass barrels, each fitted with a tamper evident 
closure, each containing 250 mg/5 mL of fulvestrant. The syringes are presented in a tray with polysterine 
plunger rod and safety needles for connection to the barrel.  
 
The product should be stored in the refrigerator, at temperatures in the range of 2 to 8 degrees Celcius, until 
time of use. To protect from light, product should be stored in the original carton until time of use.  
 
5.2.4 Pharmacokinetics: (PI) 
Distribution:  
The apparent volume of distribution at steady state is approximately 3 to 5 L/kg. This suggests that 
distribution is mainly extravascular. Fulvestrant is highly bound to plasma proteins (99%), predominantly to 
the VLDL, LDL, and HDL lipoproteins. The role of sex hormone-binding globulin appears to be minimal.  
In patients with breast cancer, there was no difference in fulvestrant PK profile related to age (range 33 to 89 
years). There also is no difference in PK profile for fulvestrant between men and women.   
 
Metabolism: 
Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular 
administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a 
number of possible biotransformation pathways analogous to those of endogenous steroids, including 
oxidation, aromatic hydroxylation, conjugation with glucoronic acid and/or sulphate at the 2, 3, and 17 
positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either 
less active or exhibit similar activity to fulvestrant in anti-estrogen models. 
 
Studies using human liver preparation and recombinant enzymes indicate that CYP 3A4 is the only P450 
isoenzyme involved in the oxidation of fulvestrant, although the overall contribution of P450 and non-P450 
routes is unknown.  
 
Excretion:  
Fulvestrant is rapidly cleared by the hepatobiliary route with excretion primarily via the feces (>90%). Renal 
elimination is negligible (<1%). After intramuscular injection of fulvestrant 250 mg, the mean clearance was 
690±226 mL/min with a half-life of approximately 40 days.  
 
For patients with moderate hepatic impairment, the 250 mg dose of fulvestrant is recommended. The safety 
of fulvestrant in patients with severe hepatic impairment has not been adequately studied.  
  
Drug-drug interactions:  
There are no significant drug-drug interactions. While fulvestrant is metabolized by CYP3A4 in vitro, drug 
interaction studies with ketoconazole and rifampin in animal studies did not alter fulvestrant 
pharmacokinetics. Dose adjustments are not needed in patients co-prescribed CYP3A4 inhibitors or inducers.  
 
5.2.5 Safety/Toxicology: (PI) 
Adverse events occurring in >5% of patients in the CONFIRM trial (randomized phase III trial comparing 
the 250 mg vs. 500 mg dose of fulvestrant in post-menopausal patients with metastatic HR+ breast cancer 
who experienced progression on prior anti-estrogen therapy) are summarized in the table below. The vast 
majority of adverse events were grade II or lower.  
 


 
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5.2.6 Agent Ordering:  
Fulvestrant is an FDA approved medication, but it is not currently approved for usage with CDK4/6 
inhibitors. The agent will be administered as standard of care.   
 
5.3 
Letrozole (Standard of care medication provided prior to randomization in patients registered 
under scenario #1, supplied by Novartis)   
5.3.1 Overview: (Prescribing information)  
Letrozole is a non-steroidal aromatase inhibitor with FDA approval for the systemic treatment of patients 
with both localized (in the adjuvant setting) and metastatic HR+ breast cancer. There is extensive clinical 
experience with letrozole, with the rates of severe adverse events exceedingly low.   
 
In postmenopausal women whose ovaries are no longer synthesizing estrogens, estrogens are mainly derived 
from the action of the aromatase enzyme, which converts adrenal androgens such as androstenedione and 
testosterone to estrone (E1) and estradiol (E2). Thus, the suppression of estrogen biosynthesis in peripheral 
tissues and cancer tissue itself can be achieved by specifically inhibiting the aromatase enzyme.  
 
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 
subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. In healthy 


 
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postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg letrozole suppressed serum estrone and 
estradiol by 75-78% and 78% from baseline, respectively. Maximum suppression is achieved in 48-72 hours. 
In postmenopausal patients with metastatic breast cancer, daily doses of 0.1 mg to 5 mg of letrozole 
suppressed plasma concentrations of estradiol, estrone, and estrone sulphate by 75-95% from baseline in all 
patients treated. With doses of 0.5 mg and higher, many values of estrone and estrone sulphate were below 
the limit of detection. Estrogen suppression was maintained throughout treatment.  
 
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not 
been observed, and adrenal insufficiency is not an expected adverse event associated with treatment. In 
postmenopausal patients treated with a daily dose of 0.1 to 5 mg of letrozole, no clinically relevant changes 
were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, 
ACTH, or plasma renin activity. Furthermore, ACTH stimulation test (a highly sensitive test for adrenal 
insufficiency) performed in these patients 6 and 12 weeks after treatment initiation did not indicate any 
attenuation of aldosterone or cortisol production. Steroid supplementation is not necessary/recommended for 
patients receiving letrozole.  
 
5.3.2 Drug Product: (Prescribing Information) 
The active ingredient of letrozole is: 4, 4'-[(1H-1,`2, 4-triazol-1-yl)-methylene] bis-benzonitrile 
(INN/USAN= letrozole). Letrozole is available as coated 2.5 mg tablets. Excipients include silica-colloidal 
anhydrous, cellulose-microcrystalline, lactose, magnesium stearate, starch-maize, sodium starch glycollate, 
hypromellose, iron oxide yellow, macrogel 8000, talc-purifed, and titanium dioxide.  
 
5.3.3 Drug Storage: (Prescribing Information) 
Store letrozole at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F 
(15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. 
 
5.3.4 Pharmacokinetics: (Prescribing Information) 
Absorption: 
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean bioavailability is 99.9%). 
Co-administration with food slightly decreases the rate of absorption (median time for maximum absorption 
is 1 hour in the fasted state vs. 2 hours fed), but the extent of absorption is not affected. Therefore letrozole 
may be taken without regard to mealtimes.   
 
Distribution: 
Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of 
letrozole in erythrocytes is about 80% of that in plasma. After administration of 14C-labelled letrozole 2.5 
mg, approximately 80% of the radioactivity in plasma was unchanged compound. Systemic exposure to 
metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume 
of distribution at steady state is about 1.87± 0.47 L/kg. 
 
Metabolism and Elimination:  
Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway for 
letrozole. (mean clearance 2.1 L/hour). The cytochrome P450 isoenzymes CYP3A4 and CYP2A6 were 
found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites 
and direct renal and fecal excretion play only a minor role in the overall elimination of letrozole. Within 2 
weeks after administration of 14C-labelled letrozole 2.5 mg to healthy postmenopausal volunteers, 88.2±7.6% 
of the radioactivity was recovered in urine and 3.8±0.9% in the feces. At least 75% of the radioactivity 
recovered in urine was attributed to the glucuronide of the carbinol metabolite, while about 6% was 
unchanged letrozole. The terminal elimination half-life in plasma is about 2 days. After daily administration 
of letrozole, steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are 
approximately 7-fold higher than concentrations measured after a single dose of 2.5 mg. This indicates a 
slight non-linearity in the pharmacokinetics of letrozole. However, since steady-state levels are maintained 


 
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over time, it does not appear that additive accumulation of letrozole occurs. Thus, continuous daily dosing is 
appropriate.  
 
In study populations (adults ranging in age from 35 to 80 years), no change in pharmacokinetic parameters 
was observed with increasing age. In a study comparing the PK of letrozole after a single oral dose in eight 
subjects with liver cirrhosis and severe hepatic cirrhosis (Child Pugh class C) to 8 healthy volunteers, 
average AUC and half-life increased by 95% and 187%, respectively. Breast cancer patients with this type of 
severe hepatic impairment are expected to be exposed to higher levels of letrozole than patients without 
severe hepatic dysfunction. If the opinion of the treating physician is that the risk is acceptable, a patient with 
severe hepatic impairment may be treated without dose reduction, but close monitoring of possible adverse 
drug reactions is recommended. In addition, in two well-controlled studies involving 359 patients with 
metastatic breast cancer, no effect of renal impairment was found on the letrozole concentration. 
 
5.3.5 Safety/Toxicology: (Prescribing Information, PI) 
There is extensive clinical experience with letrozole, and the vast majority of adverse events seen with this 
medication are grade II or lower. Adverse reactions occurring in >5% of patients in the randomized trial 
comparing tamoxifen vs. letrozole for the first line treatment of metastatic breast cancer are summarized in 
the table below.  


 
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5.3.6 Agent Ordering:  
Letrozole is an FDA approved medication for the systemic treatment of patients with HR+ breast cancer, 
manufactured by the trial’s supplier, Novartis Pharmaceuticals. The agent will be supplied to investigators by 
Novartis Pharmaceuticals Corporation. Letrozole supplied for this protocol is intended for clinical trial use 
only. Letrozole is shipped directly from the company to the participating institution (see Appendix H for 
Drug Order Form).  
 
If the patient has received letrozole previously, another aromatase inhibitor may be used that the patient has 
not previously received (anastrazole, exemestane) – this will be given as standard of care and not supplied by 
the study (ribociclib will be supplied). 
 
5.4 
Exemestane 
5.4.1 Overview: (Prescribing information)  
Letrozole is a steroidal aromatase inhibitor with FDA approval for the systemic treatment of patients with 
both localized (in the adjuvant setting) and metastatic HR+ breast cancer. There is extensive clinical 
experience with exemestane, with the rates of severe adverse events exceedingly low.    
 
5.4.2 Drug Storage: (Prescribing Information) 
Store at 25°C (77ºF); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room 
Temperature]. 
 
5.4.3 Pharmacokinetics: (Prescribing Information) 
Absorption: 
Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast 
cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 
hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the 
gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, 
respectively, compared to fasted state. 
 
Distribution: 
Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the 
fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute 
to the binding. The distribution of exemestane and its metabolites into blood cells is negligible. 
 
Metabolism and Elimination:  
Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 
10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the 
methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many 
secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The 
metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One 
metabolite may have androgenic activity [see Clinical Pharmacology (12.2)]. Studies using human liver 
preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the 
oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases. 
 
Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative 
amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces 
over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the 
dose. 
5.4.4 Safety/Toxicology: (Prescribing Information, PI) 
There is extensive clinical experience with exemestane and are similar to those described in 5.3.5. 
 


 
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5.3.5 Agent Ordering:  
Exemestane is an FDA approved medication for the systemic treatment of patients with HR+ breast cancer, 
manufactured by the trial’s supplier, and will be prescribed as standard of care. 
 
5.5 
Combining Fulvestrant with Ribociclib 
Ribociclib and fulvestrant have the following toxicities in common: nausea, fatigue, vomiting, 
gastrointestinal upset, AST increase, headache, and back pain. These overlapping adverse events are 
expected to be tolerable and manageable. 
 
In addition, there are no known drug interactions between fulvestrant and ribociclib. While fulvestrant itself 
is metabolized by CYP3A4, fulvestrant does not appear to have any affect in inhibiting or inducing the 
cytochrome P450 enzymes involved in the metabolism of ribociclib. Therefore, a drug-drug interaction 
involving fulvestrant and ribociclib is unlikely to occur.  
 
The combination of ribociclib and fulvestrant is being evaluated in a phase I study where both drugs were 
given at full dose to postmenopausal women with ER+, HER2-negative locally recurrent or metastatic 
metastatic breast cancer (IB). Dosing began on May 22, 2014. As of November 12, 2014, a total of 7 patients 
have been treated with the combination. All have completed the first 28 day cycle and 6 of the 7 patients 
have completed 6 cycles of treatment. Of these 7 evaluable patients, there were no dose adjustments, 
interruptions, dose limiting toxicities, or serious adverse events. Grade 2/3 neutropenia was observed in 6 of 
the 7 patients. One patient had a hepatitis B reactivation. The patient with the hepatitis B reactivation was 
discontinued at Cycle 5 due to progressive disease. Preliminary results of ribociclib in combination with 
fulvestrant suggest that this combination is safe and tolerable. Preliminary PK analysis suggests that 
ribociclib exposure was not affected when ribociclib (600 mg) was administered with fulvestrant (500 mg) or 
when ribociclib (400 mg) was administered with fulvestrant (500 mg) and BKM120 (30 mg). Safety of 
combining ribociclib plus an aromatase inhibitor has been already published, as per the Monaleesa-2 trial. 
 
6. 
TREATMENT PLAN 
6.1 
Study Design: 
This is a phase II, multi-center, randomized, double-blinded, placebo-controlled trial to evaluate fulvestrant 
(or exemestane) +/- ribociclib (1:1 randomization) in patients with HR+HER2- breast cancer who have 
previously progressed on an aromatase inhibitor, fulvestrant, or tamoxifen plus CDK4/6 inhibitor (either 
palbociclib or ribociclib or abemaciclib). There is no crossover.  If patient received prior fulvestrant, 
exemestane must be the hormone therapy backbone in the randomization. If patient received prior 
exemestane, fulvestrant must be the hormone therapy backbone in the randomization. If neither has been 
administered, selection of hormone therapy in the randomization will be per investigator discretion. 
Progression free survival is the primary endpoint. The trial will determine whether there is clinical benefit to 
continuing CDK4/6 inhibition beyond progression.     
 
Registration:  
Patients can be screened and registered at two different time points:  
Registration Scenario #1: Before receiving any CDK4/6 inhibitor or  
Scenario #2: At the time of disease progression while being treated with a CDK4/6 inhibitor (ribociclib or 
palbociclib or abemaciclib) + endocrine therapy  
Registration Scenario #1: If the patient has never received a CDK 4/6 inhibitor previously, the patient is 
eligible for the trial.  If the patient has not received letrozole previously, we are recommending that letrozole 
and ribociclib be administered (supplied by the study).  If the patient has, for instance, progressed on 
adjuvant letrozole, the patient can receive anastrazole plus ribociclib prior to randomization (but anastrazole 
will need to be supplied per standard of care/insurance).   
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registration for scenario 1. Other studies have allowed this, including CALGB 40503 (letrozole +/- 
bevacizumab). 
Registration Scenario #2: If a patient is on a clinical trial with ribociclib or abemaciclib or palbociclib (such 
as MONALEESA-2 or PALOMA-2) or abemaciclib and is clearly getting the CDK4/6 inhibitor (after un-
blinding) or if a patient is abemaciclib or ribociclib or palbociclib as standard of care, the patient is eligible 
for this study upon progression on the combination. Any aromatase inhibitor, fulvestrant, or tamoxifen along 
with a CDK4/6 inhibitor is allowed. (scenario #2).     
Randomization: 
In scenario #1, the study will provide patients with ribociclib + an aromatase inhibitor (such as letrozole), but 
patients will not be randomized until there is objective evidence of disease progression on treatment. In 
scenario #2, patients will be randomized after registration.  
At randomization, patients will be assigned to one of the two arms in a 1:1 ratio: 1) Fulvestrant (or 
exemestane) + ribociclib or 2) Fulvestrant (or exemestane) + placebo. The fulvestrant will be given as a 500 
mg dose IM every 2 weeks for 3 times and then every 28 days, as per standard of care. Exemestane 25 mg by 
mouth daily will be per standard of care. The investigational drug ribociclib will be given as 600 mg daily, 3 
weeks on/1 week off. Placebo will be administered on the same schedule.  
 
 
 
 
 
 
Accrual Target: N= 120 randomized, evaluable patients.  
 
6.2 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Expected adverse events and potential risks are 
described in Section 8.  Appropriate dose modifications are described in Section 7.  No investigational or 
commercial agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy while the patient is on this study. 
 
Patients registered under scenario # 1 will receive treatment with ribociclib and letrozole (or an alternative 
AI) prior to randomization and until disease progression on this regimen.  
 
Pre-Randomization Regimen Description (Only applies to registration scenario #1).  
Registration 
Scenario 
# of Pts 
Treated 
Type of Study 
Drug 
Compound 
(specify brand or 
generic) 
Dose and unit 
Frequency  
Admin Route 
Registration 
27 
Investigational 
Ribociclib 
600 mg capsule (3x 
Daily, 3 weeks 
Per Os (PO) 
Randomization (1:1) 
Fulvestrant (or exemestane) 
+ placebo  
Fulvestrant (or exemestane) 
+ ribociclib 


 
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Scenario # 1 
patients 
200 mg 
capsules/tablets)  
on / 1 week off 
Co-Therapy 
Letrozole (brand) 
2.5 mg tablet 
(1x 2.5 mg tab) 
Daily, 
continuous 
Per Os (PO) 
 
Scenario 1 is no longer accruing. 
 
Ribociclib and letrozole should be taken as follows:  
1) Patients should be instructed to take three ribociclib capsules/tablets (600 mg) with one tablet of 
letrozole (2.5 mg) with a large glass of water (~250 mL) at the same time each day.  
2) Ribociclib and letrozole can be taken without regards to food or meals; however dietary habits 
around the time dosing should be as consistent as possible throughout the study  
3) Patients should be instructed to swallow the ribociclib capsules/tablets and letrozole tablet whole and 
not to chew, crush or open them. 
4) If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the 
next scheduled dose. The occurrence and frequency of any vomiting during a treatment cycle must 
be noted in the adverse events section of the case report form.  
5) Any doses that are missed (not taken within 6 hours of the intended time) should be skipped and 
should not be replaced or made up on a subsequent day. 
6) Patients should avoid consumption of grapefruit, grapefruit hybrids, pomelos/pummelos, star fruit, 
and ‘seville oranges’ or products containing the juice of either during the entire study and preferably 
7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study 
medications. Orange juice is allowed. 
The duration of pre-randomization treatment cycles on ribociclib + AI is 28 days, with ribociclib taken orally 
during days 1 through 21 of each treatment cycle, and held during days 22-28 of each treatment cycle. 
Letrozole (or the alternative AI) is taken once daily, continuous.  
 
