Femara (Letrozole) Plus Ribociclib (LEE011) or Placebo as Neo-adjuvant Endocrine Therapy for Women With ER-positive, HER2-negative Early Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Qamar Khan

 
 
 
 
Femara (Letrozole) Plus Ribociclib (LEE011) or Placebo as Neo-adjuvant Endocrine 
Therapy for Women with ER-positive, HER2-negative Early Breast Cancer 
 
Document Date:  08/24/2018 
 
NCT Number: NCT02712723 

CONFIDENTIAL 
This material is the property of the University of Kansas Cancer Center.  Do not disclose or use except as 
authorized in writing by the study sponsor. 
 
 
 
 
Protocol:  CLEE011XUS10T 
 
Investigator-Initiated Trial 
 
 
Femara (Letrozole) Plus Ribociclib (LEE011) or Placebo as Neo-adjuvant Endocrine 
Therapy for Women with ER-positive, HER2-negative Early Breast Cancer 
 
The Feline Trial 
 
 
SPONSOR-INVESTIGATOR 
 
Qamar Khan, MD 
Department of Medicine, Division of Hematology and Oncology 
University of Kansas Medical Center 
Phone: 913-588-6029 
Fax: 913-588-4085 
Email: qkhan@kumc.edu 
 
 
 
Study Drug:  
Ribociclib (LEE011) 
 
IND Number:  
127673 
 
IND Holder Name: 
Qamar Khan, MD 
 
Initial Version:  
12-09-2015 
 
Modification Date: 
Version 2.0 – 03/02/2016 
 
 
 
Version 3.0 – 06/10/2016 
 
 
 
Version 3.1 – 08/17/2016 
 
 
 
Version 3.2 – 09/30/2016 
 
 
 
Version 4.0 – 01/04/2017 
 
 
 
Version 4.1 – 05/25/2017 
 
 
 
Version 5.0 – 08/24/2018   
 
 

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LIST OF KEY PERSONNEL 
 
LEAD INSTITUTION 
 
University of Kansas Medical Center 
3901 Rainbow Blvd 
Kansas City, KS  66160 
 
SPONSOR-INVESTIGATOR    
Qamar Khan, MD 
University of Kansas Medical Center 
3901 Rainbow Blvd 
Kansas City, KS  66160 
 
SUB-INVESTIGATORS  
Amanda Amin, MD 
Joshua Mammen, MD, PhD 
Anne O’Dea, MD 
Priyanka Sharma, MD 
 
CO-PI SURGICAL ONCOLOGY 
 
Jamie Wagner, DO 
University of Kansas Medical Center 
3901 Rainbow Blvd 
Kansas City, KS  66160 
 
CO- PI TRANSLATIONAL 
 
Cynthia X Ma, MD, PhD 
Washington University School of Medicine 
660 S. Euclid Ave, Campus Box 8056 
St. Louis, MO 63110 
 
PATHOLOGY AND LABORATORY MEDICINE 
 
Souzan Sanati, M.D. 
Washington University School of Medicine 
 
Kiran Vij, M.D. 
Washington University School of Medicine 
 
BIOSTATISTICIAN  
Francisco Diaz, PhD 
University of Kansas Medical Center 
 
 
 
 
 
 
 

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Sponsor-Investigator:  Qamar Khan, MD 
 
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Protocol Version 5.0:  08/24/2018 
 
 
LEAD INSTITUTION COMMUNITY SITES 
 
KU Cancer Center – Lee’s Summit 
4881 NE Goodview Circle 
Lee’s Summit, MO  64064 
913-574-2350 
 
KU Cancer Center - North 
8700 North Green Hills Road 
Kansas City, MO  64154 
913-574-2520 
 
KU Cancer Center – Overland Park 
12200 W. 110th St 
Overland Park, KS  66210 
913-574-2650 
 
KU Cancer Center - West 
8919 Parallel Pkwy., Suite 326 
Kansas City, KS  66112 
913-574-2620 
 
 
 
 
 
 
 
 
 
 

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Protocol Version 5.0:  08/24/2018 
 
 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing complete 
and timely information, as outlined in the protocol.  It is understood that all information pertaining 
to the study will be held strictly confidential and that this confidentiality requirement applies to all 
study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain 
the procedures required to carry out the study in accordance with accepted GCP principles and 
to abide by the terms of this protocol. 
 
Protocol Number:  CLEE011XUS10T 
Protocol Title:  Femara (Letrozole) Plus Ribociclib (LEE011) or Placebo as Neo-adjuvant 
Endocrine Therapy for Women with ER-positive, HER2-negative Early Breast Cancer 
Protocol Version and Date:  Protocol Version 5.0 dated 08/24/2018 
 
 
Investigator Signature _____________________________ _____ Date __________________  
 
 
Print Name and Title ___________________________________________________________ 
 
Site Number: 001 
 
Site Name: 
The University of Kansas Cancer Center / University of Kansas Medical Center 
 
 
 
Investigator Signature _____________________________ _____ Date __________________  
 
 
Print Name and Title ___________________________________________________________ 
 
Site Number: _____  
Site Name: 
________________________________________________________________  
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................................................................... 8 
STUDY SCHEMA ...................................................................................................................................................................... 9 
STUDY SUMMARY ............................................................................................................................................................... 10 
1.0 
BACKGROUND AND RATIONALE .............................................................................................................. 11 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................................................... 16 
3.0 
PATIENT ELIGIBILITY .................................................................................................................................. 17 
4.0 
TREATMENT ................................................................................................................................................... 21 
5.0 
STUDY CALENDAR: (CYCLE LENGTH IS 28 DAYS) ............................................................................... 30 
6.0 
STUDY PROCEDURES................................................................................................................................. 333 
7.0 
ADVERSE EVENTS ....................................................................................................................................... 366 

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8.0 
DRUG INFORMATION ................................................................................................................................ 411 
9.0 
SAMPLE COLLECTION AND STORAGE FOR FUTURE CORRELATIVE STUDIES ......................... 466 
10.0 
MEASUREMENT OF EFFECT ..................................................................................................................... 499 
11.0 
DATA AND SAFETY MONITORING ............................................................................................................ 50 
12.0 
REGULATORY CONSIDERATIONS .......................................................................................................... 511 
13.0 
REGISTRATION PROCEDURES ................................................................................................................ 522 
14.0 
STUDY MANAGEMENT ................................................................................................................................. 54 
15.0 
STATISTICAL CONSIDERATIONS .............................................................................................................. 54 
16.0 
SAMPLE SIZE JUSTIFICATION AND INTERIM ANALYSIS FOR FUTILITY .................................... 544 
17.0 
REFERENCES ................................................................................................................................................ 566 
18.0 
APPENDICES ................................................................................................................................................. 588 

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CLEE011XUS10T 
Sponsor-Investigator:  Qamar Khan, MD 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
cCR 
Clinical Complete Response 
CMP 
Comprehensive Metabolic Panel 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
Disease Free Survival 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
ER 
Estrogen Receptor 
hCG 
Human Chorionic Gonadotropin 
HER-2 
ERBB2 
IULN 
Institutional Upper Limit of Normal 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PEPI 
Pre-operative Endocrine Prognostic Index 
PFS 
Progression Free Survival 
PO 
per os/by mouth/orally 
PR 
Partial Response 
RFS 
Relapse Free Survival 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
US 
Ultrasound 
WBC 
White Blood Cells 
 
 
 
 
 
 
 

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Study Schema 
 
 
 
• 
*Randomized to 3 capsules/d 3 weeks on/1week off or 2 capsules/d continuous dosing 
(see Section 4.1 for details) 
• 
Research biopsies will be performed at baseline, at day 14 (+7d) and at surgery. 
• 
A Ki67 value of >10% at day 14 biopsy will result in discontinuation of the protocol 
therapy since this is an early indicator of endocrine resistance.  
• 
For the primary analysis, arms B and C will be combined vs arm A. 
 
 
 
 
 
 
 
 
 
 
ER+HER2-Breast 
Cancer
Clinical stage II,III
postmenopausal
B: Ribociclib 600 mg/d
3 weeks on/1 week off +
Letrozole 2.5mg/d x 6m
C: Ribociclib 400 mg/d
continuous dosing +
Letrozole 2.5 mg/d x 6m
A: Placebo* + 
Letrzole 2.5 mg/d x 6m
Primary 
Endpoint:
PEPI 0 at 
surgery
R1:1:1 

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Study Summary 
 
Title 
Femara (Letrozole) Plus  Ribociclib (LEE011) or Placebo as Neo-
adjuvant Endocrine Therapy for Women With ER+, HER2-negative Early 
Breast Cancer 
Short Title 
FELINE trial 
Phase 
II 
Methodology 
Placebo controlled randomized trial 
Study Duration 
26 months (Date of accrual of first subject to surgery date of last subject) 
Study Center(s) 
Multi-center 
Objectives 
To determine if ribociclib in combination with letrozole for 24 weeks as 
neoadjuvant endocrine therapy increases the proportion of women with 
PEPI score of 0 at surgery compared to patients treated with letrozole 
alone therefore allowing more patients excellent outcomes without 
chemotherapy.  
Number of Subjects 
120 (40 in each arm) - 6 subjects a month 
Diagnosis and Main 
Inclusion Criteria 
Stage II or III women with ER+, HER2-negative breast cancer 
Study Product(s), Dose, 
Route, Regimen 
Letrozole 2.5 mg PO daily; Ribociclib 600 mg PO daily 21 days on/7 
days off; Ribociclib 400 mg continuous daily dosing.  
Duration of 
Administration 
22 weeks 
Reference Therapy 
Letrozole 2.5 mg (control arm) 
Statistical Methodology 
In the ACOSOG Z1031 study, 16% of the patients in the letrozole alone 
arm had a PEPI score of 0. The sample size of this trial was determined 
with the assumption that 16% of the patients taking letrozole will have a 
PEPI score of 0.   Assuming that addition of ribociclib will increase the 
rate of PEPI 0 by 20%, 80 women in the two treatment arms (B+C) and 
40 women in the control arm (A) are needed to show significance. 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background: 
Breast cancer accounts for an estimated 232,670 of all cancer cases in 2014 with an estimated 
40,000 deaths in 2014 (Howlader 2011). The majority of breast cancer occurs in 
postmenopausal women, and 80% of cases are ER+ (Anderson 2002). Because the majority of 
patients are diagnosed with early stage disease and are ER+, this group accounts for a large 
percentage of breast cancer recurrences and deaths.   
 
Adjuvant therapy following surgery has significantly improved breast cancer outcome. In ER+ 
breast cancer, systemic chemotherapy followed by endocrine treatment with tamoxifen has 
been shown to decrease breast cancer mortality rate by one half (Early Breast Cancer Trialists' 
Collaborative 2011). Adjuvant aromatase inhibitors (AIs) in early stage breast cancer has further 
reduced the recurrence rate, however a significant number of patients experience recurrence of 
disease despite the current standard treatment. Using a median follow-up of 120 months, 
patients enrolled in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, experienced 
recurrence in 20% and 24% of patients treated with 5 years of adjuvant anastrozole and 
tamoxifen, respectively, with a persistent risk of relapse over time observed in both treatment 
arms [Cuzick 2010]. Thus, there is a need to improve the current standard therapy.  
1.2 
Rationale for neo-adjuvant endocrine therapy for early breast cancer:   
Despite the success of adjuvant therapy, evaluation of new agents in this setting has 
traditionally required large number of patients and years of follow up to demonstrate the 
effectiveness in reducing cancer relapse and/or mortality. Use of surrogate endpoints for 
disease free survival (DFS) and overall survival (OS) in the neo-adjuvant setting would allow 
drug screening and expedite the drug development process. Furthermore, response to neo-
adjuvant endocrine therapy may help clinicians to identify endocrine sensitive tumors that would 
not require adjuvant chemotherapy. In addition, the neoadjuvant setting has become an 
important research tool in studying mechanisms of endocrine resistance [Ellis 2004]. 
1.3 
Rationale for including stage II and stage III patients for neo-adjuvant endocrine 
therapy: 
Neoadjuvant endocrine trials of aromatase inhibitors have shown objective response rates of 
between 37% and 60% and conversion from mastectomy to BCS in up to 50% of patients [POL 
trial, IMPACT trial, P24 trial (below)].  In these studies, all of whom included women with clinical 
stage II and III, ER positive breast cancer, progression of disease on therapy occurred in <10% 
of patients. Thus, progression on an AI is an uncommon event.  
 
Many randomized trials of neo-adjuvant endocrine therapy using an AI have been completed 
and many such trials are ongoing. A summary of these is outlined below. All of these trials have 
included stage II and stage III patients and were approved by the respective regulatory 
authorities: 
 
POL trial (Olson 2009) was a single arm phase II trial of women with clinical stage II and stage 
III ER positive breast cancer in which 106 patients with good performance status were enrolled. 
Clinically node positive patients were included. Early (4 week) Ki67 of ≤10% was predictive of 
freedom from relapse. Only 1/41 patients who had a Ki67 of ≤10% at 4 weeks had a relapse 
with no adjuvant chemotherapy. Thus, on therapy Ki67 response to neo-adjuvant endocrine 
therapy predicts endocrine sensitive disease and therefore predicts relapse. Conversely, 
women with Ki67 of >10% had a RFS of 23% (5/21), indicating endocrine resistance.  
 

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In the IMPACT trial (Smith 2005, Dowsett 2007), patients with operable or locally advanced 
breast cancer including clinically node positive patients were included. Although clinical 
response was not predictive of RFS, 2 week Ki67 was. Patients who had Ki67 ≤10% at 2 weeks 
had a RFS of 11% (13/118), without adjuvant chemotherapy. Similar to the POL trial, RFS was 
26% if 2 week Ki67 was >10%.  
 