Patient adherence with ribociclib plus AI will be assessed by medication diary. The patient will be requested 
to record each dose of medication. The medication diary will be returned to research staff at the end of each 
cycle. 
Both patients registered under scenario # 1 and under scenario # 2 will receive the following regimen post-
randomization:  
Post-Randomization Regimen Description 
Treatment   
Arm 
# of Pts 
Planned 
Type of Study 
Drug 
Compound 
(specify 
brand or 
generic) 
Dose and unit 
Frequency  
Admin Route 
Arm A 
66 
Investigational 
LEE-011 
600 mg capsule 
(3x 200 mg 
capsules/tablets)  
Daily, 3 
weeks on/ 1 
week off 
Per Os (PO) 
Co-Therapy 
(Option #1) 
Fulvestrant 
(brand) 
500 mg 
injection 
 
 
Every 2 
weeks x 3, 
then every 4 
weeks 
Intramuscular 
(IM) 
 
Co-Therapy 
(Option #2) 
Exemestane 
25 mg  
Daily 
PO 
Arm B 
66 
Comparator 
Placebo 
600 mg capsule 
Daily, 3 
Per Os (PO) 


 
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(3x size ‘0’ 
capsules/tablets) 
weeks on/ 1 
week off 
Co-Therapy 
(Option 1) 
Fulvestrant 
(brand) 
500 mg 
Every 2 
weeks x 3, 
then every 4 
weeks 
Intramuscular 
(IM) 
 
Co-Therapy 
(Option #2) 
Exemestane 
25 mg  
Daily 
PO 
 
Ribociclib should be taken as follows:  
1) Patients should be instructed to take three ribociclib capsules/tablets (600 mg) with a large glass of 
water at the same time each day.  
2) Ribociclib can be taken without regard to food or meals.  
3) Patients should be instructed to swallow the ribociclib capsules/tablets whole and not to chew, crush 
or open them. 
4) If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the 
next scheduled dose. The occurrence and frequency of any vomiting during a treatment cycle must 
be noted in the adverse events section of the case report form.  
5) Any doses that are missed (not taken within 6 hours of the intended time) should be skipped and 
should not be replaced or made up on a subsequent day. 
6) Patients should avoid consumption of grapefruit, ‘seville oranges’ or products containing the juice of 
either during the entire study and preferably 7 days before the first dose of study medications, due to 
potential CYP3A4 interaction with the study medications. Orange juice is allowed. 
Post-Randomization Treatment Cycles 
The duration of a treatment cycle will be 28 days. Ribociclib or placebo will be taken orally once daily, 
during days 1 through 21 of each treatment cycle. Ribociclib or placebo will not be taken on days 22 through 
28 of each treatment cycle. (i.e. 3 weeks on, 1 week off.) An initial “loading dose” period of fulvestrant will 
consist of three 500 mg IM injections, starting on Cycle 1 Day 1 and concluding on Cycle 2 Day 1. 
Subsequently, fulvestrant will be administered in 500 mg IM injections every 4 weeks. This is the currently 
accepted optimal standard of care dosing regimen for fulvestrant. Fulvestrant is provided in 50 mg/mL 
solution for injection; 2 x 5 mL vials are injected intramuscularly with each 500 mg dose.   
Injection reactions with fulvestrant are exceedingly rare, although injection site pain is common. Pre-
medications are not recommended, although analgesics such as acetaminophen may provide relief from 
injection site pain. In the rare event of a patient who suffers an injection reaction, pre-medications are 
allowed at the discretion of the treating physician and should follow institutional standards. These can 
include acetaminophen 650mg po once, diphenhydramine 25-50 mg po/IV once 30 minutes prior to 
administration of drug, and/or an H2 receptor antagonist (such as famotidine 20 mg po/IV).  
Patient adherence with ribociclib/placebo will be assessed by medication diary. The patient will be requested 
to record each dose of medication. The medication diary will be returned to research staff at the end of each 
cycle. Patients must be instructed to return unused study drugs to the site at discontinuation or completion of 
treatment. 
6.2.1 Ribociclib 
Ribociclib is an investigational agent for the treatment of patients with hormone receptor positive metastatic 
breast cancer. It does not require specific prophylactic or supportive regimens as per the Investigator 
Brochure (IB) and based on the precedent set in ongoing clinical trials.  It is an oral therapy and can be 
administered with or without food according to the IB. The planned dose will be 600 mg oral daily (3 x 200 
mg capsules/tablets), with dose adjustments only as specified in Section 7.    
6.2.2 Fulvestrant 


 
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Fulvestrant is FDA-approved for the treatment of metastatic hormone receptor positive breast cancer.  It does 
not require specific prophylactic or supportive regimens.  It is an intramuscular therapy that should be 
prepared according to manufacturer’s recommendations.  It can be administered with or without food.  
6.2.3.  Exemestane 
Exemestane is FDA-approved for the treatment of metastatic hormone receptor positive breast cancer.  It 
does not require specific prophylactic or supportive regimens.  It can be administered with or without food. 
 
6.2.4 Treatment Duration: 
Patients will receive trial treatment until disease progression, unacceptable toxicity, or death or withdrawal 
from study based on patient choice or treating physician’s discretion. Every effort will be made to follow 
patients for primary and secondary outcomes regardless of treatment discontinuation for any reason. 
Crossover is not built into the study. 
 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a patient decides 
to discontinue from the study treatment, the investigator must make every effort (e.g. telephone, e-mail, letter) 
to determine the primary reason for this decision and record this information in the patient’s chart and on the 
appropriate CRF pages. They may be considered withdrawn if they state an intention to withdraw, fail to return 
for visits, or become lost to follow-up for any other reason. 
 
The investigator should discontinue study treatment for a given patient if, on balance, he/she believes that 
continuation would be detrimental to the patient’s well-being. Patients may voluntarily withdraw from the 
study or be dropped from it at the discretion of the investigator at any time. 
 
Premature patient withdrawal refers to the point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this time, all study treatment is 
discontinued and no further assessments are planned, unless the patient will be followed for progression and/or 
survival. 
 
Patients may be withdrawn from the study treatment if any of the following occur: 
• 
Adverse Event (Documented episode of ventricular tachycardia, or ventricular fibrillation; Complete 
heart block (Grade III AV block) or Second degree AV block Mobitz type II) 
• 
Lost to follow-up 
• 
Physician decision 
• 
Progressive Disease 
• 
Study terminated  
 
Patients must be withdrawn from the study treatment if any of the following occur: 
• 
Pregnancy 
• 
Death 
• 
Subject/Guardian decision 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
The patient must be told to notify the investigational site about any new medications he/she takes after the start 
of the study treatment. All medications (other than study drugs) and significant non-drug therapies (including 
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entry and during the study must be listed on the Concomitant medications/Significant non-drug therapies 
eCRF. 
 
Fulvestrant, letrozole, and exemestane are FDA approved agents for the treatment of patients with metastatic 
breast cancer. Per manufacturer Prescribing Information, there are no concurrent supportive or prophylactic 
regimens recommended for either fulvestrant, exemestane, or letrozole.     
 
Growth Factor Support: 
Per manufacturer Investigator Brochure (IB), there are no concurrent supportive or prophylactic regimens 
recommended for ribociclib. While the rates of grade III/IV neutropenia are considerable with CDK4/6 
inhibitors, the rates of febrile neutropenia (FN) are quite low, and well below the 20% threshold for which FN 
prophylaxis with G-CSF is recommended. Nonetheless, G-CSF is allowed at the treating physician’s 
discretion. Hematopoietic growth factors may be used according to ASCO guidelines. 
 
Radiation Therapy: 
If a subject requires additional anti-cancer therapy, the subject must be withdrawn from study treatment, with 
the exception of palliative radiotherapy (i.e., to bone metastasis or for subjects who have disease progression 
limited to the CNS but who are otherwise benefiting from study treatment), which may be allowed during the 
study but must be discussed with the overall principal investigator. Study treatment should be withheld until 
palliative radiotherapy is terminated. This treatment break should not be considered as treatment interruption. 
Palliative radiation is permitted if done solely for bone pain relief. It should not be delivered to a target lesion. 
Cumulative courses of RT should not encompass >25% of irradiated bone marrow. If palliative radiotherapy 
is initiated after the start of study treatment, the reason for its use must be clearly documented and progression 
as per RECIST 1.1 must be ruled out.  
 
Given the transient myelosuppressive effects of ribociclib and the long-term myelosuppressive effects of 
Comp to the axial skeleton in adults, subjects who have received radiation to the spine, pelvis, ribs, or femur 
should be discussed and approved by the overall principal investigator prior to study re-entry.  If anti-cancer 
treatment follows discontinuation of study treatment due to clinical progression determined by the 
investigator, the basis for this determination should be documented. 
 
Surgery: 
For subjects undergoing minor surgery, it should be scheduled during off week of LEE011/placebo, if 
possible. LEE011/placebo should preferably be discontinued five days prior to scheduled procedure and 
should remain on LEE011 hold until appropriate recovery from procedure, per treating physician’s 
discretion.  
 
General medication guidelines:  
Medications required to treat adverse events, manage cancer symptoms, treat co-morbid conditions, and 
supportive care agents, such as analgesics, anti-emetics and anti-diarrhea agents are allowed. Please consult 
the list of prohibited medications and the list of use with caution medications for further guidance. The 
patient should notify the investigational site about any new medications taken after the start of the study 
treatment. All medications administered within 28 days of study entry and during the study period must be 
listed on the concomitant medications and supplements case report form.  
 
 
Bisphosphanates / Denosumab: 
Bone directed therapy to prevent skeletal related events (SRE’s) or to treat osteoporosis with 
bisphosphonates or denosumab is permitted. While the use of bisphosphonates has been found to reduce the 
incidence of new bone metastases in patients with metastatic breast cancer, we do not anticipate this to affect 


 
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the results of this randomized control trial. Thus, treatment initiated prior to registration or after registration 
with these agents is permitted. The time of initiation of bone directed therapy should be clearly recorded on 
the case report forms.  
Concomitant therapy requiring caution 
Medications to be used with caution during ribociclib in this study are listed below. These medications should 
be excluded from patient use if possible. If they must be given based on the investigator’s judgment, then use 
with caution and consider a ribociclib interruption if the concomitant medication is only needed for a short 
time.  
• 
Moderate inhibitors or inducers of CYP3A4/5  
• 
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index 
• 
Strong inhibitors of BSEP 
• 
Medications that carry a possible risk for QT prolongation 
• 
Sensitive substrates of the renal transporters, MATE1 and OCT2 
• 
Sensitive substrates of BCR 
 
Prohibited concomitant therapy  
The following medications are prohibited during study treatment in the study (see Appendix B, this list is not 
comprehensive and is only meant to be used as a guide. Please contact the medical monitor with any questions): 
• 
Strong inhibitors or inducers of CYP3A4/5 
• 
Substrates of CYP3A4/5 with a narrow therapeutic index 
• 
Medications with a known risk for QT prolongation 
• 
Other investigational and antineoplastic therapies 
• 
Herbal preparations/medications and dietary supplements (except for vitamins) including but 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 all of these listed herbal 
medications and dietary supplements prior to first dose of study treatment. 
Drugs with QT prolongation 
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of 
ribociclib or the exposure of the QT prolonging drug). Please utilize a verified Clinical Drug Information 
system such as Lexicomp® or UpToDate® for data on drugs with a known risk, possible risk, or conditional 
risk of QT prolongation and/or Torsades de Pointes (TdP).  
Medication with a known risk for QT prolongation are prohibited during study treatment. 
Refer to the ribociclib Investigators Brochure and other drug package insert and Appendix B for information 
on possible interactions with other drugs.  
 
 
6.4 
Duration of Therapy 
In the case of registration scenario #1, patients will continue on CDK4/6 inhibitor and aromatase inhibitor 
therapy until disease progression*. At that time, patients will be randomized to receive fulvestrant (or 
exemestane) +/- continuation of CDK4/6 inhibition with ribociclib. In the case of registration scenario #2, 
patients will be randomized immediately to receive fulvestrant (or exemestane) +/- continuation of CDK4/6 
inhibition with ribociclib.  
 
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one of the following criteria applies: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study  
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. OR 
• 
Pregnancy 
• 
Removal by Sponsor (e.g., unblinding by Sponsor-Investigator).  
 
In the absence of one of the events listed above, there is no pre-defined limit on the number of potential 
cycles. 
 
* In the case of registration scenario # 1, some patients may discontinue treatment in the pre-randomization 
phase due to events other than disease progression, including those listed above. (i.e. unacceptable toxicity, 
patient decides to withdraw from the study, etc.). Those patients will come off study prior to randomization 
and will not be evaluable for the primary outcome.  
 
6.5 
Duration of Follow up 
The duration of follow up will vary depending on the registration scenario under which the patient is 
enrolled as well as the interval between treatment initiation and disease progression. Patients will have an 
end of treatment visit approximately 4 weeks after removal for any of the specified reasons listed above. 
Patients will no longer be formally followed after completion of the off-treatment visit, unless adverse 
event(s) occur that require subsequent follow-up (i.e. unresolved AEs). All adverse events, both serious and 
non-serious, and deaths that are encountered during the study and within 30 days of the last study 
intervention should be followed. See Section 8.2.  
 
6.5.1   Post-treatment Follow-up Assessments (Progression-Free Survival and Overall Survival)  
After end of treatment, patients will be followed for Overall Survival. Survivor information may be collected 
by methods that include, but are not limited to, telephone, e-mail, mail, or retrieved from online or other 
databases (eg, Social Security indexes). In addition, the start of another anticancer therapy will be recorded. 
For those patients who discontinue ribociclib for any reason other than radiographic disease progression, CT 
(with contrast) or MRI scans should be completed to further assess disease progression (per RECIST, 
Version 1.1), until the subject begins a new anti-cancer treatment or death. Refer to the Schedule of Events 
for appropriate assessments during post-treatment follow-up.  Patients will no longer be followed for survival 
after the study is officially closed, which we anticipate will be approximately 2.5 years after the last patient 
has accrued. 
 
6.6 
Criteria for Removal 
Patients will be removed from study when any of the criteria listed in Section 6.4 applies.  The reason for 
study removal and the date the patient was removed must be documented in source documentation and the 
Case Report Form. Patients continuing study treatment following unblinding by the Sponsor-Investigator 
will be treated as per standard of care and therefore will no longer be required to follow the study calendar or 
complete any of the study assessments that are not part of standard of care. Following unblinding by the 
Sponsor-Investigator, study teams will no longer be required to enter data into the database aside from SAEs 
and patient status updates (in the Screening/Enrollment tab in Velos).  
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are permitted in 
order to allow the patient to continue on the study. This applies both to patients in registration scenario # 1 
receiving the combination of ribociclib + AI, as well as to all patients receiving fulvestrant (or exemestane) 
+/- ribociclib vs. placebo. These changes should be recorded on the Dosage Administration Record case 


 
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report form in a timely manner.  
 
7.1 
Letrozole and Exemestane 
There is extensive clinical experience with letrozole 2.5 mg daily dosing and exemestane 25 mg daily dosing. 
Severe adverse events are exceedingly rare. While many patients may suffer minor adverse events including 
hot flushes and arthralgias/ myalgias, there is currently no established role for dose reduction to alleviate the 
side effects. Thus, no dose modification of letrozole or exemestane is planned in this study. Patients who do 
not tolerate letrozole may be switched from the generic to brand-name aromatase inhibitor with which they 
started (or vice versa). The toxicity profiles are similar amongst the three aromatase inhibitors (anastrazole, 
letrozole, and exemestane). 
 
If the patient enrolled in scenario #1, switching to a different aromatase inhibitor (such as letrozole to 
anastrazole) is not allowed in combination with ribociclib.  Switching from generic to brand name, or vice 
versa is allowed (example: letrozole and brand name femara). Patients can also switch from generic to brand 
name exemestane or vice versa. 
 
7.2 
Fulvestrant 
There is considerable clinical experience with fulvestrant 500 mg intramuscular dosing every 4 weeks (with 
an initial loading dose phase), and it is generally very well tolerated, with an adverse event profile similar to 
AIs. As was clearly established in the CONFIRM trial, discussed in Section 2, the higher dose of fulvestrant 
500 mg is more efficacious than the lower dose of 250 mg, with essentially no difference in adverse event 
rates. Dose reduction to 250 mg is left to the discretion of the treating physician, but it is not anticipated that 
dose reduction will improve adverse effects and it should generally be avoided given the inferior efficacy. In 
addition, dose reduction to fulvestrant 250 mg can be considered in patients with moderate hepatic 
impairment.  
 
7.3 
Ribociclib / Placebo  
Management of severe or intolerable adverse reactions requires dose reduction, temporary interruption, 
and/or discontinuation of ribociclib therapy. Refer to the table below for guidance. 
 
Dose modification guidelines: Dosing Levels 
Ribociclib/Placebo 
Dose
Number of capsules/tablets & strength 
Starting dose 
600 mg 
3 x 200 mg capsules/tablets 
First dose reduction 
400 mg 
2 x 200 mg capsules/tablets 
Second dose reduction 
200 mg 
1 x 200 mg capsules/tablets 
 
Recommendations for dose reduction, interruption or discontinuation of ribociclib/placebo in the 
management of specific adverse reactions are summarized in the tables below. Definitions of grading of each 
Adverse Event are based on CTCAE 4.0.  Clinical judgment of the treating physician should guide the 
management plan of each patient based on individual benefit/risk assessment. 
 
If ribociclib is held, the cycle continues, as the patient will be taking hormone therapy. Missed doses of 
ribociclib will not be made up. 
 
Subjects enrolled on Scenario 1a who are not able to tolerate ribociclib, despite dose reduction to the lowest 
dose (200 mg), will come off study and not be randomized to Scenario 1b. 
 
Dose modification for hematologic adverse reactions:  
LAB ABNORMALITY / 
GRADE 
DOSE ADJUSTMENT / 


 
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TOXICITY 
MANAGEMENT REC’S 
Thrombocytopenia 
Grade 1: (≥75 x 109/L) 
No dose adjustment required. 
Grade 2: (≥50-75 x 109/L) 
Dose interruption until recovery 
to grade ≤1. Re-initiate 
ribociclib/placebo at the same 
dose. 
Grade 3: (≥25-50 x 109/L) 
Dose interruption until recovery 
to grade ≤1.Re-initiate 
ribociclib/placebo at the same 
dose level. 
If grade 3 toxicity recurs, 
interrupt dose until recovery to 
grade ≤1 and then resume at next 
lower dose level.  
Grade 4: (<25 x 109/L) 
Dose interruption until recovery 
to grade ≤1. 
Re-initiate ribociclib/placebo at 
the next lower dose level. 
If toxicity recurs at grade 4: 
discontinue ribociclib/placebo. 
Absolute Neutrophil Count* 
Grade 1: (≥1.5 x 109/L) 
No dose adjustment required. 
Grade 2: (≥1.0 - < 1.5 x 109/L) 
No dose adjustment required. 
Grade 3: (≥0.5 - < 1.0 x 109/L) 
Dose interruption until recovery 
to ≥1.0 x 109/L. Re-initiate 
ribociclib/placebo at the same 
dose level. 
If grade 3 toxicity recurs, 
interrupt dose until recover to ≥ 
1.0 x 109/L. If resolved in ≤7 
days, then resume at same dose 
level. If resolved in >7 days, then 
resume at next lower dose level. 
Grade 4: (< 0.5 x 109/L) 
Dose interruption until recovery 
to ≥ 1.0 x 109/L. Re-initiate 
ribociclib/placebo at the next 
lower dose level.  
If toxicity recurs at grade 4: 
temporary dose interruption until 
recovery to ≥1.0 x 109/L and 
reduce ribociclib/placebo to the 
next lower dose level. 
Febrile Neutropenia* 
Grade 3: ANC <1.0 x 109/L with 
a single temperature of >38.3 C 
or a sustained temperature of 
>=38 C for 
more than one hour. 
Dose interruption until 
improvement of ANC ≥ 1.0 x 
109/L and no fever.  
Restart at the next lower dose 
level. 
If febrile neutropenia recurs, 
discontinue ribociclib/placebo. 
Grade 4: Same as grade 3, with 
life threatening consequences.  
Discontinue ribociclib/placebo. 
Anemia** 
Grade 1: Hgb ≥10.0 gm/dL 
No dose adjustment required. 


 
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Grade 2: Hgb ≥8.0 - < 10.0 
gm/dL 
No dose adjustment required. 
Grade 3: Hgb <8 gm/dL 
Dose interruption until recovery 
to grade ≤ 2.  
Re-initiate ribociclib/placebo at 
the same dose. 
Grade 4: Life-threatening 
consequences 
Discontinue ribociclib/placebo. 
 
*   Growth factor is allowed, per investigator discretion. 
** Transfusion allowed, per investigator discretion. 
  
Dose modification for hepatic toxicity:  
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin (fractionated if 
total bilirubin > 2 x ULN), alkaline phosphatase, and GGT. For patients with Gilbert Syndrome: total and 
direct bilirubin must  be  monitored with  intensified  monitoring  applying  to  changes  in  direct bilirubin 
only. 
 
** TOTAL BILIRUBIN without ALT/AST increase above baseline value. ULN=upper limit of 
normal.  
Grade 1 (> ULN – 1.5 x ULN)  
(confirmed 48-72h later) 
Maintain dose level. Recheck LFTs every two weeks until 
resolved.  
Grade 2 (> 1.5 – 3.0 x ULN) 
Dose interruption of ribociclib/placebo. Recheck LFTs 
weekly.  
If resolved to ≤ grade 1 within 21 days, then maintain 
dose level. 
If resolved to ≤ grade 1 within 21 days but toxicity recurs 
at grade 2, reduce 1 dose level.  
If resolved to ≤ grade 1 > 21 days, 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, discontinue 
ribociclib/placebo.  
Grade 3 (> 3.0 – 10.0 x ULN) 
Dose interruption of ribociclib/placebo. Recheck LFTs 
qweek.  
If resolved to ≤ grade 1, lower 1 dose level of 
ribociclib/placebo.  
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
 
If toxicity recurs after two dose reductions, discontinue 
ribociclib/placebo. 
Grade 4 (> 10.0 x ULN) 
Discontinue ribociclib/placebo.  
** Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before 
dose interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated 
ALP and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due to the indirect 
component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert Syndrome, 
pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, and use of other hepatotoxic 
drugs. For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin 
only. 