The P024 trial randomized patients with clinical stage II or III ER+ breast cancer to letrozole or 
tamoxifen in the neoadjuvant setting (Eiermann 2011). The primary endpoint was clinical 
response which was higher in the letrozole arm (55% vs 36%). No relapses were observed in 
patients with PEPI score of 0 (see section on PEPI below). In a combined analysis of POL and 
P24 trials, no relapse was observed in patients with a PEPI score of 0, after a FU of 62.5 
months.  
 
It is therefore clear that on-therapy assessment of short term Ki67 and of PEPI score at surgery 
is able to identify a group of women with clinical stage II or III breast cancer who have such a 
low relapse rate that they can consider foregoing adjuvant chemotherapy.  Moreover, these data 
establish that the benefits of neoadjuvant endocrine therapy are very similar to neoadjuvant 
chemotherapy, i.e., not only improving surgical outcomes (POL trial) and response rates (P024 
trial), but determining “on treatment” prognosis based on the response of the primary tumor to 
neoadjuvant therapy. Furthermore, the rather uncommon rate of clinical progression (<10%) in 
addition to the on therapy assessment of Ki67 and PEPI makes it a safe intervention for this 
group of women.  
 
The ongoing Alliance trial A011106 is a randomized trial of stage II and stage III ER positive 
breast cancer.  Sample size of this trial is 2820 patients. It includes stage II and stage III 
postmenopausal women (including T4 and clinical N3 disease), randomized to Anastrozole or 
Anastrozole + Fulvestrant. Short term Ki67 and PEPI scores are the main endpoints. This large 
trial designed by a co-operative group and approved by the regulatory authorities is a testament 
that neo-adjuvant endocrine therapy is considered a standard of care for this population.  
 
The NCCN guidelines Version 3.2015 states that preoperative endocrine therapy alone may be 
considered for receptor positive disease in postmenopausal women who have stage II and III 
breast cancer, including T4 and N3 disease. 
1.4 
Rationale for using letrozole as the standard arm: 
Neoadjuvant endocrine therapy with an AI such a letrozole has become a standard of care in 
postmenopausal women with ER+ breast cancer because of improvement in the rate of breast 
conserving surgery observed in previous neoadjuvant tamoxifen and aromatase inhibitor trials 
[Chia 2010]. In the letrozole P024 trial, 337 previously untreated ER+ and/or PR+ post-
menopausal breast cancer patients were randomized between 2.5mg of letrozole or 20mg of 
tamoxifen daily for 4 months followed by surgery (Eiermann 2011).  The clinical response rate 
was superior in the letrozole group (55% vs 36%, p<0.001).  The secondary endpoint, 
qualification for breast conserving surgery, was improved in the letrozole group (45% letrozole 
vs 25% tamoxifen, p=0.02). Furthermore, the reduction in proliferation marker Ki67 was greater 
with letrozole over tamoxifen (87% vs 75%, p=0.0009).  
1.5 
Study Agent (s) Background and Associated Known Toxicities: 
Ribociclib is an orally bioavailable highly selective small molecule inhibitor of CDK4/6.  CDK4/6 
induces G1 arrest in a variety of pRb positive cancer cells, in vitro.  In the mammalian cell cycle, 
entry into S phase is achieved by cyclin-dependent kinases 4 and 6 (CDK4/6) that activates a 
family of E2F transcription factors by phosphorylating and deactivating the retinoblastoma 

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protein (pRb).  Several lines of evidence suggest that increased CDK4/6 activity contributes to 
tumorgenesis. Agents that inhibit the activity of CDK4/6 may be able to slow or stop the 
proliferation of these cancers and thereby function as effective anti-cancer drugs.   
 
Elimination of ribociclib is dominated by oxidative metabolism mainly via CYP3A4 with a minor 
contribution by flavin-containing monooxygenase 3 (FMO3). The elimination of ribociclib may be 
affected by co-administered drugs that inhibit or induce CYP3A4. 
 
Based on its mechanism of action, the results of the preclinical toxicology studies and available 
clinical safety data as of September 10, 2014, the following are identified as the main adverse 
reactions for ribociclib: bone marrow suppression including leukopenia, neutropenia, anemia, 
and thrombocytopenia, renal toxicity, fatigue, nausea, vomiting, abdominal pain, diarrhea, 
pneumonia and prolongation of the QT interval. The risk of these toxicities may be amplified by 
concomitant administration of strong inhibitors of CYP3A4 or other combination treatments.  
1.6 
Rationale for combining CDK4/6 inhibitor ribociclib and letrozole: 
Ribociclib has shown activity in ER+ breast cancer and has been evaluated in combination with 
letrozole in phase I studies.  Tumor growth delay was seen in the letrozole plus ribociclib arm. 
 
Palbociclib is a CDK4/6 inhibitor, similar to ribociclib, being developed by Pfizer. In the phase II 
study, continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 
mg daily for 3 weeks followed by 1 week of rest until progression. Patients with postmenopausal 
ER+, HER2-negative advanced breast cancer were randomized in a 1:1 ratio in two parts, Part 
1 contained 66 patients and Part 2 had 99 patients. Data from the combination of both groups (n 
= 165) were present at the AACR meeting in 2014. The median PFS was 20 months with 
letrozole plus palbociclib compared with 10 months for letrozole alone (hazard ratio [HR] =0.5, 
p < .0004). The combination resulted in a response rate of 45% compared with 31% for the 
monotherapy. The overall clinical benefit rate was 70% versus 44%, for the combination and 
single-agent, respectively (Finn 2014)). 
 
Ribociclib has demonstrated in vivo anti-tumor activity in subsets of tumor xenograft models. 
Consistent with the compounds mechanism of action, efficacy was only observed in tumors 
expressing pRb. Tumor types where ribociclib has demonstrated robust anti-tumor activities 
include but are not limited to breast, melanoma, neuroblastoma, malignant rhabdoid, lung, 
pancreas and hematological malignancies (Ribociclib IB Edition 7, 9/10/2014). 
 
The combination of ribociclib with the nonsteroidal aromatase inhibitor letrozole was evaluated 
using a primary model of ER+ breast cancer derived from a patient tumor with a known 
sensitivity to letrozole (see Figure below). Tumor growth delay was seen in the letrozole plus 
ribociclib arm, confirming the potential for full stabilization with the double combination. These 
data provide strong rationale for the combination of CDK4/6 inhibitors with modulators of the 
estrogen receptor pathway such as letrozole (Ribociclib IB Edition 7, 9/10/2014). 
 

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In a phase Ib/II, multicenter, study, the combination of ribociclib with letrozole in adult patients 
with advanced ER+ breast cancer is being studied. Three arms (ribociclib + letrozole, BYL719 + 
letrozole, ribociclib + BYL719 + letrozole) are included in this study. The primary endpoints of 
the study are to estimate the MTD(s) and/or RP2D(s) for the 3 combinations. The phase Ib part 
is followed by a phase II part to compare the clinical efficacy of ribociclib + BYL719 + letrozole 
compared with ribociclib + letrozole or BYL719 + letrozole. The study is currently in the dose 
escalation phase Ib part. As of 28-Mar-2014, 17 patients have been enrolled: 10 have been 
treated with at least one ribociclib dose 600 mg PO daily (3-weeks-on/1-week-off) + 2.5 mg 
letrozole PO once-daily.  
 
The median age of 10 patients treated with ribociclib was 59 (range: 45–67) years, all the 
patients were female, and the distribution of ECOG performance status of 0/1 at baseline was 
5/5 patients, respectively. Among 10 patients treated with ribociclib, 2 patients were 
discontinued from the study due to progressive disease and 8 patients were still ongoing. 
Among 10 patients treated with ribociclib, the only grade 3 or 4 toxicity was neutropenia, which 
occurred in 50% of the patients.  
 
In addition to the intermittent dosing regimen, continuous dosing of ribociclib at 600 mg, 400 mg, 
and 300 mg has been evaluated in 18 patients. The median age of patients in continuous 
dosing schedule was 57 years. Male/female ratio was 5/13. Treatment has been discontinued in 
12 patients, only one discontinuation has been due to toxicity and remaining due to disease 
progression. A total of 5 events meeting the DLT criteria were observed in 5 patients and 
included grade 3 febrile neutropenia (n=1), grade 3 neutropenia (n=2), grade 4 neutropenia 
(n=1), grade 3 ALT increase (n=1). In the 5 patients receiving 400 mg continuous dosing, only 
one patient had grade 3 or 4 neutropenia. (Ribociclib IB Edition 8, 9/7/2015).  
 
Given that the safety and efficacy of letrozole is well-established, the 1:1:1 randomization 
(letrozole plus placebo vs. letrozole plus continuous dosing of ribociclib vs. letrozole plus 
intermittent dosing (3-weeks-on/1-week-off) of ribociclib) increases a patient’s opportunity of 

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receiving a potentially active combination. It also allows for the collection of more data from the 
two experimental arms to better evaluate the biological activity of treatment with ribociclib plus 
letrozole for future design of clinical trials.  
 
Ribociclib has mostly been studied with 3-weeks-on/1-week-off dosing (above). However, 
ribociclib is a cytostatic agent and there is potential for tumor escape during the off week. 
Continuous dosing will potentially prevent the potential for tumor escape. A lower dose of 
ribociclib, 400 mg will be used given the safety of this dose in the continuous fashion. This dose 
of 400 mg is less than 50% of the single agent MTD of ribociclib (900 mg 3 weeks on/1 week 
off). 
1.7 
Preoperative Endocrine Prognostic Index (PEPI) Score as a surrogate marker at 
surgery to identify women with excellent outcomes without adjuvant 
chemotherapy: 
Whereas pathologic complete response is an excellent surrogate biomarker of outcomes in 
women receiving neoadjuvant chemotherapy, the incidence of pCR is extremely low after 
neoadjuvant endocrine therapy and is not a useful marker (Calleoni 2004). Clinical response, 
which is measured by calipers or measuring tapes was the primary endpoint in the four major 
randomized neoadjuvant aromatase inhibitor (AI) studies conducted in postmenopausal women 
with stage II-III ER+ breast cancer, including the P024 trial (Letrozole vs Tamoxifen) [Eiermann 
2001], the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen 
(IMPACT) trial [Smith 2005], and the Pre-Operative "Arimidex" Compared to Tamoxifen 
(PROACT) trial [Catallioti 2006], which compared an AI to tamoxifen, and the recently reported 
ACOSOG Z1031 (letrozole vs anastrozole vs exemestane) that compared the three AIs [Ellis 
2011]. Secondary endpoints of these studies have included radiologic response and breast 
conservation rate. These endpoints are unsatisfactory since 1) measurement of clinical 
responses vary between individual examiners; 2) radiological response may not truly reflect 
tumor response; and 3) surgical outcome are impacted by bias and practice differences among 
surgeons. More importantly, clinical response rates did not correlate well with outcomes in the 
large IMPACT trial.  
 
The P024 trial randomized patients with clinical stage II or III ER+ breast cancer to letrozole or 
tamoxifen in the neoadjuvant setting.  The primary endpoint was clinical response which was 
higher in the letrozole arm (55% vs 36%). In a multivariable analysis conducted on this trial, 4 
post-neoadjuvant endocrine therapy tumor factors were determined to have independent 
prognostic value for relapse and death after relapse and are included in the PEPI score [Ellis 
2008]. These included pathological tumor size (T1/2 versus T3/4), pathological node status 
(positive or negative), the natural logarithm of the Ki67 value and the ER status of the tumor. A 
prognostic score, the preoperative endocrine prognostic index (PEPI), was developed, which 
weighs each of these factors according to their associated hazard ratios. PEPI was then 
validated in an independent data set from the IMPACT trial [Ellis 2008]. No relapses were 
recorded in either trial in patients with T1, N0 tumors with a PEPI score of 0 (residual tumor with 
Ki67 index of 2.7% - natural logarithm of 1- or less with maintained ER expression) or in the rare 
patient with a pCR. PEPI has also recently been validated in the POL Trial (PreOperative 
Letrozole trial: A multicenter phase II trial of letrozole in postmenopausal women with clinical 
stage II or III hormone receptor positive breast cancer) [Olson 2009]. In the combined analysis 
of P024 trial/POL trial, no relapse was observed with a median follow up of 61.3 months in the 
24 patients (16 pT1N0, 8 pT2N0) in the PEPI 0 category.  
 
Thus, with the above data, our primary objective is to determine if ribociclib in combination with 
letrozole as a 24 week neoadjuvant endocrine therapy increases the proportion of endocrine 
sensitive tumors with a PEPI score 0, compared to patients treated with letrozole alone. An 

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increase in the proportion of women with a PEPI score of 0 will increase the number of women 
with endocrine sensitive disease that would have excellent outcomes without receiving cytotoxic 
chemotherapy.  
1.8 
Rationale for day 14 biopsy for Ki67 assessment: 
One of the shortcomings of PEPI score is that although it is a robust predictor of outcome 
without adjuvant chemotherapy, PEPI information is only available at surgery, after neo-
adjuvant therapy is complete. Thus, there is a need for on therapy assessment of a marker that 
is able to identify endocrine sensitivity and resistance early on during neo-adjuvant endocrine 
therapy. Data from previous neoadjuvant endocrine trials indicate that 2-4 week tumor Ki67 
expression on endocrine therapy is predictive of individual patient outcome long term [Dowsett 
2007]. In the IMPACT trial, 2-week Ki67 was a significant independent predictor of RFS (HR = 
1.95; 95% CI = 1.23–3.07; P = .004) [Dowsett 2007]. The 5-year RFS rates were 85%, 75%, 
and 60% for the lowest, middle, and highest values of 2-week Ki67 expression, respectively. In 
addition, patients who had Ki67 of ≤10% at 2 weeks had a risk of recurrence of 11% (13/118), 
without adjuvant chemotherapy. Conversely the risk of recurrence was 26% if 2 week Ki67 was 
more than 10%. Similar to the IMPACT trial, early (4 week) Ki67 of ≤10% was predictive of 
relapse in the POL trial (Olson). Only 1/41 patients who had Ki67 of ≤10% had a relapse with no 
adjuvant chemotherapy. Thus, on therapy response to neo-adjuvant endocrine therapy predicts 
endocrine sensitive disease and therefore predicts relapse. Conversely, women with Ki67 of 
>10% had a RFS of 23% (5/21), indicating endocrine resistance. Day 14 determination of Ki67 
will allow us to detect breast tumors with endocrine resistance (Ki67 of >10%) early on toward 
the beginning of therapy. These patients will be offered immediate surgery or neo-adjuvant 
chemotherapy at the discretion of the treating oncologist.  
1.9 
Standard treatment options for the study population: 
Besides participation in this clinical trial, other options for women with stage II and III, ER+ 
breast cancer include standard neoadjuvant endocrine therapy with an aromatase inhibitor for 4-
6 months followed by surgery, primary surgery followed by adjuvant therapy, or neo-adjuvant 
chemotherapy followed by surgery.  
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective: 
• 
To determine if ribociclib in combination with letrozole as a 24 week neoadjuvant 
endocrine therapy increases the proportion of women with PEPI score of 0 at surgery 
compared to patients treated with placebo and letrozole therefore allowing more patients 
to have excellent outcomes without chemotherapy. 
2.2 
Secondary Objectives: 
• 
To determine if ribociclib in combination with letrozole as a 24 week neoadjuvant 
endocrine therapy increases the proportion of tumors with complete cell cycle arrest 
(defined below) compared to placebo and letrozole therefore increasing the number of 
women who would have excellent outcomes with endocrine therapy alone. 
 