 
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***AST or ALT without bilirubin elevation 
Grade 1: (>1 ULN - < 3.0x ULN).  
Maintain dose level. Monitor LFTs per protocol if same 
grade as baseline or every two weeks in case of increase 
from baseline grade 0 to 1.  
Grade 2: (> 3.0-≤ 5.0 x ULN)      
Baseline at < Grade 2: 
Dose interruption of ribociclib/placebo. Recheck LFTs 
weekly.  
If resolved to ≤ baseline value within 21 days, then 
maintain dose level 
If resolved to ≤ baseline value within 21 days but toxicity 
recurs at same grade, then reduce 1 dose level.  
If resolved to ≤ grade 1 > 21 days, reduce 1 dose level. 
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
  
Baseline at Grade 2: Maintain dose level 
Increase from baseline grade 2 to grade 3 (> 
5.0 - ≤ 20.0 x ULN) 
Dose interruption of ribociclib until resolved to ≤ baseline 
value, then lower 1 dose level of ribociclib  
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption  
 
If toxicity recurs after two dose reductions, discontinue 
ribociclib. 
Increase from baseline grade 0 or 1 to grade 
3 (> 5.0 
– ≤ 20.0 x ULN) 
Dose interruption of ribociclib until resolved to ≤ baseline 
value, then lower 1 dose level of ribociclib 
Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption 
If toxicity recurs, discontinue ribociclib 
Grade 4 (> 20.0 x ULN) 
Discontinue ribociclib/placebo 
AST or ALT and concurrent Bilirubin increase 
For patients with normal ALT or AST or 
total bilirubin at baseline : AST or ALT ≥ 
grade 2 combined with total bilirubin > 2 x 
ULN without evidence of cholestasis**  
OR 
For patient with elevated AST or ALT or 
total bilirubin at baseline : [AST or ALT > 2 
x baseline AND > 3.0 x ULN] OR [AST or 
ALT 8.0 x ULN] whichever is lower 
combined with [total bilirubin 2xbaseline 
AND >2,0 x ULN] 
 
Discontinue ribociclib/placebo 
*** Confounding factors and/or alternative causes for increased transaminases should be excluded before 
dose interruption/reduction. They include but are not limited to: concomitant medications, herbal 
preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive 
liver metastasis, ischemic liver injury, and alcohol intake. 
Additional follow-up for hepatic toxicities 
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered as clinically important events.  


 
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The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; 
patients meeting any of the following criteria will require further follow-up as outlined below: 
• For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN  
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined as: 
ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation of 
ALP liver fraction in patients with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for 
both values. It  denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic or 
hepatocellular liver injury or mixed type injury) 
In the absence of cholestasis, these patients should be immediately discontinued from study drug 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed history, 
physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.  
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, direct 
and indirect bilirubin , alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), 
creatine kinase, prothrombin time (PT)/INR and GGT. For patients with Gilbert Syndrome: total and 
direct bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin only. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose 
interruption.  Recommendations include:  
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of re-
testing can decrease to once a week or less if abnormalities stabilize or return to normal values.  
• Obtaining a more detailed history of current symptoms.  
• Obtaining a more detailed history of prior and/or concurrent diseases, including history of any 
pre-existing liver conditions or risk factors. 
• Obtaining a history of concomitant drug use (including non-prescription medications, herbal and 
dietary supplements), alcohol use, recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV, EBV 
or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
• Considering gastroenterology or hepatology consultations. 
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including hypotension or 
right heart failure as possible etiologies for liver dysfunction.  
• Liver biopsy as clinically indicated to assess pathological change and degree of potential liver 
injury 
 


 
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Dose modification for QTc prolongation:  
 
Grade 
DOSE ADJUSTMENT / MANAGEMENT REC’S 
For All Grades 
• 
Check the quality of the ECG and the QT 
value and repeat if needed 
• 
Perform analysis of serum electrolytes (K+, 
Ca++, Phos, Mg++). If outside of the normal 
range, interrupt ribociclib administration, 
correct with supplements or appropriate 
therapy as soon as possible, and repeat 
electrolytes until documented as normal. 
• 
Review concomitant medication usage for 
the potential to inhibit CYP3A4 and/or to 
prolong the QT interval. 
• 
Check compliance with correct dose and 
administration of ribociclib. 
Grade 1: QTc 450-480 ms 
• 
No dose adjustment required. 
Grade 2: QTc 481-500 ms 
• 
Interrupt ribociclib 
• 
Perform a repeat ECG one hour after the first 
QTc of ≥481ms 
• 
If QTcF prolongation resolves to < 481 ms, 
resume treatment at the next lower dose 
level;  
• • If QTcF ≥ 481 ms recurs, interrupt dose 
until QTcF resolves to < 481 ms; then 
resume KISQALI at next lower dose level.  
• 
Repeat ECGs 7 days and 14 days after dose 
resumption (then as clinically indicated) for 
any patient who has therapy interrupted due 
to QTc≥ 481 ms 
Grade 3: QTc ≥ 501 ms on at least two separate 
EKGs.  
• 
Interrupt ribociclib/placebo.  
• 
Consider consulting a local cardiologist 
• 
Interrupt KISQALI treatment if QTcF greater 
than 500 ms 
• 
Perform a repeat ECG within one hour of the 
first QTcF of ≥501ms 
• 
If QTcF remains ≥ 501ms, consult with a 
cardiologist (or qualified specialist) and 
repeat cardiac monitoring as indicated until 
the QTcF returns to <481ms 
• 
If QTcF prolongation resolves to < 481 ms, 
resume treatment at the next lower dose  
• 
level.  
• 
If QTcF remains ≥481 ms after performing 
steps 1-4 as directed in “For All Grades”, 
discontinue ribociclib 
• 
After resumption, EKG should be repeated 7 
days and 14 days  and then at least monthly.  
If stable at least monthly for 3 months, then 
can have EKG every 3 months. 


 
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• 
If QTc > 501 ms recurs, discontinue 
ribociclib/placebo  
Grade 4: QTc ≥ 501 ms (or >60 ms increased 
from baseline) AND signs or symptoms of 
serious arrhythmias such as torsades de pointes.  
Discontinue ribociclib/placebo.  Obtain local 
cardiologist (or qualified specialist) consultation 
and consider repeating cardiac monitoring as 
indicated until the QTc returns to <481 ms. 
 
Dose modification for ILD/pneumonitis:  
 
Grade 
Dose Adjustment and Management Recommendations 
Grade 1 
(asymptomatic) 
No dose adjustment required..Initiate appropriate medical therapy and monitor as 
clinically indicated. 
Grade 2 
(symptomatic) 
Interrupt ribociclib dose until recovery to Grade ≤1, then resume ribociclib at the 
next lower dose level*.  
Grades 3 and 4 
(severe) 
Discontinue ribociclib 
* An individualized benefit-risk assessment should be performed before resuming ribociclib  
 
 
Dose modification for other adverse reactions:  
Grade 
DOSE ADJUSTMENT / MANAGEMENT 
REC’S 
Grade 1 
No dose adjustment recommended. Initiate 
appropriate medical therapy and monitor 
Grade 2 
Dose interruption until recovery to grade ≤1. Then 
resume at same dose level.  
If the same toxicity recurs at grade 2, interrupt 
ribociclib/placebo until recovery to grade ≤1. Re-
initiate ribociclib/placebo at the next lower dose 
level. 
Grade 3 
 Dose interruption until recovery to grade ≤1. Re- 
initiate ribociclib/placebo at the next lower dose 
level. If the same toxicity recurs at grade 3, re-
initiate ribociclib/placebo at the next lower dose 
level with recovery to grade ≤1, per investigator 
discretion 
Grade 4 
Discontinue ribociclib/placebo.  
 
7.4 
Renal Impairment:  
Based on pharmacokinetic/excretion studies in animals, there is minimal excretion of un-metabolized 
ribociclib in the urine, suggesting a limited role for renal elimination of the drug. Thus, there are currently no 
standard recommendations for ribociclib dose reduction based on renal impairment. Renal impairment does 
not affect aromatase inhibitor, such as letrozole or exemestane, or fulvestrant PK in humans (Section 5). 
Patients with baseline renal impairment are excluded from the study. Patients who develop renal impairment 
should be managed according to the adverse event guidelines above, including dose interruption until 
resolution and dose reductions for mild impairment, and withdrawal from study for more severe impairment.  
 
7.5 
Interstitial Lung Disease/Pneumonitis: 
Patients receiving CDK4/6 inhibitors should be monitored for pulmonary symptoms indicative of 
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respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt treatment immediately and 
evaluate the patient. Treatment should be permanently discontinued in patients with recurrent symptomatic 
or severe ILD/pneumonitis. 
 
 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
An Adverse Event (AE) is any undesirable sign, symptom or medical condition or experience that develops 
or worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests. 
 
Adverse events will be monitored from the time the subject signs informed consent. Subjects will be 
instructed to report all AEs during the study and subjects will be assessed for the occurrence of AEs 
throughout the study. All AEs (serious and non-serious) must be recorded on the source documents and case 
report forms regardless of the assumption of a causal relationship with the study drug. 
 
Adverse Events that begin or worsen after informed consent should be recorded in the Adverse Events 
section of the case report form (CRF). Conditions that were already present at the time of informed consent 
should be recorded in the baseline symptoms section of the CRF. Adverse Event monitoring should be 
continued for at least 30 days following the last dose of study treatment. Adverse Events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE. 
 
The following list of AEs (Section 8.1) and the characteristics of an observed AE (Section 8.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
8.1 
Synopsis of Common Adverse Events with the study drugs 
Synopsis of common adverse events with ribociclib:  
Below is a synopsis of common adverse events in patients being treated with ribociclib, as provided in the 
investigator’s brochure (IB). 
 
Ribociclib is currently being investigated in patients as a single agent in 3 phase I studies, and in combination 
in 10 studies, including 8 phase Ib/II studies, a randomized phase II study, and a randomized phase III study 
(MONALEESA-2). Ribociclib is also being investigated in 3 clinical pharmacology studies in healthy 
subjects. Details on these studies can be found in the ribociclib IB, Section 5.1 and Section 5.2. 
 
In single agent trials, a total of 196 patients have been treated. Ribociclib is also being evaluated in several 
combination trials with: letrozole, with letrozole and the PI3K inhibitor BYL719, with letrozole and the PI3K 
inhibitor buparlisib, with fulvestrant and buparlisib, with the mTOR inhibitor everolimus and exemestane, 
with LGX818, with MEK162, and with MEK162 and LGX818. The results of the phase I combination of 
letrozole and ribociclib are detailed in the IB.  
 
In the phase I monotherapy trials, patients with metastatic solid tumors or lymphomas were treated with 
increasing doses of ribociclib orally, once daily for 21 days followed by a 7-day off-drug period (28-day 
cycles). Doses ranging from 50 mg to 1200 mg were evaluated. In addition, continuous dosing of ribociclib 
at 600 mg was evaluated. Treatment has been discontinued in 111 of 132 patients (84%); the primary reasons 
for treatment discontinuation were: progression of disease (72%), adverse events (6%); withdrawal of 
consent (2%); and loss to follow up (1%).  
 


 
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The most frequently reported AEs (≥10%), regardless of grade, causality and ribociclib dose were:  
➢ Fatigue (53.8%) 
➢ Nausea (50.8%) 
➢ Neutropenia (47.7%) 
➢ Leukopenia (46.2%) 
➢ Anemia (37.1%) 
➢ Vomiting (34.8%) 
➢ Thrombocytopenia (34.1%) 
➢ Diarrhea (32.6%) 
➢ Lymphopenia (30.3%) 
➢ Decreased appetite (21.2%)  
➢ Hyperglycemia (21.2%) 
➢ Constipation (19.7%) 
➢ Hypoalbuminemia (18.9%) 
➢ Dyspnea (18.2%) 
➢ Cough (16.7%) 
➢ Fever (15.9%) 
➢ Rise in serum creatinine (15.9%) 
➢ Abdominal pain (15.2%) 
➢ aspartate aminotrans feraseincrease (15.2%) 
➢ Edema (15.2%) 
➢ Headache (15.2%) 
➢ Back pain (14.4%) 
➢ Dizziness (13.6%) 
➢ QTc prolongation (11.4%) 
➢ Alkaline phosphatase increase (10.6%) 
➢ Hypocalcemia (10.6%) 
For either continuous or intermittent dosing, the onset of neutropenia (most frequently Grade 
2) occurs by Day 15, reaching a nadir in the third or fourth week with recovery during the week of drug 
holiday. Some patients require additional time for recovery (7 to 14 days). During this regime, growth factors 
are allowed. 
 
QTc changes become evident in the first cycle by Day 8 and later (once steady state is reached), are 
associated with the maximum drug levels between 1 to 8 h post-dose, and remain stable or improve in 
subsequent cycles. Asymptomatic Grade 2 QTc prolongation was observed with increasing frequency at 
doses greater than 600 mg, and was considered the dose limiting toxicity. Two patients at 600 mg and two 
patients at 900 mg had asymptomatic QTc prolongation >500 ms (grade 3). One grade 1 atrioventricular 
block of first degree was reported as potentially related to ribociclib (at a dose of 140 mg). No other cardiac 
abnormalities were observed as related adverse events in any patient 
 
There have been 4 deaths related to study drug reported as of April 2014. The following serious adverse 
events shown in the table below have been reported with a suspected causal relationship to ribociclib 
administration. For a complete list of AEs, all grades and Grade 3/4 that are suspected to be related to 
ribociclib refer to the Investigator Brochure. 
 
Serious Adverse Events:  
System Involved / Type of AE 
Event(s)  
Blood and lymphatic system  
Anemia, febrile neutropenia, neutropenia, 
thrombocytopenia, Leukopenia, Lymphopenia 
Gastrointestinal 
Nausea, Vomiting, Diarrhea 


 
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Hepatobiliary disorders 
Hepatic function abnormal  
Hepatocellular injury 
Cholecystitis 
Investigations (incl. laboratory abnormalities) 
Electrocardiogram QT prolonged 
Transaminases increased 
Blood creatinine increased 
 
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients 
treated with KISQALI and other CDK4/6 inhibitors. Across clinical trials (MONALEESA-2, 
MONALEESA-3, MONALEESA-7), 1.1% of KISQALI-treated patients had ILD/pneumonitis of any grade, 
0.3% had Grade 3 or 4, and 0.1% had a fatal outcome. Additional cases ofILD/pneumonitis have been 
observed in the postmarketing setting, with fatalities reported. 
 
Reported frequency includes the cases reported with the following terms: pneumonitis, interstitial lung 
disease, pulmonary fibrosis, organizing pneumonia, acute respiratory distress syndrome (ARDS), interstitial 
pneumonia, pleural fibrosis. Novartis frequency includes only those events which occurred according to the 
broad SMQ for ILD/pneumonitis and included the following terms: ARDS, alveolitis, hypersensitivity 
pneumonitis, interstitial lung disease, lung infiltration, pneumonitis, pulmonary fibrosis. 
  
Additionally, the 1 death reported in MONALEESA-3 (originally published in J Clin Oncol on August 20, 
2018) was classified as acute respiratory distress syndrome in a patient who had lung metastases. 
 
Synopsis of common adverse events with fulvestrant:  
Fulvestrant is very well tolerated. Below is a table of common adverse events in patients being treated with 
fulvestrant 250 mg (N=374) and 500 mg (N=362), as reported in the phase III CONFIRM trial. 75 The only 
grade 3 toxicities that occurred in greater than 1% of patients were joint disorders/pain and GI disturbances.  
 
 
 
Synopsis of common adverse events with letrozole and exemestane:  
Common adverse events are similar amongst all 3 aromatase inhibitors (anastrazole, letrozole, and 
exemestane)  
 


 
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Below is a synopsis of common adverse events reported in patients being treated with letrozole and 
exemestane, based on extensive post-marketing experience, according to the Prescribing Information. While 
serious adverse event rates are considerable, the vast majority of serious AEs are not clearly treatment 
related. Moreover, as patients are frequently treated with letrozole for 5 to 10 years in the adjuvant setting, 
the cumulative incidence of non-treatment related adverse events can be considerable. Adverse events 
reported in clinical trials with shorter durations of follow up are quite comparable to those seen with other 
AIs and with fulvestrant.   
 
Adverse Events Reported in >10% of patients:  
Cardiovascular: Edema (7% to 18%) 
Central nervous system: Headache (4% to 20%), dizziness (3% to 14%), fatigue (8% to 13%) 
Endocrine & metabolic: Hypercholesterolemia (3% to 52%), hot flashes (6% to 50%) 
Gastrointestinal: Nausea (9% to 17%), weight gain (2% to 13%), constipation (2% to 11%) 
Neuromuscular & skeletal: Weakness (4% to 34%), arthralgia (8% to 25%), arthritis (7% to 25%), bone pain 
(5% to 22%), back pain (5% to 18%), bone mineral density decreased/osteoporosis (5% to 15%), bone 
fracture (10% to 14%) 
Respiratory: Dyspnea (6% to 18%), cough (6% to 13%) 
Miscellaneous: Diaphoresis (≤24%), night sweats (15%)  
Adverse Events Reported in 1 to 10% of patients:  
Cardiovascular: Chest pain (6% to 8%), hypertension (5% to 8%), chest wall pain (6%), peripheral edema 
(5%); cerebrovascular accident including hemorrhagic stroke, thrombotic stroke (2% to 3%); 
thromboembolic event including venous thrombosis, thrombophlebitis, portal vein thrombosis, pulmonary 
embolism (2% to 3%); MI (1% to 2%), angina (1% to 2%), transient ischemic attack 
Central nervous system: Insomnia (6% to 7%), pain (5%), anxiety (<5%), depression (<5%), vertigo (<5%), 
somnolence (3%) 
Dermatologic: Rash (5%), alopecia (3% to 5%), pruritus (1%) 
Endocrine & metabolic: Breast pain (2% to 7%), hypercalcemia (<5%) 
Gastrointestinal: Diarrhea (5% to 8%), vomiting (3% to 7%), weight loss (6% to 7%), abdominal pain (6%), 
anorexia (1% to 5%), dyspepsia (3%)  
Genitourinary: Urinary tract infection (6%), vaginal bleeding (5%), vaginal dryness (5%), vaginal 
hemorrhage (5%), vaginal irritation (5%) 
Neuromuscular & skeletal: Limb pain (4% to 10%), myalgia (7% to 9%) 
Ocular: Cataract (2%) 
Renal: Renal disorder (5%) 
Respiratory: Pleural effusion (<5%) 
Miscellaneous: Infection (7%), influenza (6%), viral infection (6%), secondary malignancy (2% to 4%) 
 
Adverse Events Reported in < 1% of patients:  
Anaphylactic reaction, angioedema, arterial thrombosis, cardiac failure, carpal tunnel syndrome, endometrial 
cancer, endometrial hyperplasia, endometrial proliferation, erythema multiforme, hepatitis, leukopenia, 
memory impairment, stomatitis, tachycardia, thrombocytopenia, toxic epidermal necrolysis, trigger finger 
 
 
Adverse events reported in the phase III study of letrozole vs. tamoxifen in the first line setting for metastatic 
breast cancer in post-menopausal patients with a median follow up of 32 months is reported below.82 
 


 
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8.2 
Definitions and Reporting 
8.2.1  Adverse Event (AE) 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. The occurrence of AEs should be sought by non-directive questioning of the subject during the screening 
process after signing informed consent and at each visit during the study. As far as possible, each AE should 
be evaluated to determine: 
• The severity grade (CTCAE Grade 1-5) 
• Reasonable possibility that AE is related to the study treatment: Definite, Probable, Possible, Unlikely, 
Unrelated (Section 8.3.4) 
• Start and end dates, unless unresolved at final exam 
 
Action taken with respect to study drug (i.e., none, dose adjusted, temporarily interrupted, permanently 
discontinued, unknown, not applicable) 
• Outcome (e.g., not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved 
with sequelae, fatal, unknown) the outcome ‘unknown’ should only be used when absolutely no data can be 
retrieved with regards to the event outcome e.g. if the subject is lost to follow-up. 
• Whether it is serious, as per Serious Adverse Event (SAE) definition provided below. 
 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements, see Section 8.2.2. 
 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is given, this 
action should be recorded on the AE CRF as well as the Prior/Concomitant medications CRF. 
 