• 
To determine if ribociclib in combination with letrozole for 24 weeks results in improved 5 
year RFS compared to letrozole alone. 
 
• 
To examine the differences in clinical, pathologic and radiologic response rates between 
the two ribociclib containing arms (combined) vs letrozole. An increase in response rate 

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with the addition of ribociclib will be an indication of synergistic activity of ribociclib when 
combined with letrozole and will help design future adjuvant trials. 
 
• 
To examine the difference in clinical, pathologic and radiologic response as well as PEPI 
scores between the three treatment arms. 
 
• 
To examine if short term Ki67 expression at 2 weeks and degree of Ki67 suppression 
compared to baseline differs between the two ribociclib containing arms (combined) vs 
letrozole. 
2.3 
Exploratory Objectives: 
• 
To evaluate tumor tissue, serum, and plasma specimens collected at baseline, on-
therapy, and at surgery for biomarker discovery (through methods such as gene 
expression profiling, DNA and RNA sequencing and proteomics) in studies that aim to 
understand signaling pathways associated with endocrine therapy sensitivity and 
pathways of resistance. 
2.4 
Primary Endpoint: 
• 
Rate of PEPI score 0 at surgery between ribociclib containing arms (combined) vs 
letrozole alone arm. PEPI score 0 is defined as: 
• 
pT stage 0, 1 or 2 at surgery, after 24 weeks of neoadjuvant therapy 
• 
Negative axillary lymph nodes present at surgery 
• 
Ki67 of ≤ 2.7% at surgery  
• 
Tumor is ER+ at surgery.  
2.5 
Secondary Endpoints: 
• 
Rate of complete cell cycle arrest at 2 weeks between ribociclib containing arms 
(combined) vs letrozole alone arm: Complete cell cycle arrest is defined as Ki67 at day 
14 of ≤ 2.7%.  
 
• 
Pathologic complete response rate (pCR rate): pCR rate is defined as the proportion of 
patients with no histologic evidence of invasive tumor cells in the surgical breast 
specimen and the axillary lymph nodes. 
 
• 
Clinical complete response rate (cCR rate): cCR rate is defined as the proportion of 
patients with no residual tumor by clinical exam.  
 
• 
5 year RFS 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria: 
Subjects must meet all of the inclusion criteria to participate in this study. 
3.1.1 Ability to understand and the willingness to sign a written informed consent 
3.1.2 Pathologically confirmed invasive breast cancer by core needle biopsy 
3.1.3 Female subjects, age ≥ 18 years. 

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3.1.4 Only postmenopausal women will be eligible. Subjects will be classified as being 
postmenopausal if they have had: 
• 
Bilateral surgical oophorectomy, or 
• 
No spontaneous menses > 1 year or 
• 
No menses for < 1 year with FSH and estradiol levels in postmenopausal 
range, according to institutional standards 
3.1.5 Performance Status ECOG 0-2 
3.1.6 Invasive breast cancer must be ER+ in ≥66 % of the cells or ER Allred score 6-8. If ER is 
positive in < 66%, the staining intensity (weak, intermediate, strong) is needed to 
calculate the Allred Score to determine eligibility. In institutions where ER expression is 
classified only by <1%, 1-10%, and >10% cut-offs, >10% expression is required for 
inclusion.   
3.1.7 Invasive breast cancer must be HER2 negative. HER2 negative is defined as a single 
test or both tests used to determine HER2 status (ISH and IHC) show: 
• 
IHC 1+ as defined by incomplete membrane staining that is faint/barely 
perceptible and within > 10% of the invasive tumor cells;  
• 
IHC 0 as defined by no staining observed or membrane staining that is 
incomplete and is faint/barely perceptible and within ≤ 10% of the invasive 
tumor cells 
• 
ISH single-probe average HER2 copy number < 4.0 signals/cell 
• 
ISH dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number 
< 4.0 signals/cell 
3.1.8 Documentation of mammogram, ultrasound and MRI of the ipsilateral breast all 
performed within 42 days prior to registration.  
3.1.9 Clinical T2-T4c, (by clinical measurement and/or breast imaging), any N, M0 invasive 
breast cancer, by AJCC 7th edition clinical staging, with the goal being surgery to 
complete excision of the tumor in the breast and the lymph node. For clinically node 
positive disease, any T is allowed.  Palpable breast primary is not required. 
Note:  
 
o Patients with contralateral invasive breast cancer are not eligible.  
o Patients with ipsilateral multifocal/multi-centric invasive breast cancer are eligible. 
The largest lesion will be evaluated for response assessment and calculation of 
PEPI score.  
o Patients with ductal carcinoma in situ in either breast are eligible.  
3.1.10 Tissue acquisition: Subject must agree to provide the required research biopsies at 
baseline, at day 14 (+7 d) and at surgery for biomarker and correlative studies. 
3.1.11 Subject has adequate bone marrow and organ function as defined by the following 
laboratory values at screening: 
• 
Absolute neutrophil count ≥ 1500 /uL 
• 
Platelets ≥ 100,000 /uL 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Potassium, total calcium (corrected for serum albumin), magnesium, sodium 
and phosphorus within institutional upper limit of normal (IULN) or corrected 
to within normal limits with supplements before first dose of study medication. 