Once an AE is detected, it should be followed until its resolution or until it is judged to be permanent; 
assessment should be made at each visit (or more frequently if necessary) of any changes in severity, the 
suspected relationship to the study drug, the interventions required to treat it, and the outcome. 
 
Disease progression should not be regarded or reported as an AE itself, unless it is associated with a separate 
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Laboratory abnormalities that constitute an AE in its own right (are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy or require changes in study treatment), should be 
recorded on the AE CRF. Whenever possible, a diagnosis, rather than a symptom should be provided (i.e., 
anemia instead of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be 
followed until they have returned to normal or an adequate explanation of the abnormality is found. 
 
When an abnormal laboratory or test result corresponds to a sign or symptom of a previously reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. A Grade 3 
or 4 (severe) event, as per CTCAE, does not automatically indicate a SAE unless it meets the definition of 
serious, as defined below, and/or as per the investigator’s discretion. 
 
8.2.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that 
either: 
 
• Results in death. 
 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death from the reaction 
as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour hospitalization or 
prolonged a hospitalization beyond the expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to study entry are not considered 
SAEs if the illness or disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than planned). 
 
• Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a 
person’s ability to conduct normal life functions. 
 
• Is a congenital anomaly or birth defect; or 
 
• Is an important medical event when, based upon appropriate medical judgment, it may jeopardize the 
participant and require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical 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.  
 
Events not considered to be serious adverse events are hospitalizations for: 
 
• Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition, or for elective procedures. 
 
• Elective or pre-planned treatment for a pre-existing condition that did not worsen. 
 
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and not 
resulting in inpatient admission. 
 
• Respite care 


 
L oc al Pr ot oc ol #:  A A A P 9 5 0 6  
Versi o n D ate: Fe br u ar y 1 , 2 0 2 4 
 
Pa ge 6 0  of 1 1 3  
 
8. 2. 3  U n a ntici p ate d Pr o ble m  
A n U na ntici pate d Pr o ble m ( U P) is a n y i nci de nt, e x perie nce or o utc o me i n v ol vi n g ris k t o s u bjects or ot hers i n 
a n y h u ma n s u bject researc h t hat meets all of t he f oll o wi n g criteria:  
 U ne x pecte d (i n ter ms of nat ure, se verit y or fre q ue nc y) gi ve n (a) t he researc h pr oce d ures t hat 
are descri be d i n t he I R B -a p pr o val pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt, a n d ( b) t he 
c haracteristic s of t he s u bject p o p ulati o n bei n g st u die d;  
 Relate d or p ossi bl y relate d t o partici pati o n i n s uc h researc h (i.e., t here is a reas o na ble 
p ossi bilit y t hat t he i nci de nt, e x perie nce or o utc o me ma y ha ve bee n ca use d b y t he pr oce d ures 
i n v ol ve d i n s uc h researc h); an d  
 S u g gests t hat t he researc h places s u bjects or ot hers at a greater ris k of har m (i ncl u di n g 
p h ysical, ps yc h ol o gical, ec o n o mic or s ocial har m) t ha n was pre vi o usl y k n o w n or rec o g nize d.   
8. 2. 4  S us pecte d A d verse Re acti o n  
A S us pecte d A d verse Reacti o n ( S A R) is a n y A E f or w hic h t here is a reas o na ble p ossi bilit y t hat it was ca use d 
b y t he dr u g.  
Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he 
A E.  E xa m pl es of reas o na ble p ossi bilit y are:  
 A si n gle occ urr e nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be str o n gl y ass ociate d wit h 
dr u g e x p os ure.  
 O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h dr u g e x p os ure, 
b ut is ot her wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he dr u g.  
 A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical trial t hat i n dicates t hat t h ose 
e ve nts occ ur m or e fre q ue ntl y i n t he dr u g treat me nt gr o u p t ha n i n a c o nc urre nt or hist orical 
c o ntr ol gr o u p.  
8. 2. 5  E x pecte d ness  
A d verse e ve nts ca n be ' E x p ecte d' or ' U ne x pecte d.'  
 
E x pecte d  a d verse e ve nts are t h ose t hat ha ve bee n pre vi o usl y i de ntifie d as res ulti n g fr o m a d mi nistrati o n of t he 
a ge nt. F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d e x pecte d w he n it a p pears i n t he c urre nt 
a d verse e ve nt list, t he I n vest i gat or’s Br oc h ure, t he pac ka ge i nsert or is i ncl u de d i n t he i nf or me d c o nse nt 
d oc u me nt as a p ote ntial ris k.  
 
F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d u ne x pecte d  w he n it varies i n nat ure, i nte nsit y 
or fre q ue nc y fr o m i nf or mati o n pr o vi de d  i n t he c urre nt a d verse e ve nt list, t he I n vesti gat or’s Br oc h ure, t he 
pac ka ge i nsert or w he n it is n ot i ncl u de d i n t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k.  
 
8. 2. 6  Attri b uti o n  
Attri b uti o n is t he relati o ns hi p bet wee n a n a d verse e ve nt or seri o us a d v erse e ve nt a n d t he st u d y treat me nt. 
Attri b uti o n will be assi g ne d as f oll o ws:  
 
• Defi nite –  T he A E is clearl y relate d t o t he st u d y treat me nt.  
• Pr o ba ble –  T he A E is li kel y relate d t o t he st u d y treat me nt.  
• P ossi ble –  T he A E ma y be relate d t o t he st u d y treat me nt.  
• U nli kel y - T he A E is d o u btf ull y relate d t o t he st u d y treat me nt.  
• U nrelate d - T he A E is clearl y N O T relate d t o t he st u d y treat me nt.  
 
8. 2. 7 E x pe dite d A d verse E ve nt Re p orti n g  
Partici pati n g i n vesti gat ors will assess t h e occ urre nce of A Es a n d S A Es at a ll partici pa nt e val uati o n ti me 
p oi nts d uri n g t he st u d y.  
 


 
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All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, or 
detected by physical examination, laboratory test or other means, will be recorded in the participant’s 
medical record and on the appropriate study specific case report forms. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
For multi-site trials where a Columbia University Medical Center investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting requirements set by 
Columbia University Medical Center. The study must be conducted in compliance with FDA regulations, 
local safety reporting requirements, and reporting requirements of the principal investigator. 
 
Each investigative site will be responsible to report SAEs that occur at that institution to their respective IRB 
per local policies and procedures. It is the responsibility of each participating investigator to report serious 
adverse events to the study sponsor (i.e. Melissa Accordino, MD, MS) as described below. 
 
In addition to the reporting requirements for SAEs, a separate case report form will be made for reporting of 
any grade adverse events attributable to research biopsies. These events will not require expedited reporting 
unless they also meet the requirements for SAE reporting, as detailed below. 
 
Copies of all IND safety reports submitted to the FDA and/or institutional IRB by the institution under the 
institution’s IND will be shared with the Novartis Pharmacovigilance representative, so that these reports can 
be evaluated and included in the Investigator Brochure and future Novartis IND safety submissions per 
regulations. 
 
8.2.8  Serious Adverse Event Reporting 
All serious adverse events, regardless of suspected causality, that occur after the patient began treatment, or 
within 30 days of the last dose of treatment must be reported to Columbia University Medical Center Overall 
Principal Investigator on the local institutional SAE form. This includes events meeting the criteria outlined 
in Section 8.2.2, as well as the following: 
 
•   All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically listed in the 
protocol as not requiring reporting. 
 
•   All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in the trial OR 
when the event occurs within 30 days of the last study intervention. 
 
Note: If the participant is in long term follow up, report the death at the time of continuing review.  
 
Participating investigators must report each serious adverse event to a Columbia University Medical Center 
Principal Investigator (Dr. Accordino) within 24 hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the serious adverse event immediately (e.g., participant 
sought treatment elsewhere), the participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the adverse event. Report serious adverse 
events by telephone, email or facsimile to: 
 
Name of Contact:  
 
Melissa Accordino, MD  
Address: 
 
 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center  
161 Fort Washington Avenue 


 
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New York, NY 10032 
Email:   
 
 
p9506@lists.cumc.columbia.edu 
Phone:   
 
 
212-305-1945 
Fax: 
 
 
 
212-305-0178 
 
Within the following 5 calendar days, the participating investigator must provide follow-up information on 
the serious adverse event. Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will continue or discontinue study 
participation. 
 
Follow-up information is sent to the same person to whom the original SAE 
Report Form was sent, using a new SAE Report Form stating that this is a follow- up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of 
the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how it was treated, and 
whether the subject continued or withdrew from study participation or if study drug was interrupted or 
discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug (new occurrence) 
and is thought to be related to the supplier’s study drug, Novartis and Columbia University Medical Center 
may urgently require further information from the Investigator for reporting to Health Authorities. 
 
The Sponsor may need to issue an Investigator Notification (IN) to inform all Investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.  
 
8.2.9.  Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE, unless there is suspicion that study drug may have 
interfered with the effectiveness of a contraceptive medication or method.  The procedures that will be 
followed based on whether a pregnancy is confirmed by a positive serum or urine test result are listed below: 
 
o Investigator must notify the Sponsor/Principal Investigator via the 
p9506@lists.cumc.columbia.edu account, who in turn will notify Novartis Pharmaceuticals 
Corporation within 24 hours of learning of the occurrence 
 
o Investigator must notify the Principal Investigator and Novartis Pharmaceuticals Corporation 
within 24 hours of learning of the occurrence 
 
o Study drug must be discontinued immediately.  
 
o Subject must be withdrawn from the study.  
 
o Investigator must complete and submit the Pregnancy Initial and Follow-up report forms to 
the Principal Investigator and to Novartis Pharmaceuticals Corporation.   
 
o A serum pregnancy test must be performed to confirm the urine test result. (The serum test 
should be performed at the investigative site to ensure the test will be performed promptly 
and the result available immediately for review.) 
 
If a negative serum test does not confirm the urine test result, then: 
 


 
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•   The Investigator will use his/her expert judgment, based on an assessment of the potential benefit/risk to 
the subject, to determine if it is in the subject’s best interest to resume study drug and continue participation 
in the study. 
 
To ensure subject safety, each pregnancy in a subject during maternal or paternal exposures to study drug 
must be reported within 24 hours of learning of its occurrence.  Data on fetal outcome and breast-feeding are 
collected for regulatory reporting and drug safety evaluation. The pregnancy should be followed- up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications by 
following until the first well-baby visit. Pregnancy should be recorded on a Clinical Study Pregnancy Form 
and reported by the investigator to Novartis Pharmaceuticals Corporation. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the study drug of 
any pregnancy outcome and follow-up to the first well-baby visit. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form and to Novartis Pharmaceuticals Corporation. 
 
8.2.10  Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to one of the Columbia University Medical Center Overall 
Principal Investigators on the toxicity Case Report Forms. 
 
8.2.11  Reporting to the Institutional Review Board (IRB) 
Unanticipated Problems (Ups) are to be reported to the IRB.  SAEs not constituting UPs are to be reported to 
the HICCC DSMC.   
 
A copy of the submitted institutional SAE form should be forwarded to: 
 
Name of Contact:  
 
Melissa Accordino, MD  
Address: 
 
 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center  
161 Fort Washington Avenue 
New York, NY 10032 
Email:   
 
 
p9506@lists.cumc.columbia.edu 
Phone:   
 
 
212-305-1945 
Fax: 
 
 
 
212-305-0178 
 
SAEs are to be reported to the HICCC DSMC, if they are considered UPs, then they must be submitted to 
CUMC IRB per institutional policies. 
 
Unanticipated Problems must be reported promptly, but not later than 7 calendar days following the 
occurrence of the UP or the Principal’s Investigator’s acquiring knowledge of the UP. 
 
Expected AEs must be reported at the time of continuing review of a protocol. 
 
8.2.12  Reporting to the Food and Drug Administration (FDA) 
Columbia University Medical Center’s Overall Principal Investigator (Sponsor-Investigator), as holder of the 
IND, will be responsible for all communication with the FDA. The Sponsor-Investigator will report to the 
FDA, regardless of the site of occurrence, any adverse event that is serious, unexpected and reasonably 
related (i.e., possible, probable, definite) to the study treatment. 
 
The Sponsor-Investigator must report the following SARs: 
o To the FDA, as soon as possible, but no later than 7 calendar days after the S-I's initial 
receipt of the information, any unexpected fatal or life-threatening SAR. 


 
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o To the FDA and all participating investigators, as soon as possible but no later than 15 
calendar days after the S-I determines that information qualifies for reporting, in an IND 
safety report, any SAR that is both serious and unexpected. 
o To the FDA and all participating investigators, as soon as possible but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
findings from epidemiological studies, pooled analysis of multiple studies or clinical studies, 
whether or not conducted under an IND or by the S-I, that suggest a significant risk in 
humans exposed to the drug.  
o To the FDA and all participating investigators, as soon as possible, but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
findings from animal or in vitro testing, whether or not conducted by the S-I, that suggest a 
significant risk in humans exposed to the drug.  
o To the FDA and all participating investigators, as soon as possible, but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
clinically important increase in the rate of a Serious SAR over that listed in the protocol or 
Investigator Brochure. 
o Expected SAEs and AEs should be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant information is available.  
However, if the results of a sponsor’s investigation show that an adverse drug experience not initially 
determined to be reportable are so reportable, the sponsor must report such experience as soon as possible, 
but no later than 15 calendar days after the determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will be reported to 
FDA as soon as possible but in no event later than 15 calendar days after initial receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800- FDA-0178) using 
Form FDA 3500A (Mandatory Reporting Form for investigational agents) or FDA Form 3500 (Voluntary 
Reporting Form for commercial agents). Forms are available at http://www.fda.gov/medwatch/getforms.htm. 
 
8.2.13 Reporting to Novartis Pharmaceuticals Corporation 
The Sponsor-Investigator will report to investigational agent manufacturer any serious adverse events within 
24 hours of becoming aware of it on the Novartis Serious Adverse Reporting and transmitted to Novartis via 
the telefax confirmation sheet so that these reports can be evaluated and included in the Investigator’s 
Brochure and for IND safety submissions per regulations. Reporting will occur by sending the reporting form 
along with any additional documentation sent to the regulatory authorities. 
 
The Overall Principal Investigator will send copies of any IND Safety reports submitted to the FDA to 
Novartis Pharmaceuticals Corporation so that these reports can be evaluated and included in the 
Investigator’s Brochure or Novartis Pharmaceuticals Corporation IND safety submissions.  
 
8.2.14  Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy. 
 
8.2.14  Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered after the patient has 
provided informed consent, throughout the study, and within 30 days of the last study intervention should be 
followed to their resolution, or until the participating investigator assesses them as stable, or the participating 
investigator determines the event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record and subject binder to facilitate source data verification. 


 
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For some SAEs, the sponsor or designee may follow-up by telephone, fax, and/or monitoring visit to obtain 
additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital discharge 
summary, consultant report, or autopsy report). 
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be related to 
participation in this study. Participating investigators should notify Columbia University Medical Center’s 
Overall Principal Investigator and their respective IRB of any unanticipated death or adverse event occurring 
after a participant has discontinued or terminated study participation that may reasonably be related to the 
study. 
 
8.3 
Guidelines for Processing IND Safety Reports 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to notify the 
FDA and all participating investigators of any serious and unexpected adverse experiences that are possibly 
related to the investigational agent. The CUMC Sponsor/Principal Investigator will review all applicable 
IND Safety Reports and has the responsibly for forwarding the IND Safety Reports to the Affiliate 
Institutions. The Affiliate Institution investigators are to review, send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents. All Affiliate site 
INDSR submissions, along with IRB acknowledgment (per local policies and procedures) are to be 
forwarded to CUMC for placement within the trial master file. 
 
8.4 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the initial neoplasm.   Second malignancies require ONLY routine reporting unless otherwise 
specified. 
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
The list of available targeted therapies to treat patients with breast cancer is growing, and as a result it is 
becoming increasingly important to develop biomarkers that can predict response and/or toxicity from each 
given therapy in order to ensure that each patient is receiving personalized therapy from which she is most 
likely to benefit. In addition, biomarkers that are able to capture the extent of response early within the 
treatment course are likely to be beneficial in guiding therapies in the future.  
 
Several biomarkers have already been evaluated in clinical trials involving the CDK4/6 inhibitors palbociclib 
and ribociclib. These biomarkers mainly fall into two broad categories: 1) genetic/epigenetic events that 
result in alterations in activity in the p16/cyclin D1/Rb pathway and 2) downstream effects of CDK4/6 
inhibition. In the PALOMA-1 study, the presence of CCND1 amplification or p16 loss did not appear to 
predict responses to palbociclib in the front line setting, in spite of the fact that presence of either event 
appears to predict response in cancer cell lines. This is likely in part because a significant majority of ER-
positive HER-2-negative breast cancers do in fact have increased CDK4/6-cyclin D activity to some extent 
and are thus likely to benefit from CDK4/6 inhibition in the front line setting. However, the presence of 
genomic events such as CCND1 amplification that markedly increase CDK4/6-cyclin D activity may be 
more important in predicting response to continuation of CDK4/6 inhibition beyond disease progression, as 
these tumors are more likely to be dependent/addicted to this pathway. In addition, adequate downstream 
target inhibition early in the treatment course may help differentiate patients who are likely to benefit from 
continuation of CDK4/6 inhibition beyond disease progression.  
 
We propose evaluating tissue biomarkers as surrogates for p16/cyclin D1/Rb activity and to assess 
downstream effects of CDK4/6 inhibition. In addition, we propose to collect serum and plasma specimens for 
future biomarker studies involving the study cohort. We will also be collecting an archival 
primary/metastatic FFPE tumor (required) and additional optional formalin fixed samples at the specified 


 
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biopsy time points, unless unavailable. Immunohistochemistry (IHC) data reported from the lab will include 
quantitative data such as percent tumor and percent positive cells or a semi quantitative measure of protein 
expression in cellular compartments (i.e. cytoplasm, nucleus, membrane). The pathologist determines 
whether the staining in a cellular compartment is absent (0+), slight (1+), moderate (2+), or strong (3+). The 
histoscore (i.e. H-Score) for each cellular compartment may also be calculated as a more precise measure of 
staining within a compartment, and ranges between 0 and 300. 
 
Biomarker Assessment: 
➢ Archived tissue from primary and/or metastatic tissue is required, unless not available. 
➢ Optional biopsies for tissue biomarker assessment will be performed in consenting patients prior 
to starting study drugs, at time of progression on letrozole plus ribociclib (in patients registered 
under scenario#1), and upon progression on Fulvestrant (or exemestane) +/- ribociclib. These 
optional biopsies are strongly recommended, as they have the potential to provide invaluable 
information. If pre-treatment biopsy is not available or accessible, we will plan to use archived 
tissue from primary and/or metastatic tissue.  (Appendix E). 
➢ For registration scenario # 1, optional tissue biopsies for biomarker evaluation will be performed 
at 3 time points: pre-treatment, at time of progression on aromatase inhibitor plus ribociclib, and 
progression on Fulvestrant (or exemestane) +/- ribociclib. 
➢ For registration scenario # 2, optional tissue biopsies for biomarker evaluation will be performed 
at 2 time points: prior to treatment with Fulvestrant (or exemestane)  +/- ribociclib and at 
progression on Fulvestrant (or exemestane) +/- ribociclib. 
➢ For patients who agree to the optional biopsies, up to 5 core biopsies are recommended. The 
following will be requested: 10 immunoblanks [each having 4 micron sections on charged 
slides], one intervening H&E stained slide, and 12 regular slides each with 10 microns sections. 
➢ Serum and plasma will be collected at multiple time points (Section 10: Study Calendar, and 
Appendix C) and stored for future biomarker driven studies.  In addition, whole blood samples 
will be collected to perform plasma ctDNA biomarkers (ESR-1 and PIK3CA mutations 
(Appendix D). 
➢ For registration scenario # 1, peripheral blood will be collected for proposed and future 
biomarker evaluations at 5 time points: a) pre-treatment, after completing 1 cycle of treatment 
(Cycle2a Day1 visit), progression on aromatase inhibitor plus ribociclib, after completing 1 cycle 
of treatment post-randomization (Cycle2b Day1 visit), and progression on Fulvestrant (or 
exemestane) +/- ribociclib. One lavender (EDTA) tube and two red top (non-anticoagulant) tubes 
are recommended for collection. 
➢ For registration scenario # 2, peripheral blood will be collected for proposed and future 
biomarker evaluations at 3 time points: pre-treatment, after one cycle of treatment (Cycle2 Day1 
visit), and at progression on Fulvestrant (or exemestane) +/- ribociclib. One lavender (EDTA) 
tube and two red top (non-anticoagulant) tubes are recommended for collection. 
Exploratory Analyses:  
Potential exploratory biomarkers that will be examined when possible include: 
➢ Tissue overexpression or amplification of Cyclin D1 and Cyclin E (by IHC and FISH) 
➢ Phospho-Rb expression (by IHC)  
➢ Rb1 loss (by IHC) 
➢ p16INK4A loss (by IHC)  
➢ TK1 and TOP2A expression (as measures of E2F1 transcriptional activity, by IHC).  
 