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(Supplements used for this purpose to be approved by PI).  However, if the 
investigator believes the lab abnormalities are minor and clinically 
insignificant, the patient may be enrolled in the study. 
• 
INR ≤ 1.5 
• 
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50mL/min 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 
x ULN.   
• 
 Total bilirubin ≤ IULN; or total bilirubin ≤ 3.0 x IULN or direct bilirubin ≤ 1.5 
ULN in patients with well documented Gilbert’s Syndrome. 
3.1.12 Subject has fasting cholesterol panel and triglyceride done before first treatment 
3.1.13 Must be able to swallow ribociclib / placebo capsules 
3.2 
Exclusion Criteria: 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
3.2.1 Current use of other investigational agents. 
3.2.2 Inflammatory breast cancer defined as clinically significant erythema of the breast and/or 
documented dermal lymphatic invasion (not direct skin invasion by tumor or peau 
d’orange without erythema). 
3.2.3 An excisional biopsy of this breast cancer 
3.2.4 Surgical axillary staging procedure prior to study entry. 
Note: FNA or core needle biopsy of axillary node is permitted. 
3.2.5 Hormone replacement therapy of any type, megestrol acetate, or raloxifene within four 
weeks prior to first study treatment.  
3.2.6 Clinical or radiographic evidence of metastatic disease. Metastatic workup is not 
required. 
Note: isolated ipsilateral supraclavicular node involvement is permitted 
3.2.7 Treatment for this cancer including surgery, radiation therapy, chemotherapy, 
biotherapy, hormonal therapy or investigational agent prior to study entry. 
3.2.8 History of invasive breast cancer prior to the current diagnosis. 
3.2.9 Patient has a known hypersensitivity to any of the excipients of ribociclib or Letrozole. 
3.2.10 Patient has a concurrent malignancy or malignancy within 3 years prior to starting study 
drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer. 
3.2.11 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). 
3.2.12 Patient has a known history of HIV infection (testing is not mandatory). 
3.2.13 Patient has any other concurrent severe and/or uncontrolled medical conditions that 
would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate 
patient participation in the clinical study or compromise compliance with the protocol 

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(e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled 
fungal, bacterial or viral infections, etc.). Hepatitis testing at screening is not mandatory, 
but may be done per investigator discretion. 
3.2.14 Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered a major surgery). 
3.2.15 Patient with Child-Pugh score B or C 
3.2.16 Patient has a history of non-compliance to medical regimen or inability to grant consent. 
3.2.17 Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment. 
3.2.18 Patient is currently receiving warfarin or other coumarin-derived anticoagulant for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH) or fondaparinux is allowed 
3.2.19 Clinically significant, uncontrolled heart disease and/or recent events including any of the 
following: 
• 
History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis within 12 months prior to screening.   
• 
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• 
Documented cardiomyopathy 
• 
Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by 
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening 
• 
History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal 
arrhythmias, or conduction abnormality within 12 months of screening 
• 
Congenital long QT syndrome or family history of long QT syndrome 
• 
Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening 
• 
Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening.  
3.2.20 On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or 
not interpretable) or QTcF> 450 msec (using Fridericia’s correction). All as determined 
by screening ECG. 
3.2.21 Patient is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to starting study drug (APPENDIX B): 
• 
Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pomelos, star fruit, and Seville oranges 
• 
Those having a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5 
• 
Those having a known risk to prolong the QT interval or induce Torsades de 
Pointes  
• 
Herbal preparations/medications as listed in Appendix B 
3.3 
Staging Criteria: 
Subjects will be staged prior to registration according to the clinical staging criteria adapted from 
the American Joint Committee on Cancer (AJCC) Cancer Staging Data Forms of the AJCC 

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Cancer Staging Manual, 7th Edition, 2009. 
4.0 
TREATMENT 
4.1 
Treatment Dosage and Administration: 
 
Arm A (Control):  
 
 
Agent 
 
Dose and Route 
 
Day 
 
Schedule 
 
Letrozole 
 
2.5 mg daily by 
mouth 
 
Days 1-28 
Every 4 weeks 
x 6 cycles 
 
Ribociclib 
matching 
placebo 
(random 
assignment of 
placebo) 
3 capsules daily by 
mouth  
or 
2 capsules daily by 
mouth 
Days 1-21 
(21 days on, 7 days off) 
or  
Days 1-28  
 
 
Arm B (Experimental): 
 
 
Agent 
 
Dose and Route 
 
Day 
 
Schedule 
 
Letrozole 
 
2.5 mg daily by  
mouth 
 
Days 1-28 
Every 4 weeks 
x 6 cycles 
 
 
Ribociclib  
600 mg daily by mouth 
(3 capsules of 200 mg) 
Days 1-21 
(21 days on, 7 days off) 
 
Arm C (Experimental): 
 
 
Agent 
 
Dose and Route 
 
Day 
 
Schedule 
 
Letrozole 
 
2.5 mg daily by  
mouth 
 
Days 1-28 
Every 4 weeks 
x 6 cycles 
 
 
Ribociclib  
400 mg daily by mouth 
(2 capsules of 200 mg) 
Days 1-28 
 
 
 
• 
Protocol treatment to begin within 14 days of randomization 
• 
Each cycle is 28 days (+/-3 days) or 4 weeks, except cycle 6 (see below).  
• 
Surgery must be performed between days 8-22 of cycle 6.   
4.1.1 Ribociclib or Placebo must be taken as follows: 
• 
Subjects should be instructed to take the ribociclib/placebo capsules with a large 
glass of water (~250mL) at the same time each day. 

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• 
Ribociclib can be taken without regard to meals; however, dietary habits around the 
time of dosing should be as consistent as possible throughout the study. 
• 
Subjects should be instructed to swallow the ribociclib/placebo capsules whole and 
not to chew, crush or open them. 
• 
If vomiting occurs during the course of treatment, no re-dosing of the subjects is 
allowed before the next scheduled dose. 
• 
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. 
• 
Subjects must avoid consumption of grapefruit, Seville oranges, star fruit, pomelos, or 
products containing the juice of each during the entire study and preferably 7 days 
before the first dose of study medication, due to potential CYP3A4 interaction with the 
study medications. Orange juice is allowed. 
4.1.2 Letrozole should be taken at the same time each day with water.  
4.2 
Treatment assignment and randomization: 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled and is retained as the primary identifier for the subject throughout her 
entire participation in the trial. The Subject No. consists of the Center Number (Center No.) with 
a sequential subject number suffixed to it, so that each subject is numbered uniquely across the 
entire database.  
 
Subjects will be randomized 1:1:1 to one of three treatment arms (Section 4.1). Within the 
placebo arms, subjects will be randomized to either receive ribociclib placebo on days 1-21 or 
days 1-28 of each cycle. 
 
A randomization scheme (block of randomization numbers) will be sent to each affiliate site from 
the University of Kansas Biostatistics Department.  This will be maintained in a location 
accessible only to designated unblinded personnel OR unblinded pharmacist.  Subjects will be 
assigned to the next sequential number corresponding to the treatment assignment.  Only the 
affiliate site unblinded pharmacists will have access to the treatment assignment to maintain the 
blind.  The unblinded pharmacist will prepare and label the study medication in a blinded fashion 
for dispensing. 
4.3 
Schedule of evaluations: 
4.3.1 Tumor (breast and axilla) will be clinically assessed by measuring tape, ruler or caliper 
prior to the start of study treatment, every four weeks (+/- 3 days) during, and at the 
discontinuation of neo-adjuvant endocrine therapy. Bi-dimensional measurements 
should be obtained using the same technique (measuring tape, ruler or caliper) and if 
possible, by the same person at each evaluation. 
4.3.2 Mammogram, MRI and ultrasound of the diseased breast will be performed at baseline 
and a mammogram and ultrasound will be performed at completion of neoadjuvant 
therapy. A MRI of the breast at completion of treatment may be performed at the 
discretion of treating physician (surgeon).  
4.3.3 A core biopsy of the breast cancer will be performed on Day 14 (+7d) of cycle 1 and Ki67 
will be measured. If the Ki67 is expressed in >10% of the cells, subject will be taken off 
the study treatment and treatment will be provided at the discretion of the treating 
physician. See section 9 for details regarding details of specimen handling and 
turnaround time for this Ki67 measurement. Any chemotherapy administered prior to 

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surgery will be recorded. Tumor biopsies for research and Ki67 calculation at surgery 
will be performed per Section 6.5.3.  
4.3.4 MRI of the breast will be performed after completion of 2 cycles of treatment (Day 1 of 
cycle 3 (+/- 7 days) for response assessment. If there is evidence of progression on 
MRI, subject will be taken off the study and treatment will be provided at the discretion 
of the treating physician.   
4.3.5 If there is physical evidence for clinical progression with bi-dimensional measuring tape, 
ruler or caliper tumor measurements of the primary tumor an MRI should be done to 
confirm/rule out progressive disease. If there is physical evidence for clinical progression 
with clinical assessment of the lymph node mass, an ultrasound of the axilla should be 
done to confirm/rule out progressive disease.  
4.3.6 If progression is confirmed by MRI of the breast or ultrasound of axilla, subject will be 
taken off the study and treatment will be provided at the discretion of the treating 
physician, such as surgery as soon as possible or to begin other anti-neoplastic 
approaches such as chemotherapy.  
NOTE:  Other anti-neoplastic approaches such as chemotherapy or radiation must not 
be administered while the patient is taking study drug.  
 
4.3.7 Study drug should be continued until the day before surgery.  If immediate surgery is the 
decision, due to disease progression, collect the core biopsies (two frozen and two 
formalin fixed) and the correlative blood samples at the time of surgery. See section 9.  
4.3.8 If the subject is to discontinue her assigned neo-adjuvant therapy and go on to receive 
non-protocol treatment, correlative blood specimens and core biopsies (two frozen and 
two formalin fixed) should be obtained before discontinuing assigned neoadjuvant 
treatment. 
4.3.9 If disease progression is not confirmed by MRI of breast or US of axilla, study drug may 
be continued at the investigator’s discretion. 
4.3.10 Clinical progression outside the primary site (i.e., the development of a new breast mass 
or the development of clinical suspicion for advanced disease) should lead to further 
imaging evaluation and if confirmed, study drug will be discontinued after correlative 
samples of the primary tumor have been obtained. Subsequent management is at the 
investigator’s discretion.  
4.4 
Dose modifications and management of toxicity for Letrozole: 
There will be no letrozole dose reductions. If unanticipated grade 3 or 4 toxicity is 
encountered, which is considered at least possibly related to letrozole, the patient will be 
discontinued from letrozole therapy.  Missed doses of letrozole are not made up. 
4.5 
Dose modifications and management of toxicity for Ribociclib/Placebo: 
For severe adverse reactions the following dose reduction guidelines will be used:  
ARM B 
(Intermittent dosing arm) 
Ribociclib/Placebo 
Dose 
Number of capsules 
Starting dose 
600 mg 3 x 200 mg capsules 
First dose reduction 
400 mg 2 x 200 mg capsules 
Second dose reduction 
200 mg 1 x 200 mg capsule 
Discontinue  
NA 
NA 

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ARM C 
(Continuous dosing arm) 
Ribociclib/Placebo 
Dose 
Number of capsules 
Starting dose 
400 mg 2 x 200 mg capsules 
First dose reduction 
200 mg 1 x 200 mg capsule 
Discontinue  
NA 
NA 
 
If a patient discontinues ribociclib/placebo, she will continue on study taking letrozole 
alone.   
 
If a patient requires a temporary hold of study drug on Day 1 of a cycle, Day 1 will be 
delayed until patient restarts study drug.  There is no need to repeat all procedures listed 
for Day 1 in Section 5.0. 
 
4.5.1 Ribociclib/Placebo dose adjustment and management recommendation for related 
hematological adverse reactions:  
 
Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Thrombocytopenia 
Grade 1 
 (≥ 75,000 /uL) 
No dose adjustment required. 
Grade 2 
(50,000/uL - < 75,000/uL) 
Dose interruption until recovery to ≥ 75,000/uL. 
Re-initiate ribociclib/placebo at the same dose. 
Grade 3 
(25,000/uL - < 50,000/uL) 
Dose interruption until recovery to grade ≥ 
75,000/uL. 
Re-initiate ribociclib/placebo at the same dose 
level. 
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to ≥ 75,000/uL and reduce ribociclib/placebo to the 
next lower dose level. 
Grade 4 
(< 25,000/uL) 
Dose interruption until recovery to ≥ 75,000/uL.  
Re-initiate ribociclib/placebo at the next lower dose level. 
If toxicity recurs at grade 4: discontinue ribociclib. 
Absolute neutrophil count (ANC) 
Grade 1 
(≥ 1,500/uL) 
No dose adjustment required. 
Grade 2 
(1,000 - < 1,500/uL) 
No dose adjustment required. 
Grade 3 
(500 - < 1,000/uL) 
Dose interruption until recovery to > 1,000/uL. 
Re-initiate ribociclib/placebo at the same dose level. 
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to > 1,000/uL and reduce ribociclib/placebo dose to 
the next lower dose level. 
Grade 4 
(< 500/uL) 
Dose interruption until recovery to > 1,000/uL. 
Re-initiate ribociclib/placebo at the next lower dose 
level. 
If toxicity recurs at grade 4: temporary dose interruption until 
recovery to > 1,000/uL and reduce ribociclib/placebo at the 

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next lower dose level. 
Febrile neutropenia 
Grade 3 
ANC < 1,000/uL with a 
single temperature > 
38.3°C (101°F) or a 
sustained temperature of ≥ 
38°C (100.4°F) for more 
than one hour 
Dose interruption until ANC ≥ 1,000/uL and no fever. 
Restart at the next lower dose level. 
If febrile neutropenia recurs: discontinue 
ribociclib/placebo. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue ribociclib/placebo. 
Anemia (Hemoglobin) 
Grade 1 
(≥ 10 g/dL) 
No dose adjustment required. 
Grade 2 
(8 – 10 g/dL) 
No dose adjustment required. 
Grade 3 
(< 8 g/dL) 
Dose interruption until recovery to ≥ 8 g/dL. 
Re-initiate ribociclib/placebo at the same dose. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue ribociclib/placebo. 
 