Serum and plasma will be collected and stored for potential future exploratory analyses.82  
 


 
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10. 
STUDY CALENDAR 
Baseline evaluationsare to be conducted within 28 days prior to start of registration.  Scans, including CT 
scans and bone scan (or PET CT) must be done < 28 days prior to registration. Each cycle is of 28-day 
duration.  
 
 
10.1 
Table 1: Registered Prior to Receiving AI + CDK 4/6 Inhibitor (Scenario #1) 
CycleC 
Screen 
C1a 
C1D
15 
C2a 
C2D1
5 
C3a 
C4a+ 
ProgressionA 
C1 
D1 
b 
C1D
15b 
C2b 
C3b 
C4b+ 
End of-
Treatm
entN 
Day 
-28 to -
1B     
 
All pertinent assessment time points relate to Day 1 of the respective cycle +/- 4 days with the exception of scans and 
biopsies.  B   
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
H/P (incl PS)C 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessmentC 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Aromatase 
Inhibitor (AI)D 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Ribociclib D 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Fulvestrant 
(or 
exemestane) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Ribociclib/ 
PlaceboD 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
β-HCG 
(premenop)E 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Chem7/ 
LFT C, F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG G 
X 
 
X 
X 
 
 
X 
X 
 
 
 
 
X 
 
CT C/A/P + Bone 
Scan (Or PET) B, H, I, 
J  
X B 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
Pill diary Review  
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Blood BiomarkerK 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
XG 
Tissue BiopsyL 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
QuestionnaireM 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
A At progression, patients are taken off of AI + CDK 4/6 inhibitor.  Randomized to Fulvestrant (or exemestane) +/- ribociclib. If the 
window between ending progression and starting the Fulvestrant (or exemestane) +/- ribociclib is greater than 28 days, the labs should 
be repeated. There is no required timeline between completion of AI+CDK 3/6 inhibitor and initiation of Fulvestrant (or exemestane) 
+/- ribociclib. 
 
 
 
B Exceptions to the +/- 4 days are CT C/A/P + bone scan (OR PET) which should be performed within 28 days of trial registration and 
after each third cycle of treatment (within 14 days of day 1 of each third cycle – ideally within 7 days of day 1) and tissue biopsy (+/- 
7 days). The +/- 4 day window includes C1D15. 
 
 
 
C Every 4 weeks, except during the first 2 cycels.   Day 1 visits for each cycle should occur at 28±4 days from day 1 of the previous 
cycle.  Blood draws on that day should also fall within this +/- 4 day window. Exceptions to the +/- 4 days are CT C/A/P + bone scan 
(OR PET) as described above.  
 
 
 
D Ribociclib (and/or placebo) will be supplied per study.  If letrozole, will be supplied by study. On D1 of every cycle prior to drug 
dispensation and dose administration, subject’s disease status/non-progression will be confirmed by the treating investigator, 
including clinical and radiographic assessment. RECIST restaging will be confirmed for the most recent scans received, including 
documentation of investigator sign off on calculation of percentage change from baseline and nadir and overall response, prior to 
treatment. If the new scan information becomes available mid cycle, the study team will inform the subject if treatment 
discontinuation is required per protocol in real time, and document date of treatment discontinuation. 
 
 
 
E Serum Pregnancy test (women of childbearing potential) 
 
 
 
F Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium.  
 
 
 
G EKG will be performed at baseline, C1D15, C2a, C4a, Progression, and C4b.  If grade 3 or 4 QTC prolongation occurs, see Section 
7.3 for monitoring/dose modification. If no EKG abnormalities, additional EKGs are not required for cycles after C4a or C4b, except 
Progression. 
 
 
 
H Scans should be performed within 28 days of study registration, prior to every third cycle of treatment (i,e, preferably within 7 days 


 
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10.2 
Table 2: Registered After Progression on AI or tamoxifen or fulvestrant + CDK 4/6 
Inhibitor (Scenario #2) 
of Cycle 4a day 1, Cycle 7a day 1, Cycle 10a day 1, and so on, but allowance for up to within 14 days of the next treatment cycle). 
Corresponding RECIST restaging will be conducted in real time following scans and signed (electronically or wet ink) by the 
investigator, including confirmation of overall disease status per RECIST v.1.1. 
 
 
 
I If patients have known brain metastases and are eligible for this trial, head CT or brain MRI must be performed along with systemic 
imaging. If a patient does not have known brain metastases and is asymptomatic, no baseline brain imaging is required.  
 
 
 
J Baseline bone scan required in all patients (whose baseline imaging is CTs of C/A/P) 
NOTE: If bone scan done ≤ 6 weeks prior to registration showed no evidence suggesting bone metastases and no clinical indication of 
skeletal pain or other evidence suggesting bone metastases, a repeat baseline bone scan is not required.  If there is evidence of disease 
on the bone scan, bone scans should be continued every 3 cycles (~12 weeks of treatment +/- 4 days), as clinically indicated.  
 
 
 
K Serum (2 red top tubes) and plasma (1 lavendar tube) will be collected at each time point and stored for future potential studies. 
(Appendix C on collection details.)   In addition, whole blood samples (2 Biocept provided tubes) will be collected and sent same day 
to Biocept (Appendix D). 
 
 
 
L Archived tissue from primary and/or metastatic tissue is required, unless unavailable. If patient is amenable and has accessible 
tumor, repeat biopsy is optional. These biopsies should be considered in patients with accessible disease. Biopsies can be within 7 
days of the cycle (+/- 7 days). 
 
 
 
M   PROMIS Global Health and PROMIS-29 and EQ-5D-3L will be performed at baseline, C4, Progression, C4b, and Off-Study. 
Questionnaires are not required for cycles after C4a or C4b, except Progression and Off-Study. 
 
 
 
N  Within 4 weeks of completing study treatment. Post-treatment follow-up every 12 weeks (+/- 1 week) for survival follow-up until 
study closure, which we anticipate will be up to 2.5 years after last patient enrolled (Section 6.6). 
 
 
 
O Adverse event assessments every 4 weeks should include a review of concomitant medications with the patient.  
Cycle 
Screen 
C1D1 
C1D15 
C2 
C2D15 
C3 
C4+ 
End of 
TreatmentL 
Day 
-28 to - 1 
A 
 
All pertinent assessment time points relate to Day 1 of the respective cycle +/- 4 days with the 
exception of scans and biopsies.A 
Informed consent 
X 
 
 
 
 
 
 
 
History and Examination (incl PS) 
B 
X 
X 
X 
X 
 
X 
X 
X 
Adverse event assessment B,N 
 
X 
X 
X 
 
X 
X 
X 
Fulvestrant(or exemestane) 
 
X 
X 
X 
 
X 
X 
 
Ribociclib (or Placebo)C 
 
X 
X 
X 
X 
X 
X 
 
β-HCG (if premenopausal) D 
X 
 
 
 
 
 
 
 
INR 
X 
 
 
 
 
 
 
 
CBC, Chem7, LFTs,E 
X 
X 
X 
X 
X 
X 
X 
X 
EKG F 
X 
 
X 
X 
 
 
X 
 
CT C/A/P + Bone Scan (Or PET) 
B,G,H,I 
X 
 
 
 
 
 
X 
X 
Pill Diary Review  
 
 
X 
X 
 
X 
X 
X 
Blood BiomarkerJ 
X 
 
 
X 
 
 
 
X 
Tissue BiopsyK 
X 
 
 
 
 
 
 
X 
QuestionnaireM 
X 
 
 
 
 
 
X 
X 
 
 
A Exceptions to the +/- 4 days are CT C/A/P + bone scan (OR PET) which should be performed within 28 days of trial registration 
and after every third cycle of treatment (within 14 days of day 1 of each third cycle – ideally within 7 days of day 1)  and tissue 
biopsy (+/- 7 days). 
 
 
B Every 4 weeks.   Day 1 visits for each cycle should occur at 28±4 days from day 1 of the previous cycle.  Blood draws on that day 
should also fall within this +/- 4 day window. Exceptions to the +/- 4 days are CT C/A/P + bone scan (OR PET) as described above.  
The +/- 4 day window includes C1D15. 
 
 
C Ribociclib (or placebo) will be supplied per study.  On D1 of every cycle prior to drug dispensation and dose administration, 
subject’s disease status/non-progression will be confirmed by the treating investigator, including clinical and radiographic 
assessment. RECIST restaging will be confirmed for the most recent scans received, including documentation of investigator sign 
off on calculation of percentage change from baseline and nadir and overall response, prior to treatment. If the new scan 
information becomes available mid cycle, the study team will inform the subject if treatment discontinuation is required per 
protocol in real time, and document date of treatment discontinuation. 
 
 
D  Serum Pregnancy test (women of childbearing potential) 
 
 
E Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium.  
 
 
F EKG will be performed at baseline, C1D15, C2,  and Cycle 4.  If grade 3 or 4 QTC prolongation occurs, see section 7.3 for 
monitoring/dose modification. If no EKG abnormalities, additional EKGs are not required for cycles after C4a or C4b, except 


 
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10.3 
Table 3: Treatment Post Unblinding for Patients who were Active/On Treatment when 
Unblinded (Scenario #2) 
 
The table below applies to Scenario 2 patients who were Actively receiving treatment when unblinded by the 
Sponsor-Investigator at the end of August 2023, due to the expiration and discontinuation of the Novartis 
manufactured placebo for this study. Guidance was provided to all study sites noting that all patients 
that are Active/On Treatment on scenario 2 will undergo an unblinding process following which 
patients will continue to receive the assigned treatment: patient who received Ribociclib will 
continue to do so and patients who received Placebo will continue to receive the endocrine 
treatment alone, as part of the study. Please note, the study does not allow for crossover between the 
study groups.   
 
 
Patient Visit1 (ongoing) 
SAE2  
X 
Disease Progression3 
X 
Patient Status on Study4   
X 
 
1. Visit frequency should be determined as per standard of care.  
2. All SAEs experienced by patients receiving study treatment should be reported as per section 8.2.7 
and entered in the Velos database.  
3. Disease Progression should be documented in the patient statuses in velos, as reason for removal 
from study treatment, if applicable.  
4. Any update to the patients’ stuay status should be entered in Velos.  
 
11. 
MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this phase II study, patients should be re-evaluated for response every 3 cycles (~12 
weeks of treatment +/- 7 days). This includes the pre-randomization phase of the study in patients registered 
under scenario #1 (i.e. patients who have never received CDK4/6 inhibition with an aromatase inhibitor at 
time of registration).  
 
Progression. 
 
 
G  Scans should be performed within 28 days of study registration, prior to every third cycle of treatment (i,e, preferably within 7 
days of Cycle 4a day 1, Cycle 7a day 1, Cycle 10a day 1, and so on, but allowance for up to within 14 days of the next treatment 
cycle). Corresponding RECIST restaging will be conducted in real time following scans and signed (electronically or wet ink) by 
the investigator, including confirmation of overall disease status per RECIST v.1.1. 
 
 
H If patients have known brain metastases and are eligible for this trial, head CT or brain MRI must be performed along with 
systemic imaging. If a patient does not have known brain metastases and is asymptomatic, no baseline brain imaging is required.  
 
 
I  Baseline bone scan required in all patients (whose baseline imaging is CTs of C/A/P)  
NOTE: If bone scan done ≤ 6 weeks prior to registration showed no evidence suggesting bone metastases and no clinical indication 
of skeletal pain or other evidence suggesting bone metastases, a repeat baseline bone scan is not required.  If there is evidence of 
disease on the bone scan, bone scans should be continued every 3 cycles (~12 weeks of treatment +/- 4 days), as clinically 
indicated. 
 
 
J  Serum (2 red top tubes) and plasma (1 lavendar tube) will be collected at each time point and stored for future potential studies. 
(Appendix C on collection details.). In addition, whole blood samples (2 Biocept provided tubes) will be collected and sent same 
day to Biocept (Appendix D). 
 
 
K  Archived tissue from primary and/or metastatic tissue is required, unless unavailable. If patient is amenable and has accessible 
tumor, repeat biopsy is optional. These biopsies should be considered in patients with accessible disease. Biopsies can be within 7 
days of the cycle (+/- 7 days). 
 
 
L Within 4 weeks of completing study treatment. Post-treatment follow-up every 12 weeks (+/- 1 week) for survival follow-up until 
study closure, which we anticipate will be up to 2.5 years after last patient enrolled (Section 6.6). 
 
 
M PROMIS Global Health and PROMIS-29 and EQ-5D-3L will be performed at baseline, C4, and  Off-Study.  Questionnaires are 
not required for cycles after C4, except Off-Study. 
 
 
N Adverse event assessments every 4 weeks should include a review of concomitant medications with the patient. 


 
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Response and progression will be evaluated in this study using the international criteria proposed by the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first treatment on 
study. (Either ribociclib with letrozole (or anastrozole) in patients registered under scenario #1 or fulvestrant 
(or exemestane) +/- ribociclib in patients registered under scenario #2.)  
 
Evaluable for objective response:  Only those patients who have measurable disease present at baseline, have 
received at least one cycle of therapy on study, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target disease.  The response assessment 
is based on the presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered measurable, as long 
as they meet the criteria above.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph node must be 
≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet 
the definition of measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured at 
baseline.  Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 


 
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representative of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
Skin color photography (if skin lesions at screening) will be performed every 12 weeks (+/-  1 week) to 
assess for disease progression or response, particularly in patients with no measurable disease by radiologic 
criteria. (Appendix I). 
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT scan is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is variable. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence.  It 
is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans should be 
performed with breath-hold scanning techniques, if possible. 


 
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PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always 
of optimal diagnostic CT quality for use with RECIST measurements.  However, if the site believes that the 
CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or 
serially performed. FDG avidity is not part of the RECIST criteria, but may provide adjunct information for 
evaluation (see section “FDG-PET” below).  
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical response.  Tumor 
markers have a limited role in the evaluation of metastatic breast cancer, and measurements are not required 
under this protocol.  
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on 
a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
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by disease-specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered progression, even if the sum of the 
diameters of the other target lesions has not increased by 20%). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of the diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  Unequivocal progression should not normally trump target lesion status.  It must 
be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the progression status should be confirmed at a later time by the 
Principal Investigator and/or review panel. 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 


 
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For Patients with Measurable Disease (i.e., Target Disease) +/- Non-Target Disease 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions* Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*          See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. (Not applicable in this trial).  
***       In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment, based on intention to treat analysis.  
 
For Patients with Non-Measurable Disease Only (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease. As SD is 
increasingly used as an endpoint for assessment of efficacy in some trials, to assign this 
category when no lesions can be measured is not advised.  
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first 
date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 


 
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11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever 
occurs first.  
 
Percent progression-free at 24 weeks is defined as the proportion of patients who remain progression-free at 
24 weeks from study entry day #1 (binary proportion). For the primary outcome measure in this study, 
because patients will be registered under two different scenarios, PFS will be measured using the date of 
randomization as day #1.  
 
11.1.7 Response Review 
All responses are reviewed by an expert(s) independent of the study at the study’s completion. Simultaneous 
review of the patients’ files and radiological images is the best approach. 
 
11.2 
Safety Assessment 
11.2.1 Safety 
While on study patients will undergo a) standard of care history and physical exam and b) standard of care 
blood work including complete blood count with differential, liver function tests, and serum chemistry -- at 
baseline, at the beginning of each treatment cycle, at time of disease progression in patients registered under 
scenario#1, and at a final visit when patient is off-study. (4 weeks after final treatment). A standard 
comprehensive adverse event assessment will be performed at the beginning of each treatment cycle. In 
addition, radiological studies performed for response assessment will occasionally detect asymptomatic 
adverse events or provide adjunct information in the case of symptomatic adverse events.  
 
Adverse events will be graded based on the Common Terminology Criteria for Averse Events (CTCAE) 
version 4.0.  
 
11.2.2 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first treatment on 
study.  
 
11.2.3 Disease Parameters 
Patients with both measurable and un-measurable disease will be enrolled in the study. Treatment will 
continue until disease progression as defined above or unacceptable toxicity develops as determined by the 
treating physician.  
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
*** Please see Appendix F for Guidelines for Affiliate Institutions for Registration and Data Reporting 
Requirements.  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8 (Adverse Events: 
List and Reporting Requirements).  The Data Safety Monitoring Plan is described in Section 12.3.  
 
12.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data management 
system that will be used for data collection. CRFs for the study will be built into Velos for data entry. The 
system has full auditing capabilities which is web-based and housed on a server in a fully HIPAA compliant 
server room with restricted access and video camera monitoring.  All users must login with their own 
application username and password.  Users off campus must first access the Virtual Private Network with 
their assigned campus username and password and then use their application credentials.  Users are only able 
to view study information if they are indicated as study personnel in our electronic IRB system, or an affiliate 
IRB system. Users are limited to access based on the role assigned in their corresponding protocol.  Subject 
data is entered directly into the system, which (in the case of Columbia subjects) confirms the correct identity 


 
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of patients via an interface with the electronic medical patient index.  Staff with the appropriate IRB defined 
roles can run reports within the system for reporting purposes. 
 
12.2 
Data Reporting 
Responsibility for Data Submission 
Case Report Forms will be completed for each subject enrolled into the clinical study through Velos 
eResearch. It is the investigator’s responsibility for ensuring that all clinical and laboratory data entered on 
the corresponding CRFs are complete, accurate and authentic. 
➢ Please refer to the tables provided in separate documentation regarding the case report form 
completion and source document submission requirements.  
12.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving Comprehensive 
Cancer Center (HICCC) will monitor every subject who receives treatment on this protocol for toxicity. This 
protocol will adhere to the policies of the currently approved HICCC Data and Safety Monitoring Plan 
(DSMP), which is in accordance with NCI and CUMC-IRB policy and guidelines.  The committee is led by 
Dr. J. Gregory Mears and consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to review patient 
safety and the conduct of the trial. The PI will submit data and safety monitoring reports to the DSMC at a 
frequency to be determined by the DSMC based on risk to the subjects (***DSMC forms will be provided 
separately ***).  
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for safety review to 
the CUMC IRB. Any modifications that are required by the DSMC to ensure patient safety will be submitted 
to the IRB. All protocol deviations, violations, and eligibility waivers will be submitted to and approved by 
the DSMC prior to being reported to the IRB. All study data reviewed and discussed during these meetings 
will be kept confidential.  
 
The Coordinating Site will assure that there is a mechanism in place to distribute the report to all 
participating investigators for submission to their local IRB.  The report will document that a review of data 
and outcomes across all centers took place on a given date.  It will summarize the DSMC’s review of the 
cumulative toxicities reported from all participating sites without specific disclosure by treatment arm.  It 
will also inform site investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
 
12.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the Compliance 
Oversight Committee of the IRB at Columbia University Medical Center may audit the study at any time, per 
institutional policies and procedures. 
 
The investigator-sponsor and Columbia University Medical Center will permit direct access of the study 
monitors and appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number of subject 
charts, and data elements to be monitored. The Compliance Coordinator will review the study status and 
summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints (e.g., stopping rules), etc. 
for the full DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 


 
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1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote clinical 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see below for 
further details). 
 
a. The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
2. The Compliance Coordinator will communicate with the site coordinator/Site Principle Investigator 
to schedule the monitoring visit and arrange for access to study materials and documentation. 
 
3. The assigned Compliance Coordinator will monitor IIT trials within 1 month after the first subject is 
enrolled and throughout the life of the study to ensure that the study is being conducted in 
accordance with the protocol, GCP, applicable federal and local regulations, and per all applicable 
SOPs. The Compliance Coordinator is responsible to notify the PI and CRNP/CRN/CRC of 
upcoming monitor visits and convey what information and documentation will be required for the 
visit(s).  The Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures are 
conducted according to the study protocol. The Compliance Coordinator will also verify that the data 
reported in the CRF’s accurately reflect source documents, that all toxicities have been reported to 
date, and that all SAE’s/UPs/deviations/violations have been reported according to local IRB and 
HICCC DSMC requirements. The Compliance Coordinator will issue queries and ensure resolution 
in a timely and efficient manner.  The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate any 
deficiencies as appropriate. 
12.5 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act (HIPAA).  Those regulations require a signed subject 
authorization informing the subject of the following:  
1. What protected health information (PHI) will be collected from subjects in this study 
2. Who will have access to that information and why 
3. Who will use or disclose that information 
4. The rights of a research subject to revoke their authorization for use of their PHI  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects who 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
12.6 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents   Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
12.7 Reporting to Novartis Pharmaceuticals Corporation 
The primary site (CUMC) Principal Investigator will send complete Data transfers every six months during 
the course of the study to Novartis Pharmaceuticals Corporation. Novartis Pharmaceuticals Corporation may 


 
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request additional data transfers over the course of the study. The data will be provided in a readable format 
for all study participants. The data will not include any protected health information as defined under 
HIPAA. 
 
Additionally, Novartis Pharmaceuticals Corporation will be provided monthly study status updates including 
a summary of: 
• 
Recruitment (screened, enrolled, discontinued and on-going with dates and study drug dosing 
regimens)  
• 
SAEs and safety reports to regulatory authorities 
• 
Regulatory correspondence including IRB approval letters, IRB approved protocol, informed consent 
documents, and documents related to Novartis Pharmaceuticals Corporation.   
• 
Investigational product Inventory 
• 
Payment milestones. 
12.8 Records Retention 
Records relating to a specific research activity, including research records collected by investigators must be 
maintained for at least seven years after completion of the research (45 CFR 46.115(b); 21 CFR 56.115(b); 
21 CFR 312.62). This was selected, as New York State (location of Sponsor) requires at least seven years for 
information.  This retention period applies whether or not any subjects were enrolled in the study. 
 
If the research is FDA regulated, records should be retained for at least two years after approval of the 
investigational agent by FDA; if it is not approved, records should be retained at least two years after the 
study is terminated and FDA is notified (note the additional requirement below for clinical research studies).   
 
Clinical records, including consent forms that document clinical intervention or clinical diagnostic procedure 
research-related procedures, must be retained in medical records by the institution for at least seven years, 
per CUMC and NYP policy, which is based on state law. 
 
Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to notify the 
FDA and all participating investigators of any serious and unexpected adverse experiences that are possibly 
related to the investigational agent. The CUMC Principal Investigator will review all applicable IND Safety 
Reports and has the responsible for forwarding the IND Safety Reports to the Affiliate Institutions. The 
Affiliate Institution investigators are to review, send a copy to their IRB according to their local IRB’s 
policies and procedures, and file a copy with their regulatory documents. All Affiliate site INDSR 
submissions, along with IRB acknowledgment (per local policies and procedures) are to be forwarded to 
CUMC for placement within the trial master file. 
 
*** Please see Appendix F for Guidelines for Affiliate Institutions for Registration and Data Reporting 
Requirements.  
 
13. 
STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Primary Endpoint (Sample Size: N=120 randomized evaluable patients) 
This is a multi-center phase II, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy 
of fulvestrant (or exemestane) with or without ribociclib in patients who have previously progressed on an 
aromatase inhibitor (preferably letrozole) plus CDK4/6 inhibitor (ribociclib or palbociclib or abemaciclib).  
 
Primary Endpoint 
The primary endpoint is progression free survival, defined as the time from randomization to the 
development of progressive disease or death. 


 
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Disease status will be assessed with comprehensive radiographic studies every three treatment cycles 
(approximately every 12 weeks (+/- 1 week), but the development of new signs or symptoms of disease in 
between scheduled evaluations may prompt off-schedule radiographic or non-radiographic evaluations. 
Disease status will be assessed based on RECIST 1.1 criteria for measurable (target) and non-measurable 
(non-target) disease, as outlined in detail in Section 11.  
 
Secondary Endpoints: 
All secondary endpoints, including overall response rate (complete response + partial response rates), 
clinical benefit rate (overall response rate + stable disease rate), overall survival, duration of response, 
adverse event rate, and biomarker assessment are exploratory in nature. In addition, patients registered 
under scenario #1 will be assessed for progression free survival, overall response rate, clinical benefit rate, 
and safety while receiving ribociclib with an aromatase inhibitor (pre-randomization). As there is no 
comparator arm for this pre-randomization part of the study, further statistical analyses on these will not be 
possible.   
Response rates will be estimated as the proportion of enrolled patients who achieve response, as defined in 
Section 11.  Patients who are lost to follow-up without a valid response assessment will be classified as non-
responders. 
 
Statistical analysis: 
Progression-free survival will be estimated by Kaplan-Meier method and group differences between groups 
will be assessed using log-rank tests. Sensitivity analyses for PFS will be performed taking into 
consideration, but not limited to imputation of incomplete lesion measurements and study discontinuation 
due to progression/relapse, drug toxicity or death. Missing data patterns will be examined by summarizing 
the number of subjects randomized but not treated, the number of subjects who discontinued prematurely and 
the corresponding factors for early discontinuation.  Given the potential the interval between two consecutive 
assessments may be longer in one arm, leading to an erroneous conclusion about differences between groups, 
we will perform an additional analysis (i.e. generalized log-rank) with interval censoring, especially if there 
is a difference in assessment schedules and considerable missing data. 
 
Summary statistics will be calculated to describe the sample characteristics in each group. The distribution of 
patient responses (as defined by RECIST criteria) will be described using percentages % (n). Continuous 
outcomes will be summarized using mean ± SD (standard deviation) or median (interquartile range) for non-
normal data. Group comparisons will be evaluated using chi-squared or Fisher’s Exact tests for categorical 
data and two-sided t-tests or ANOVA for continuous outcomes.  
 
Analyses for of primary and secondary outcomes will be based on intention to treat principle, with the 
exception of safety endpoints, which will only be assessed in patients who receive at least one dose of 
treatment on study.  
 
Subject to sample size limitations, subgroup analyses for subjects randomized to fulvestrant versus 
exemestane will also be considered. 
 
All statistical analyses will be performed using SAS (version 9.4, SAS Institute Inc., Cary, North Carolina) 
with a type I error set at 0.05. 
 
 
Sample Size Justification:  
Assuming a median PFS of 3.8 months with fulvestrant alone upon progression83, we predict that the 
addition of ribociclib to fulvestrant will lead to a median PFS of at least 6.5 months.  Based upon the 
Evaluation of Faslodex versus Exemestane Clinical Trial (EFFECT), a randomized, double-blind, placebo-
controlled, phase III trial of fulvestrant versus exemestane in patients who progressed on prior non-steroidal 
aromatase inhibition, the median time to progression was 3.7 months in each arm (HR=0.96, 95% CI 0.82 


 
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to 1.13, p=0.65). Thus, this new protocol amendment allows subject to be randomized to either fulvestrant 
or exemestane +/- ribociclib69., without an impact on the study design and power. A one-sided log-rank test 
with an overall sample size of N=120 randomized and evaluable subjects and with the significance level 
alpha set at 2.5%, achieves 80% power to detect an effect size (difference in PFS) of 3 months. We will 
accrue approximately 150 patients to allow for a 20% drop-out rate, non-evaluable and non-randomized 
subjects.  
 
 
13.2 
Accrual Rate 
Number of Patients & Centers 
The goal is to accrue approximately 150 patients across 11 different academic centers in the United States, 
with the expectation that each center will accrue approximately 7 patients per year over 2 years. We 
previously participated in a study with a similar patient population (Fulvestrant +/- Bortezemib: SABCS oral 
discussion 2014), with an accrual rate as above.  
 
13.3 
Evaluation of Toxicity 
The frequency of subjects experiencing toxicities will be tabulated.  
The case report form will be utilized for AE reporting, based upon the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0.  
 
The descriptions and grading scales in CTEP Version 4.0 of the CTCAE can be located on the CTEP website 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All patients will be evaluable for toxicity from the time of their first treatment with the investigational drug. 
 
13.4 
Correlative Studies 
Correlative studies for this phase II study are exploratory and will be used for hypothesis generation only.  
 
13.5 
Reporting and Exclusions 
All patients included in the study must be assessed for toxicity and disease status. 
 
13.6 
Unblinding Procedures 
 
The Investigator, the study site personnel, and the subject will remain blinded to each 
subject's treatment with Ribociclib/Placebo throughout the course of the study. 
 
Access to blinded subject treatment information during the study will be made available to the 
investigator/limited site personnel, only if identification of the study drug is required for a medical 
emergency. Medical emergency includes a situation in which the knowledge of the specific blinded 
treatment will affect the immediate management of the subject/subject's conditions, or when 
knowledge of previous treatments is required for enrollment in another trial, or as part of managing 
a serious adverse event. 
 
Investigators should note that emergency unblinding is reserved only for emergency situations 
where lack of knowledge about the actual study drug treatment interferes with appropriate 
emergency management. The occurrence of an SAE or progressive disease should not 
routinely precipitate the immediate unblinding of the label. 
 
In the event of a Suspected Unexpected Serious Adverse Reaction (SUSAR) (see 
Section 8.2.8) related to the blinded treatment, the subject’s treatment code will usually be 


 
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broken before reporting to health authorities and central ethics committees in an unblinded 
fashion. In compliance with 21 CFR 312 on the collection and verification of presentation of 
AE/reaction reports arising from clinical trials on medicinal products for human use, investigators 
and persons responsible for the ongoing conduct of the study will not usually receive unblinded 
copies of SUSAR reports, unless unblinded information is judged necessary for safety reasons. 
 
At the end of August 2023, the Placebo drug manufactured and provided by Novartis, expired and 
an unblinding of the Scenario 2 patients who were on treatment at the time was required. Guidance 
was provided to all study sites noting that all patients that are Active/On Treatment on scenario 2 
will undergo an unblinding process following which patients will continue to receive the assigned 
treatment: patient who received Ribociclib will continue to do so and patients who received Placebo 
will continue to receive the endocrine treatment alone, as part of the study. Please note, the study 
does not allow for crossover between the study groups.  
 
13.6.1 Unblinding requests 
 
If emergency unblinding is necessary for the treatment of a subject, the unblinding should be first 
approved by the Sponsor-Investigator at least 24 business hours in advance. The request must 
provide the study ID, date the request is needed, an explanation of the medical need and must be 
made by the PI/designee.  
 
These requests must be submitted to the study email p9506@lists.cumc.columbia.edu between the 
hours of 9:00 am EST – 5:00 pm EST.  
 
Once the unblinding is processed, the appropriate designee will separately communicate the 
treatment allocation via email to limited personnel from the site requesting the unblinding. The 
study team should maintain documentation of the treatment allocation.  
 
Investigators may only unblind subjects under emergency unblinding rules. If a subject is 
unblinded by the Investigator, they must first discontinue study drugs. 
 
 
14. 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and Institutional 
research policies and procedures. An IND annual report will be submitted to the FDA in accordance with 
21.CFR 312.33. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision of 
the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the sponsor before commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject is submitted 
to any study procedure.  This consent form must be signed by the subject or legally acceptable surrogate, and 
the investigator-designated research professional obtaining the consent.  
 


 
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15. 
CONSENT: LEGAL AUTHORIZED REPRESENTATIVE IF PATIENT WITHOUT 
CAPACITY 
We may enroll individuals with limited decision making capacity on to the protocol. This is not an 
exclusion criterion in the protocol and there is the prospect of benefit to participants in this study 
since participation may improve their condition. The principal investigator and co-investigator will 
be responsible for making an initial assessment as to whether a subject is competent to provide 
consent. If this is the case, the investigator will obtain an independent assessment of the individual’s 
capacity to provide informed consent by a licensed physician, not otherwise involved in the research 
study. 
 
The research team will be present to answer all the LAR’s questions adequately before they decide 
to participate and will be given detailed information about the study purpose, procedures, 
requirements, risks, benefits, and possible alternatives. The research team will be present to answer 
all the LAR's questions adequately before they decide whether or not to participate. They will sign 
the consent form on the designated signature line and sign the HIPAA authorization form (unless 
already embedded into the informed consent document). 
 
Although not expected given the potential subjects to be enrolled who have limited decision making 
capacity in this study, in the event that a subject regains their capacity to consent; their ability to 
provide consent will be assessed first by the principal investigator or co-investigator and then by an 
independent licensed physician and they will then be re-consented. 
 
16. 
STUDY FINANCES 
16.1 
Conflict of Interest: 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the 
Columbia University Conflict of Interest Committee with a Committee-sanctioned conflict management plan 
that has been reviewed and approved prior to participation in this study.  All CUMC investigators will follow 
the University conflict of interest policy. 
 
17. 
PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed on 
to any third party without the consent of the sponsor.  Any investigator involved with this study is obligated 
to provide the sponsor with complete test results and all data derived from the study. 
 
18. 
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HER2-negative metastatic breast cancer (MBC) whose dis. Cancer Res Cancer Research. 
46. Turner, N, Ro, J. (2015). PALOMA3: A double-blind, phase III trial of fulvestrant with or without 
palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative 
metastatic breast cancer that progressed on prior endocrine therapy. Journal of Clinical Oncology. 
47. Goldman, J., Garon, E., Conklin, D., Wong, D., Wolf, B., Silveira, D., . . . Slamon, D. (2014). 498 
CDK4/6 inhibitor (LY2835219) exhibits potent anti-tumor activity in human lung cancer cell lines 
with intact retinoblastoma. European Journal of Cancer, 162-162.  
48. Tate, S., Cai, S., Ajamie, R., Burke, T., Beckmann, R., Chan, E., . . . Cronier, D. (2014). Semi-
Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of 


 
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LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor 
Xenografts. Clinical Cancer Research, 3763-3774.  
49. Shapiro, G, Rosen, LS, Tolcher, AW. (2013). A first-in-human phase I study of the CDK4/6 
inhibitor, LY2835219, for patients with advanced cancer. Supplement in Journal of Clinical 
Oncology. 
50. Patnaik, A, Rosen, LS, Tolaney, SM, Shapiro, G. (2014). Clinical activity of LY2835219, a novel 
cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. Abstract 
CT232. AACR annual meeting 2014.  
51. Dukelow, T., Kishan, D., Khasraw, M., & Murphy, C. (2015). CDK4/6 inhibitors in breast cancer. 
Anti-Cancer Drugs, 1-1.  
52. Murphy, C., & Dickler, M. (2015). The Role of CDK4/6 Inhibition in Breast Cancer. The 
Oncologist, 483-490.  
53. Kim, S., Loo, A., Chopra, R., Caponigro, G., Huang, A., Vora, S., . . . Brain, C. (2013). Abstract 
PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6- Reactivating 
Rb in cancer. Molecular Cancer Therapeutics.  
54. Investigator's Brochure: NVP-LEE011.   
55. Infante, J., Shapiro, G., Witteveen, P., Gerecitano, J., Ribrag, V., Chugh, R., . . . Cassier, P. (2013). 
Abstract A276: Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor 
of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. Molecular 
Cancer Therapeutics.  
56. Samson, K. (2014). LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers. 
Oncology Times, 39-40.  
57. Juric, D., Hamilton, E., Estévez, L., Boer, R., Mayer, I., Campone, M., . . . Munster, P. (2015). 
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 Res Cancer Research.  
58. Bardia, A., Chavez-Macgregor, C., Modi, S., Campone, M., Ma, B., Kittaneh, M., . . . Oliveira, M. 
(2014). 500 Triple blockade with LEE011, everolimus, and exemestane in women with ER /HER2− 
advanced/metastatic breast cancer: Results from a Phase Ib clinical trial. European Journal of 
Cancer, 163-163.  
59. Susman, E. (2015). Fulvestrant Packs Wallop in First-Line Advanced Breast Cancer Patients. 
Oncology Times, 30-31.  
60. Agrawal, A., Robertson, J., & Cheung, K. (2007). Chapter 5 Fulvestrant in metastatic disease. 
Endocrine Therapies in Breast Cancer.  
61. Ciruelos, E., Pascual, T., Vozmediano, M., Blanco, M., Manso, L., Parrilla, L., . . . Cortes-Funes, H. 
(2014). The therapeutic role of fulvestrant in the management of patients with hormone receptor-
positive breast cancer. The Breast, 201-208.  
62. Hole, S., Pedersen, A., Hansen, S., Lundqvist, J., Yde, C., & Lykkesfeldt, A. (2015). New cell 
culture model for aromatase inhibitor-resistant breast cancer shows sensitivity to fulvestrant 
treatment and cross-resistance between letrozole and exemestane. International Journal of Oncology 
Int J Oncol.  
63. Rao, X., Leva, G., Li, M., Fang, F., Devlin, C., Hartman-Frey, C., . . . Nephew, K. (2010). 
MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling 
pathways. Oncogene, 1082-1097.  
64. Fornari, F., Gramantieri, L., Ferracin, M., Veronese, A., Sabbioni, S., Calin, G., . . . Negrini, M. 
(2008). MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular 
carcinoma. Oncogene, 5651-5661.  
65. Howell, A. (2002). Fulvestrant, Formerly ICI 182,780, Is as Effective as Anastrozole in 
Postmenopausal Women With Advanced Breast Cancer Progressing After Prior Endocrine 
Treatment. Journal of Clinical Oncology, 3396-3403.  
66. Mauriac, L., Pippen, J., Albano, J., Gertler, S., & Osborne, C. (2003). Fulvestrant (Faslodex™) 
versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of 


 
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postmenopausal women with visceral and non-visceral metastases: Combined results from two 
multicentre trials. European Journal of Cancer, 1228-1233.  
67. Jonat, W., Howell, A., Blomqvist, C., Eiermann, W., Winblad, G., Tyrrell, C., . . . Azab, M. (1995).  
A randomized trial of the new specific aromatase inhibitor ‘Arimidex’ (anastrozole) versus 
megestrol acetate (MA) in the treatment of postmenopausal women with advanced breast cancer 
(ABC). The Breast, 227-228. 
68. Howell, A., Robertson, J., Abram, P., Lichinitser, M., Elledge, R., Bajetta, E., . . . Osborne, C. 
(2004). Comparison of Fulvestrant Versus Tamoxifen for the Treatment of Advanced Breast Cancer 
in Postmenopausal Women Previously Untreated With Endocrine Therapy: A Multinational, Double-
Blind, Randomized Trial. Journal of Clinical Oncology, 1605-1613.  
69. Chia, S., Gradishar, W., Mauriac, L., Bines, J., Amant, F., Federico, M., . . . Piccart, M. (2008). 
Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane 
After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone 
Receptor-Positive, Advanced Breast Cancer: Results From EFECT. Journal of Clinical Oncology, 
1664-1670.  
70. Mehta, R., Barlow, W., Albain, K., Vandenberg, T., Dakhil, S., Tirumali, N., . . . Hortobagyi, G. 
(2011). S1-1: A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as 
First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226. 
Cancer Res Cancer Research.  
71. Bergh, J., Jonsson, P., Lidbrink, E., Trudeau, M., Eiermann, W., Brattstrom, D., . . . Henriksson, R. 
(2012). FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in 
Combination Compared With Anastrozole Alone As First-Line Therapy for Patients With Receptor-
Positive Postmenopausal Breast Cancer. Journal of Clinical Oncology, 1919-1925.  
72. Robertson, JF, Nicholson, RI. (2001). Comparison of the short-term biological effects of 7alpha-[9-
(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus 
tamoxifen in postmenopausal women with primary breast cancer. Cancer Research.  
73. Robertson, J., Llombart-Cussac, A., Rolski, J., Feltl, D., Dewar, J., Macpherson, E., . . . Ellis, M. 
(2009). Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for 
Advanced Breast Cancer: Results From the FIRST Study. Journal of Clinical Oncology, 4530-4535.  
74. Robertson, J., Llombart-Cussac, A., Feltl, D., Dewar, J., Jasiówka, M., Hewson, N., . . . Ellis, M. 
(2015). Abstract S6-04: Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced 
breast cancer: Overall survival from the Phase II ‘FIRST’ study. Cancer Res Cancer Research.  
75. Leo, A., Jerusalem, G., Petruzelka, L., Torres, R., Bondarenko, I., Khasanov, R., . . . Martin, M. 
(2010). Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 
500 mg in Postmenopausal Women With Estrogen Receptor-Positive Advanced Breast Cancer. 
Journal of Clinical Oncology, 4594-4600.  
76. Hershman, D., Kushi, L., Shao, T., Buono, D., Kershenbaum, A., Tsai, W., . . . Neugut, A. (2010). 
Early Discontinuation and Nonadherence to Adjuvant Hormonal Therapy in a Cohort of 8,769 Early-
Stage Breast Cancer Patients. Journal of Clinical Oncology, 4120-4128.  
77. Verma, S, Miles, D, Gianni, L, Krop, IE. (2013).Trastuzumab Emtansine for HER2-Positive 
Advanced Breast Cancer. New England Journal of Medicine N Engl J Med, 2442-2442.  
78. Wang, L., Wang, J., Blaser, B., Duchemin, A., Kusewitt, D., Liu, T., . . . Briesewitz, R. (2007). 
Pharmacologic inhibition of CDK4/6: Mechanistic evidence for selective activity or acquired 
resistance in acute myeloid leukemia. Blood, 2075-2083.  
79. Giessrigl, B., Schmidt, W., Kalipciyan, M., Jeitler, M., Bilban, M., Gollinger, M., . . . Krupitza, G. 
(2013). Fulvestrant induces resistance by modulating GPER and CDK6 expression: Implication of 
methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. British Journal 
of Cancer Br J Cancer, 2751-2762.  
80. Takaki, T. (2005) Preferences for Phosphorylation Sites in the Retinoblastoma Protein of D-Type 
Cyclin-Dependent Kinases, Cdk4 and Cdk6, In Vitro. Journal of Biochemistry. 381–386. 
81. Mouridsen, H, Gershanovich, M, Sun, Y……. (2003). Phase III study of letrozole versus tamoxifen 
as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and 


 
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update of efficacy from the International Letrozole Breast Cancer Group. Journal of Clinical 
Oncology. 2101-9 
82. DeMichele, A, Clark, A, Tan, K, Heitien, D…..(2015). CDK 4/6 inhibitor palbociclib (PD0332991) 
in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. 
Clinical Cancer Research: 995-1001 
83. Turner, N, Ro, J, Andre, F. …(2015). Palbociclib in Hormone-Receptor–Positive Advanced Breast 
Cancer. New England Journal of Medicine. 10.1056 
84. Minckwitz, G, Bois, A, Schmidt, M….(2009). Trastuzumab Beyond Progression in Human 
Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 
26/Breast International Group 03-05 Study. Journal of Clinical Oncology.  
85. American Society of Clinical Oncology/College of American Pathologists Guideline 
Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in 
Breast Cancer 
http://www.instituteforquality.org/sites/instituteforquality.org/files/unabridged_er_pr_revised_6.28.1
0_1.pdf 
86. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: 
American Society of Clinical Oncology/College of American Pathologists Clinical Practice 
Guideline Update.  
http://jco.ascopubs.org/content/31/31/3997.full.pdf+html 
87. http://www.nihpromis.org/science/validitystudies.aspx 
88. Janssen, MF, Bernie E. … (2008). Comparing the standard EQ-5D three-level system with a five-
level version. Value Health.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A: ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
100 
Normal, no complaints, no 


 
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carry on all pre-disease performance 
without restriction. 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
APPENDIX B: STRONG CYP3A4 AND CYP3A5 INDUCERS AND INHIBITORS 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as Facts and Comparisons or Lexicomp; medical reference texts such as 
the Physicians’ Desk Reference may also provide this information. The Principal Investigator 
should be alerted if the subject is taking any agent on these lists. The list below should not be 
considered a complete list. 
 
List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit 
juice, idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavirnelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir 
(VIEKIRA PAK), posaconazole, ritonavir,  saquinavir/ritonavir, 
telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, 
voriconazole 
Strong CYP3A4/5 inducers 
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's 
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Category 
Drug Name 
CYP3A4/5 substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, lomitapide5, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, simvastatin, sirolimus, 
tacrolimus 
Medications with a known 
risk for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
bepridil chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, 
cisapride, citalopram, clarithromycin, disopyramide, dofetilide, 
domperidone, donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacin, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, levomethadyl, mesoridazine methadone, moxifloxacin, 
ondansetron, oxaliplatin, papaverine HCl (intra-coronary), pentamidine, 
pimozide, probucol, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, terlipressin, 
terodiline, terfenadine, thioridazine, vandetanib 
Herbal preparations/ 
medications or dietary 
supplements 
Herbal preparations/medications or dietary supplements known as strong 
inducers or inhibitors of CYP3A4/5 or those with a known risk of QT 
prolongation are prohibited throughout the study. These  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 herbal medications or 
dietary supplements 7 days prior to first dose of study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on 
the study. Anticancer therapy (chemotherapy, hormonal therapy, 
including but not limited to all SERMS [including raloxifene], biologic or 
radiation therapy [except for palliative radiotherapy as outlined in the 
protocol], and surgery) other than the study treatments must not be given 
while the patient is on the study medication. If such agents are required, 
then the patient must discontinue the study drug. 
 
 


 
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Category 
Drug Name 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes) or drugs which have <2-fold difference in the minimum toxic concentrations and 
minimum effective concentrations in the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of December 2019. Check https www.crediblemeds.org/healthcare-
providers/drug-list for the most updated list.  
5 Drug has warning for risk of hepatotoxicity. As far as possible, avoid co-administration of QT 
prolonging drugs or any other drugs with the potential to increase the risk of drug-related QT 
prolongation (e.g., via a potential DDI that increases the exposure of ribociclib or the exposure of the QT 
prolonging drug). A definitive list of drugs with a known risk, possible risk, or conditional risk of QT 
prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana University 
“Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction Database, and FDA 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
 
 
 
 
 
 


 
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List of medications to 
be used with caution 
during study drug 
treatment Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida), cimetidine, 
crizotinib, diltiazem, faldaprevir,  imatinib,  isavuconazole, netupitant, nilotinib, 
tofisopam, Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein, lopinavir5, modafinil, 
nafcillin, telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine, apixaban, aprepitant,  atorvastatin, avanafil, 
bosutinib, brotizolam, budesonide, buspirone, cannabinoids6, cannabidiol6, 
cobimetinib,   darifenacin, dasatininb, ebastine, eletriptan, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole, 
ivabradine, ivacaftor, lumefantrine, lurasidone, maraviroc, midazolam, 
midostaurin, naloxegol, neratinib, perospirone, quetiapine, ridaforolimus, 
rivaroxaban, sildenafil, simeprevir, , ticagrelor, tilidine,  tolvaptan, triazolam, 
ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine, rifamycin, simeprevir, telmisartan, 
timcodar, troglitazone, , velpatasvir 
 
 


 
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Medications that carry 
a possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, 
atazanavir, atomoxetine,  bedaquiline, bendamustine, bortezomib, bosutinib, 
buprenorphine, cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib, 
clozapine, cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, 
epirubicin, eribulin mesylate, ezogabine (retigabine), famotidine, felbamate, 
fingolimod, flupentixol,  gemifloxacin, granisetron, hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, ketanserin, lapatinib, 
lenvatinib, leuprolide, loperamide, lithium, melperone, midostaurin, 
mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, , 
nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, olanzapine, 
osimertinib,  oxytocin, paliperidone, palonosetron,  panabinostat, pasireotide, 
pazopanib, perflutren lipid microspheres, perphenazine, pilsicainide, 
pimavanserin, pipamperone, promethazine, prothipendyl, quetiapine, ranolazine 
rilpivirine, risperidone, romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, 
telavancin,tetrabenazine, tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene, trimipramine, tropisetron, vardenafil, vemurafenib, venlafaxine, 
vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
 Amantadine, , carboplatin, cisplatin, cephalexin, cephradine, ipratropium,  
lamivudine, linagliptin, metformin, , oxaliplatin, oxybutynin, phenformin, 
picoplatin, pilsicainide, pindolol, , ranitidine, sorafenib,  tropisetron, trospium, 
umeclidinium,  and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl 
estradiol, sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax 
1 Sensitive substrates include drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor. 
 2 The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir and atazanavir is prohibited when combined with ritonavir (see Table 14-1) 
6 Based data that, exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy THC, 
increased by ~2-3 folds when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al, 
Springerplus. 2013; 2: 236 
 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana University 
“Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction Database and FDA 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
 
 
 


 
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APPENDIX C: SERUM AND PLASMA BIOSPECIMEN COLLECTION 
Samples should be obtained at protocol specified time points, using supplies available onsite. All specimens 
will be stored onsite. Samples are collected according to the calendar in Section 10.  
 
1. Plasma 
Collect 
Blood Processing 
Store 
At least 3 ml whole blood 
in EDTA tube (lavender top) 
Gently invert 8 to 10 times to 
mix the blood. Centrifuge at 
2400 rpm for 10 min at 4oC. 
Carefully aliquot 0.5 ml of 
plasma to each vial for a total of 
3 vials. Total plasma for all 3 
vials should amount to 1.5 ml. 
Store at -70 Celsius. Ship to 
Columbia University Medical 
Center when requested. 
 
1. Serum (Two) 
Collect 
Blood Processing 
Store 
 
 
At least 3 ml serum 
in non-anticoagulant and/or 
speckled tube (red top) 
Gently invert 8 to 10 times to 
mix the blood. Centrifuge at 
2400 rpm for 10 min at 4oC. 
Carefully aliquot 0.5 ml of 
serum to each vial for a total of 
6 vials. Total serum for all 6 
vials should amount to 3 ml. 
Store at -70 Celsius. Ship to 
Columbia University Medical 
Center when requested. 
 
 
Refer to Study Calendar (Section 10) for collection time points of serum and plasma. 
➢ For registration scenario # 1, peripheral blood will be collected for proposed and future biomarker 
evaluations at 5 time points: a) pre-treatment, after completing 1 cycle of treatment (Cycle2a Day1 
visit), progression on aromatase inhibitor plus ribociclib, after completing 1 cycle of treatment post-


 
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randomization (Cycle2b Day1 visit), and progression on fulvestrant (or exemestane) +/- ribociclib. 
One lavender (EDTA) tube and two red top (non-anticoagulant) tubes are recommended for 
collection. 
➢ For registration scenario # 2, peripheral blood will be collected for proposed and future biomarker 
evaluations at 3 time points: pre-treatment, after one cycle of treatment (Cycle2 Day1 visit), and at 
progression on fulvestrant (or exemestane) +/- ribociclib. One lavender (EDTA) tube and two red top 
(non-anticoagulant) tubes are recommended for collection. 
• 
Be sure to label tubes with provided labels and note date and time of collection. 
• 
When requested, ship batched samples along with a copy of this document, as follows:  
• 
Serum samples should be shipped to:    
Biovica Inc 
6195 Cornerstone Court E, St 101 
San Diego, CA  92121 
ATTN:  Laboratory (or Hector Tamburini) 
PHONE:  858-230-6164 
EMAIL:  hector.tamburini@biovica.com, Cc: amy.williams@biovica.com 
 
Samples should be shipped frozen with gel packs or dry ice. 
Please use overnight shipping and ship packages on a Mon, Tues, or Wed.  
E-mail an inventory list with study ID and sample/tube ID’s to: hector.tamburini@biovica.com and 
Cc:  amy.williams@biovica.com 
 
 
• 
Please ship all residual samples to:  
Sunil Badve, MD, FRCPath 
Professor and Vice Chair, Pathology Cancer Program 
Department of Pathology and Laboratory Medicine 
Emory University School of Medicine 
1364 Clifton Road NE, Room H184,  
Atlanta, GA 30322 
sbadve@emory.edu   
Phone +1 (404) 712 8579 
Fax +1 (404) 727 3133 
 
Please include with each shipment a sample tracker (see next page). Prior to shipping the samples, 
please reach out to the Biovica email and to Dr. Badve via email to ensure the lab team will be 
available to receive the shipment when anticipated to arrive. Please refrain from shipping samples 
towards the weekend, holidays, or days with inclement weather.  
 
 


 
L oc al Pr ot oc ol #:  A A A P 9 5 0 6  
Versi o n D ate: Fe br u ar y 1 , 2 0 2 4 
 
Pa ge 9 5  of 1 1 3  
 
S C E N A RI O # 1  
Site N u m ber:  
S u bject 
I D 
Pre -
Treat me nt  
C 2a D 1  
Pr o gressi o n 
o n AI  or 
ta m o xife n or 
f ul vestra nt + 
ri b o bicli b 
C 2 b D 1  
Pr o gressi o n o n 
f ul vestrant  ( or 
e xe mesta ne)  +  
ri b ocicli b 
T otal # 
of 
cr y o vials 
Date 
S hi p pe d / C o or di nat or 
I nitials 
 
 
Plas ma  
 
Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
 
 
 
 
Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
 
 
 
Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
Pla s ma 
 
Ser u m  
 
Plas ma  
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Ser u m  
 
Plas ma  
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Ser u m  
 
 
 
 
Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
 
Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
 
 
 
S C E N A RI O # 2  
Site N u m ber:  
S u bject 
I D 
Pre -Treat me nt  
C 2 D 1  
Pr o gressi o n o n 
f ul vestra nt ( or 
e xe mesta ne)  +  
ri b ocicli b 
T otal # of 
cr y o vials 
Date S hi p pe d / C o or di nat or I nitials 
 
 
Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
Plas ma  
 
Ser u m  
 
 
 
 
Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
 
 
 
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
 
 
 
 
Plas ma  
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Ser u m  
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Plas ma  
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Ser u m  
 
Plas ma  
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Ser u m  
 
 
 
 
 
 
 


 
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APPENDIX D: WHOLE BLOOD FOR CTDNA BIOMARKERS 
 
2. Whole Blood (Two) 
Collect 
Blood Processing 
Shipment 
 
 
 
 
At least 2 x 8 ml vials of whole 
blood using the Biocept sample 
collection tube. 
No processing required. Gently 
invert the tube 5 times.  
Ship on same day to Biocept at 
ambient temperature. 
 
 
Biocept ctDNA Target-SelectorTm Technology 
Biocept has developed a proprietary minimally-invasive blood-based method for the detection of 
biomarkers (e.g., mutations) from patients with cancer. This ctDNA technology has uniquely high 
sensitivity and specificity. Recent data show >96% sensitivity and >98% specificity with 93% 
correlation to tissue (AMP 2015). 
 
When detecting rare mutations associated with cancer, particularly when using circulating tumor 
DNA (ctDNA) from blood sample, a significant challenge is to be able to detect mutations 
associated with ctDNA in a vast excess of normal wild-type DNA. To make this possible the 
Target-SelectorTm technology was developed. This technology is designed to suppress 
amplification of wild-type targets, while not suppressing amplification of mutation sequences that 
differ from wild-type by even a single nucleotide variant (SNV). The Target-SelectorTm has been 
demonstrated to distinguish targets with SNVs by >20oC, which is unprecedented. This large 
temperature discrimination makes it possible to use amplification temperatures where the wild-type 
is completely blocked without effecting amplification of mutants. This is accomplished using a very 
sensitive switch that is embedded in the Selector construct. When the switch is “open”, due to a 
mismatch, amplification can take place. When the switch is “closed”, due to a perfect complement, 
amplification is blocked. In addition to highly selective blocking, the Selector also contains 
fluorescent labels and quenchers that allow the Selector construct to provide a fluorescent read-out 
in real-time PCR assays. When using real-time PCR, Selector assays are completely quantitative, 
and give high discrimination of (mutant:wild-type).   The Selector can also be used to preferentially 
amplify sequences of interest prior to sequencing. It has been demonstrated that when Selector is 
combined with sequencing the detection of rare mutations is increased >20,000 fold.   
 
Sample Collection 
 
Draw sufficient blood and transfer into the required tubes provided in the shipping kit. 
USE ONLY THE TUBES PROVIDED. Gently invert the tube 5 times after blood is added. 


 
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DO NOT refrigerate or freeze the specimen. Keep at room temperature. 
 
Note: Expiration date is identified on the outside of the kit and on the Biocept’s blood collection 
tube. If the kit is expired, please contact Customer Service. Label the tubes with the date of draw. 
Include three unique patient identifiers (study number, subject number, site number). 
 
Packaging 
 
Insert tubes into the absorbent sleeve, place sleeve inside the provided biohazard bag and seal. Wrap 
gel blanket around the bagged tubes, place inside the Styrofoam cooler, and close with lid. Please 
place your Biocept Study Requisition form on top and close the kit. 
 
Shipping the Sample 
 
Place the kit inside FedEx LabPak and seal. Contact FedEx (800-G0-FEDEX) to schedule a pickup. 
Please notify Biocept Customer Service with the FedEx tracking number either at 
CustomerService@biocept.com or 888-332-7729. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX E: ARCHIVED TISSUE AND BIOPSY COLLECTION AND SHIPMENT 
All formalin-fixed paraffin embedded (FFPE) from archived tumor and study-related biopsies will 
be stored onsite until requested by the coordinating center. Ideally, all slides will be cut at the same 
time, within 6 weeks of time of request, and sent to the coordinating center to distribute for analysis 
at the Columbia University Molecular Pathology Core and Columbia University Genome Center.  
 
Ship to: 
Sunil Badve, MD, FRCPath 
Professor and Vice Chair, Pathology Cancer Program 
Department of Pathology and Laboratory Medicine 
Emory University School of Medicine 
1364 Clifton Road NE, Room H184,  
Atlanta, GA 30322 
sbadve@emory.edu   
Phone +1 (404) 712 8579 
Fax +1 (404) 727 3133 
 
Complete these forms separately for each subject; enclose with shipment along with accompanying 
pathology report.  
The tissue samples will be shipped from each participating site to Dr. Badve’s lab at Emory. Prior 
to shipping the samples, please reach out to Dr. Badve via email to ensure the lab team will be 
available to receive the shipment when anticipated to arrive. Please refrain from shipping samples 
towards the weekend, holidays or days with inclement weather.  
 
I. 
Archived Diagnostic Tissue 
Subject ID: ______________________ 
Archival tissue, diagnostic biopsy                                                                               
 Not available  
Number of 
slides 
Slide preparation 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on charged 
slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
Enclose redacted accompanying pathology report. 
Archival tissue, biopsy at recurrence                                                           
 Not available/applicable  
Number of 
slides 
Slide preparation 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on charged 
slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
Enclose redacted accompanying pathology report. 
Date  
Name of person responsible for this shipment 
 
 
 


 
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II.  Study-related biopsies 
Archived tissue from primary and/or metastatic tissue is required, unless not available. 
 
Optional biopsies for tissue biomarker assessment will be performed in consenting patients prior to 
starting study drugs, at time of progression on letrozole plus ribociclib (in patients registered under 
scenario#1), and upon progression on fulvestrant (or exemestane) +/- ribociclib.   
➢ For registration scenario # 1, optional tissue biopsies for biomarker evaluation will be performed at 3 
time points: pre-treatment, at time of progression on aromatase inhibitor plus ribociclib, and 
progression on fulvestrant (or exemestane) +/- ribociclib. 
➢ For registration scenario # 2, optional tissue biopsies for biomarker evaluation will be performed at 2 
time points: prior to treatment with fulvestrant (or exemestane) +/- ribociclib and at progression on 
fulvestrant +/- ribociclib. 
 
Please indicate the time point on the form below.  
For patients with accessible tumor, up to 5 core biopsies are recommended.  
 
The following will be requested, if available. 
A) 10 immunoblanks [each having 4 micron sections on charged slides], one intervening H&E 
stained slide, and 12 regular slides each with 10 microns sections: Paraffin-embedded tissue 
will be requested. Sites will not cut and send to CUMC until requested (see IIA). 
B) Fresh Core biopsies to be sent to Dr. Laura Kaufman at Columbia University for organoid 
system assessment (NY sites, if possible for pickup) OR Dr. Carlos Artega at UT-
Southwestern. 
C) Fresh Core biopsies to be sent to Champions Oncology for patient-derived xenograft testing 
and implantation  
 
The tissue samples will be shipped from each participating site to Dr. Badve’s lab at Emory, using 
the address below. Please include with the shipment a sample tracker (see next page) as well as the 
corresponding de-identified pathology report. Prior to shipping the samples, please reach out to 
Dr. Badve via email to ensure the lab team will be available to receive the shipment when 
anticipated to arrive. Please refrain from shipping samples towards the weekend, holidays or days 
with inclement weather. Following review and processing by Dr. Badve, some of the samples will 
be shipped to an external lab – BostonGene, for further analysis.  
 
Sunil Badve, MD, FRCPath 
  
Professor and Vice Chair, Pathology Cancer Program 
Department of Pathology and Laboratory Medicine 
Emory University School of Medicine 
1364 Clifton Road NE, Room H184,  
Atlanta, GA 30322 
sbadve@emory.edu   
Phone +1 (404) 712 8579 
Fax +1 (404) 727 3133 
 
 
 


 
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IIA. Paraffin Embedded Tissue 
 
Paraffin-embedded tissue will be requested. Sites will not cut and send to CUMC until requested 
Subject ID: ______________________ 
FFPE tissue, Pre-treatment biopsy   
 Core biopsies  
Number 
of slides 
Slide preparation 
Date Collected 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on charged 
slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
 
Enclose redacted accompanying pathology report (if available). 
FFPE tissue, Biopsy after progression   
 POD on ribociclib/AI or tamoxifen or fulvestrant    
 
POD on fulvestrant (or exemestane) +/- ribociclib 
 Core biopsies  
Number 
of slides 
Slide preparation 
Date Collected 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on charged 
slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
 
Enclose redacted accompanying pathology report (if available). 
Date  
Name of person responsible for this shipment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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IIB. Fresh Core Biopsies for Organoid Assessment 
 
A. NY Sites, if possible for pickup (Kaufman Lab) 
 
Fresh core biopsies should be obtained and placed immediately into cryogenic tubes 
containing freezing media. Samples can be frozen at -80 and shipped to Dr. Kaufman in 
batches overnight – or picked up by her lab members.  
 
1. Prepare cryogenic tubes with 1 mL BAMBANKER freezing media 
2. Tubes should be labeled per study protocol 
3. Obtain fresh core biopsies (2 cores) 
4. Place 1 core each into 1 cryogenic tube containing 1 mL of BAMBANKER freezing media 
5. Store tubes at -80 until they are ready to be shipped.  
6. Samples should be shipped OVERNIGHT on dry ice to: 
Dr. Laura Kafuman 
Columbia University 
Department of Chemistry 
6th Floor, Havemeyer Hall 
New York, NY 10027 
 
B. Other sites (Arteaga Lab) 
 
1 Collect fresh core biopsies (2 cores) 
2. Tubes should be labeled per study protocol 
3. Ship sample in small Ship sample in small container or 50ml tube completely filled with 
DMEM + 20% FBS  on ice pack (at 4 degree and Avoid freezing) 
4. Samples should be shipped SAME DAY or OVERNIGHT on ice pack (not dry ice) to: 
Saurabh Mendiratta/Kyung-min Lee  
6001 Harry Hines Blvd. NB5.112 
(Simmons Comprehensive Cancer Center)  
UT Southwestern Medical Center Dallas, TX- 75390-8807 
Phone : 214-648-6167 
 
 
 


 
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FFPE tissue, Pre-treatment biopsy   
 Core biopsies (preferred 2) 
Number tubes 
Date Collected 
Slide IDs (if applicable) 
 
 
 
Enclose redacted accompanying pathology report (if available). 
Number tubes 
Date Collected 
Slide IDs (if applicable) 
 
 
 
Enclose redacted accompanying pathology report (if available). 
Date  
Name of person responsible for this shipment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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IIB. Fresh Core Biopsies for Patient-Derived Xenograft Evaluation 
 
TUMORGRAFT (PDX) PROCESS 
Fresh tissue is collected from patients through surgical resection or biopsy; in order to maximize the 
success of tumor engraftment, the preferred tissue requirements are 0.5 cm3 or three to four 18 
gauge needle cores, respectively.  However, models can be generated from smaller volumes of 
tissue.  
Specimens will be placed into 1 50-ml vial containing transport medium that will be provided by 
Champions and labeled with a unique trial number identifier.   Tubes containing the tissue specimen 
will be packaged in an insulated container with a coolant block.  Transportation of the specimen to 
the designated implantation site will be arranged in advance with Champions Clinical Operations 
team. Ideally, the time from tumor extraction to placement in media should be as soon as possible 
but less than 30 minutes. Exact times will be recorded. The site will be trained by Champions on the 
exact steps for tissue collection. 
Upon receipt of the tumor specimen at the designated implantation site, tumor tissue is 
macroscopically dissected and implanted, under anesthesia, into immune-deficient mice within the 
flanks and/or mammary fat pad following Champions standard operating procedures (SOPs). 
Champions operates under approved IACUC protocols. Fresh tumor tissue is implanted into up to 5 
mice (dependent upon amount of tissue received) and monitored for growth for up to 6 months. If 
no growth is observed models are discontinued.  If a tumor grows and is palpable they are 
monitored until tumors reach approximately 1000 -1500 mm3 (a process known as “engraftment”), 
they are harvested, fragmented and re-implanted into additional mice (a process known as 
“expansion”).  Histology is confirmed for all models developed. 
The ability to establish a viable PDX model and the time it takes is dependent on a number of 
factors including amount and viability of tissue, tumor type, and time to implantation. The average 
time to establish a model also varies depending on amount of tissue and tumor type.   
Once the PDX model is established the tissue can be “banked” as a live model for future use or used 
immediately for drug sensitivity testing.  For this purpose, randomized cohorts of mice undergo 
treatment with drugs or drug combinations selected depending on the research hypothesis. Drug 
activity in the model is reported as tumor growth inhibition (% TGI) relative to the control 
(untreated) group of mice and in terms of a modified RECIST criteria response. Every PDX model 
is cyro-preserved as a living sample and can be retested at any time in the future for translational 
research purposes.    
ASSESSMENT OF RESPONSE IN THE TUMORGRAFT 
Agent Efficacy: All test agents will be formulated according to manufacturer’s specifications for 
testing in a mouse model. Cohorts of 3-4 mice will be randomized into treatment groups. Drug 
sensitivity testing will last for a total of 28 days.  Beginning Day 0, tumor dimensions will measured 
twice weekly by digital caliper and data, including individual and mean estimated tumor volumes 
(Mean TV ± SEM), are recorded for each group. Tumor volume was calculated using the formula: 
TV= width2 x length x π/2. 
Tumor Growth Inhibition: At study completion, percent tumor growth inhibition (%TGI) values 
will be calculated and reported for each treatment group (T) versus control (C) using initial (i) and 
final (f) tumor measurements by the formula: %TGI=[1-(Tf-Ti)/(Cf-Ci)] x 100.  


 
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RECIST: Individual mice reporting a tumor volume >120% of the Day 0 measurement are 
considered to have progressive disease (PD). Individual mice with neither sufficient shrinkage nor 
sufficient tumor volume increases are considered to have stable disease (SD). Individual mice 
reporting a tumor volume ≤70% of the Day 0 measurement for two consecutive measurements over 
a seven day period are considered partial responders (PR). If the PR persisted until study 
completion, percent tumor regression (%TR) is determined using the formula: %TR= (1-Tf /Ti) x 
100; a mean value is calculated for the entire treatment group. Individual mice lacking palpable 
tumors for two consecutive measurements over a seven day period are classified as complete 
responders (CR). All data collected in this study will be managed electronically and stored on a 
redundant server system.  
 
FFPE tissue, Pre-treatment biopsy   
 Core biopsies (preferred 2) 
Number tubes 
Date Collected 
Slide IDs (if applicable) 
 
 
 
Enclose redacted accompanying pathology report (if available). 
Number tubes 
Date Collected 
Slide IDs (if applicable) 
 
 
 
Enclose redacted accompanying pathology report (if available). 
Date  
Name of person responsible for this shipment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX F: GUIDELEINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER 
STUDIES 
1. Multi-site Communication: 
The CPDM office at CUMC provides administration, data management, and organizational support for the 
affiliate sites in the conduct of a multicenter clinical trial.  The CPDM office will coordinate regularly 
scheduled conference calls with affiliate sites.  
The following issues will be discussed as appropriate:  
• 
Enrollment information  
• 
Cohort updates (i.e. DLTs) 
• 
Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety 
information) 
• 
Protocol violations 
• 
Other issues affecting the conduct of the study 
 
2. New Protocol Distribution, IRB Submission, Modifications and Annual Renewals 
• 
Protocol specific documents are distributed to affiliate sites once CUMC IRB approval has been 
obtained.  
• 
The affiliate site must submit a draft of site specific revisions to protocol and/or consent form 
documents for review and approval by the sponsor-investigator prior to submission to the local IRB. 
Draft documents should be sent to the study specific email address. The site will be provided 
confirmation that they are approved to submit to their local IRB.  
• 
Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of 
distribution to the site by the sponsor-investigator.  
 
3. Regulatory Documents: 
3.1 Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following documentation 
is collected prior to the initiation of an affiliate site.   
• 
CV of PI, Sub-I’s and other research staff listed on FDA 1572 (signed and dated copy within 2 
years) 
• 
Medical Licenses of PI and Sub-I’s (current copy) 
• 
Human subjects training certificates for PI and Sub-I’s 
• 
CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
• 
Local Laboratory Director’s CV and License 
• 
Local Laboratory Reference Ranges  
• 
IRB roster or statement of compliance 
• 
FDA Form 1572, if applicable (wet ink originals required) 
• 
Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals required) 
 
3.2 Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper requests are made of 
sites and that the following documentation is collected throughout the course of the study. 
• 
IRB approval letters for all protocol modifications and all renewals 
• 
IRB-approved consent forms 
• 
Current IRB roster, if statement of compliance is not provided as part of site initiation  
• 
FDA Form 1572, if applicable as updates are required 
• 
Updated investigator and site information where relevant (e.g., CV, medical licensure and Financial 
Disclosure for new sub-investigator, local laboratory information) 
 
 


 
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Regulatory documents may be sent to p9506@lists.cumc.columbia.edu or to the following address if wet 
ink originals are required: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
1. Central Registration Procedures- **Affiliate Institution Research Participant Registration 
Process**:  
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to any 
administration of study drug/intervention/local institution registration.  Please see instructions below: 
 
1.1 Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate Institution 
CRN and/or CRC is required to submit the following documents to the coordinating center’s 
designee (CUMC’s study specific Clinical Research Coordinator or Clinical Research Nurse).  The 
coordinating center’s designee will review the documents for accurateness, and subsequently submit 
the documents to the CPDM Central Registration Office via email at 
p9506@lists.cumc.columbia.edu, with a request to register the patient “pending eligibility.” The 
title of the email should read, “AAAP9506 Pending Subject Registration Request (PHI)”.  The 
following documents should be submitted with the pending registration request: 
• 
Redacted Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (i.e. tissue, DNA, etc.) as applicable 
• 
Redacted Signed HIPAA (or institutional equivalent) 
• 
MCT CPDM Demographics Note to File form  
 
1.2 The Affiliate Institution’s investigator/research nurse/data manager/coordinator must contact the 
coordinating center’s designee (CUMC’s study specific Clinical Research Coordinator or Clinical 
Research Nurse) via telephone or email to communicate the following: 
• 
Notify of pending registration request  
• 
Confirm method of registration request submission (email or fax) 
• 
Communicate expected time-line of registration request submission (i.e., same day, next day, within 
the hour, etc.) 
 
1.3 To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study specific 
designee: 
• 
A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
• 
Copies of redacted source documentation necessary for each item to be verified on the CUMC 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, serum chemistry, 
pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with providing 
source documentation of any other items needed for screening/eligibility that are not 
captured in other source document forms. (e.g., positive investigator statements of unique 
eligibility items not captured via other direct source documentation, concomitant medication 
lists, etc.) 
 


 
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Please note: subject line of email or fax should include the following: “AAAP9506 Complete Subject 
Registration Request (PHI)”. 
 
1.4 Upon receipt of the above mentioned documents, the designated study specific Clinical Research 
Coordinator will review all documents and verify patient eligibility.  If any questions arise during the 
review process, queries in the form of emails will be addressed to the applicable affiliate site study 
team personnel for clarification prior to enrollment.  Upon verification, the CUMC study specific 
designee will then forward all documents to the CPDM Central Registration Office for central 
registration (as described above). The CPDM Central Registration Registrar will review all 
applicable documents and communicate to the CUMC study specific designee in order to clarify any 
items.  The CUMC study specific designee will communicate with the applicable site study team 
personnel for additional clarifications necessary prior to enrollment. 
 
1.5 Upon receipt of the subject registration notification email, the CUMC study specific designee will 
forward the notification email (which will include the study specific patient ID) to the affiliate site’s 
Principal Investigator, Consenting Professional, and applicable research personnel.  This notification 
should be filed in the patient research binder accordingly. Protocol therapy may not be initiated prior 
to receipt of this notification from the coordinating center. 
 
1.6 All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be required 
within the corresponding submissions. 
 
2. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review and 
submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all entities prior to 
implementation at the Affiliate site.  If a prospective protocol deviation request is submitted for review (from 
an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and correspondence and CUMC IRB 
deviation approval letter(s)/correspondence should be forwarded to the Affiliate site for documentation. The 
Affiliate site is also required to obtain prospective local IRB approval as per institutional policies/procedures 
prior to implementing the proposed deviation. All documents and determinations must be clearly 
documented in the study subject’s medical record, research chart and regulatory binder, as described. Please 
note that the HICCC DSMC will no longer be approving deviations to eligibility criteria.  
 
 
3. Guidelines for Affiliate Site Monitoring  
 
3.1 On-Site MCT Monitoring:  
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate sites, as 
appropriate/feasible. Other sites will have monitoring performed remotely (see below for further 
details). 
• 
The study Monitoring Visit Log will be completed and signed by the monitor and 
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
 Principle Investigator to schedule the monitoring visit and arrange for access to study materials and    
 documentation. 
 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject is enrolled 
at the Affiliate site and throughout the life of the study to ensure that the study is being conducted in 
accordance with the protocol, GCP, applicable federal and local regulations, and per all applicable 


 
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SOPs. The Compliance Coordinator is responsible to notify the participating site PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and documentation will 
be required for the visit(s).  The Compliance Coordinator is responsible for verifying that informed 
consent is properly obtained, eligibility is met (via the central registration process), and all study 
procedures are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all toxicities have 
been reported to date, and that all SAE’s/UPs/deviations/violations have been reported according to 
Coordinating Center, local IRB and HICCC DSMC requirements. The Compliance Coordinator will 
issue queries and ensure resolution in a timely and efficient manner.  The Compliance Coordinator 
will also monitor for applicable regulatory compliance and research pharmacy compliance (if 
applicable) and communicate any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made 
available (if applicable) and before any subjects are enrolled on a study at the Affiliate site. 
 
3.2 MCT Remote Monitoring:  
 
1. 
When necessary (due to logistical constraints), Affiliate sites will be monitored remotely by a 
designated Compliance Coordinator. Sites will be informed of this remote monitoring process on a site by 
site basis. 
 
2. 
Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory level, as well as 
a clinical data/source documentation review level. 
 
3. 
Redacted source documents (applicable to supporting the protocol specific CRF data requirements) 
will be sent to the designated Compliance Coordinator via fax or secure email for all subjects enrolled at 
Affiliate sites. Timelines for submission procedures will be defined on a case-by-case basis.   
 
4. 
The Compliance Coordinator will review all submitted redacted source documents against the data 
entered on the protocol specific CRFs. The Compliance Coordinator will issue queries when/if necessary. 
 
5. The Affiliate site research staff will respond to queries within 30 days. If queries remain outstanding, 
the Compliance Coordinator will send a delinquent query reminder for the outstanding items. 
 
6. The remote monitoring procedures will include review of applicable redacted source documentation 
and supporting applicable documents to determine compliance regarding: 
• 
Informed consent procedures 
• 
Eligibility criteria 
• 
Protocol specific treatment compliance 
• 
Protocol specific toxicity/outcome documentation/compliance 
• 
Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, 
follow-up) 
• 
Participating site IRB documents (e.g., IRB amendment approvals, annual renewals, 
SAE/UP submissions, violation/deviation submissions, INDSR submissions, etc). 
• 
Required specimen submissions (e.g., tissue specimens, research blood specimens, 
etc.) 
• 
Pharmacy accountability records 
• 
Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
 
7. Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and Affiliate sites 


 
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after each remote monitoring review. Reports will include information regarding data submission 
timeliness/accuracy, protocol adherence items, query resolution status, regulatory status, and overall 
Affiliate site performance. These reports will be generated by the Compliance Coordinator and 
reviewed with the Compliance Core Manager prior to dissemination. 
 
 
  
 
 
4. Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be assigned a unique 
code number consisting of site number followed by a number with each new subject being assigned the next 
sequential number (e.g. 04-10). All sites will be required to enter their data in the Velos eResearch, the 
Clinical Trial Management System used for all Cancer-related clinical research at CUMC. All users must 
login with their own application username and password.  Users off campus must first access the Virtual 
Private Network with their assigned campus username and password and then use their application 
credentials.   
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP recommendations.  
 
Except when required by law, study information shared with persons and organizations outside of Columbia 
University Medical Center must not identify the patient by name, social security number, address, telephone 
number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical meeting, the patient 
not be identified. Otherwise, all results will be kept confidential and will not be divulged (except as required 
by law) without permission.  
 
Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and strong 
credibility when it comes to the discovery of new treatment concepts, implementation of new clinical 
research techniques, and acceptance of its researcher's findings by the medical establishment. In accord with 
these ethics, CUMC encourages and supports its investigators in the sharing of final research data and/or 
details of newly developed clinical treatments. 
 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state laws, and 
HIPAA privacy regulations. The primary reason for this is to protect the privacy of patients who participate 
in clinical trials. The data can be made available for continuing review by federal agencies upon request and 
for ongoing study safety reviews by the Principal Investigator, Statistician, Data Safety and Monitoring 
Board (DSMC), and, in other instances, the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other investigators and 
University staff, the IRB, FDA, and other reporting agencies, and/or transferred to other collaborators.  Prior 
to transfer, the data collected must comply with, and must be limited by, the CUMC's guidelines for 
Protecting the Rights and Privacy of Human Subjects.   
 
Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source documents 
and eligibility checklist. Velos eResearch will be used as the electronic clinical trials and data management 
system. Affiliate sites will enter data directly into Velos eResearch via customized case report forms for the 
study. The research staff will generate reports from Velos eResearch to ensure timely submission of data by 
affiliate sites. This resource allows for the timely analysis of particular data sets for safety analysis. 


 
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APPENDIX G: DRUG ORDER FORM 
 


 
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APPENDIX H: SKIN COLOR PHOTOGRAPHY 
 
In the case of patients with discrete skin lesions, one to three target lesions > 10 mm in size should be 
followed. Every 12 weeks (+/- 1 week), target lesion size should be documented using high quality color 
photography, placing a ruler next to the target lesion to accurately document size. If there are multiple target 
lesions, separate photographs for each lesion should be performed. Documentation should be submitted in 
the case report form.  
 
In patients with diffuse or patchy skin involvement (i.e. dermal involvement), the extent of involvement 
should be clearly demonstrated in photographs. Photographs should be taken from a consistent distance and 
angle from the patient.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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