4.5.2 Recommendations for Ribociclib/Placebo dose modification in case of related hepatic 
toxicities 
 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1  
> IULN – 1.5 x IULN (confirmed 48 to 72hrs later) 
Maintain dose level with LFTs monitored bi-weekly 
Grade 2  
> 1.5 – 3.0 x IULN 
Dose interruption of ribociclib/placebo 
If resolved to ≤ grade 1 in ≤ 21 days, maintain dose level 
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
reduce 1 dose level 
If toxicity recurs after two dose reductions, discontinue 
ribociclib/placebo 
Grade 3  
> 3.0 – 10.0 x IULN 
Dose interruption of ribociclib/placebo 
If resolved to ≤ grade 1 in ≤ 21 days, reduce 1 dose 
level  
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
discontinue ribociclib/placebo 
Grade 4  
> 10.0 x IULN 
Discontinue ribociclib/placebo 

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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 IULN) due to hemolysis or Gilbert Syndrome, pharmacologic treatment, viral hepatitis, 
alcoholic or autoimmune hepatitis, other hepatotoxic drugs. Hepatitis testing is not mandatory; to be done per 
investigator discretion. 
 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only. 
Bilirubin will be fractionated if elevated. 
 
 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
AST or ALT 
AST or ALT without bilirubin elevation > 2 x IULN 
Same grade as baseline or increase from baseline 
grade 0 to grade 1 (confirmed 48 to 72 hrs later) 
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or bi-weekly, in case 
of increase from baseline grade 0 to 1. 
Increase from baseline grade 0 or 1 to grade 2  
> 3.0– 5.0 x IULN 
or 
from baseline grade 2 to grade 3  
> 5.0 – 20.0 x IULN 
Dose interruption of ribociclib/placebo. 
If resolved to ≤ baseline value in ≤ 21 days, then 
maintain dose level 
If resolved to ≤ baseline value in > 21 days or toxicity 
recurs, then reduce 1 dose level 
If toxicity recurs after two dose reductions or recovery to ≤ 
baseline value is > 28 days, discontinue 
ribociclib/placebo 
Increase from baseline grade 0 or  
1 to grade 3  
> 5.0 – 20.0 x IULN 
Dose interruption of ribociclib/placebo until resolved to ≤ 
baseline value, then lower 1 dose level of 
ribociclib/placebo 
If recovery to ≤ baseline value is > 28 days, discontinue 
ribociclib/placebo 
If toxicity recurs, discontinue ribociclib/placebo 
Grade 4  
> 20.0 x IULN 
Discontinue ribociclib/placebo 
AST or ALT and concurrent Bilirubin 
AST or ALT ≥ grade 2  
> 3 x IULN in patients with normal values at 
baseline and total bilirubin > 2 x IULN 
Or 
AST or ALT ≥ grade 3  
> 5 x IULN in patients with grade 1 or 2 at baseline, 
and total bilirubin > 2 x IULN 
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 liver metastasis, and alcohol intake. 
 
4.5.3 Additional follow-up for related hepatic toxicities 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x IULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT. For patients with Gilbert Syndrome: total and direct 
bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin only. 

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Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
• 
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. 
• 
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. Hepatitis testing is not mandatory; to be done per investigator 
discretion. 
• 
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. 
 
4.5.4 Ribociclib/placebo dose adjustment and management recommendation for related non-
hematological adverse reactions  
Grade 
Dose Adjustment and Management Recommendations 
1 
No dose adjustment required. Initiate appropriate medical therapy and monitor. 
2 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor. 
Re-initiate ribociclib/placebo at the same dose. 
• 
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. 
3 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor. 
Re-initiate ribociclib/placebo at the next lower dose level. 
• 
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade ≤ 1 and reduce 
ribociclib/placebo dose to the next lower dose level. 
• 
If toxicity recurs at grade 3, discontinue ribociclib/placebo.  
4 
Discontinue ribociclib/placebo and treat with appropriate medical therapy. 
 
4.5.5 Dose modification guidance in case of QT prolongation  
Grade 
Dose Modification 
For all grades 
• 
Check the quality of the ECG  
• 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If 
below the lower limit of normal, 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 
1 
No dose adjustment required. 

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QTcF 450-480 ms 
2 
QTcF 481-500 ms 
Interrupt ribociclib 
Perform a repeat ECG one hour after the first QTcF of ≥481ms 
If QTcF <481 ms, restart ribociclib at the same dose. No dose adjustment 
required for the first occurrence 
• If QTcF remains ≥481 ms, repeat ECG as clinically indicated until the QTcF 
returns to <481 ms. Restart ribociclib at the same dose level. No dose 
adjustments required for first occurrence.  
• If QTcF ≥481 ms recurs, ribociclib should be reduced by 1 dose level (please 
refer to the dosing schedule table)  
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patient who has therapy interrupted due to QTcF ≥481 ms 
3 
QTcF ≥ 501 ms on at least two 
separate ECGs 
Interrupt ribociclib/placebo 
• 
Consider consulting a local cardiologist 
• 
Perform a repeat ECG one hour after the first QTcF of ≥501 ms. 
• 
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to < 481 ms. 
• 
If QTcF returns to < 481 ms, ribociclib/placebo should be reduced by 1 
dose level (please refer to the dosing schedule table). 
Repeat ECGs 7 days and 14 days after dose resumption for any patient who 
has therapy interrupted due to QTcF ≥ 501 ms 
• 
If QTcF of ≥ 501 ms recurs, discontinue ribociclib/placebo 
4 
QT/QTcF ≥ 501 or > 60 ms 
change from baseline 
and 
Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia 
Discontinue ribociclib/placebo 
• Obtain local cardiologist consultation 
• Perform a repeat ECG one hour after the first QTcF of ≥501 ms 
If QTcF remains ≥501 ms, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to <501 ms. 
  
4.5.6 Management of All Other Related Adverse Reactions: 
Consider performing an analysis of serum potassium, calcium, phosphorus, and 
magnesium, for all adverse reactions that are potentially associated with electrolyte 
imbalance (e.g. diarrhea, nausea/vomiting). If the electrolyte values are below the lower 
limit of normal, interrupt ribociclib administration, correct electrolytes with supplements 
as soon as possible, and repeat electrolyte testing until documented normalization of 
the electrolytes. 
4.6 
Surgery: 
4.6.1 Schedule: Surgery should be scheduled during days 8-22 of the 6th cycle of 
neoadjuvant endocrine therapy. Protocol therapy will be continued until the day before 
surgery.  
Note:  A surgical delay beyond the time frame described above, requires a discussion 
with the principal investigator or co-investigator. Given the subject population (older with 
co-morbid illnesses) it may be appropriate for a subject to remain on the endocrine 
agent to allow a delay in surgery to allow a recovery from inter-current illness for 
example. These issues will be dealt with on a case-by-case basis. 
4.6.2 Breast surgery: The type of breast surgery (either mastectomy or lumpectomy) is 
determined by the treating surgeon according to institutional standard, with the goal to 

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completely excise the tumor. A negative margin is required unless further excision is not 
possible. 
4.6.3 Lymph node surgery: The type of lymph node surgery (sentinel lymph node with or 
without axillary lymph node dissection) will be determined by the treating surgeon 
according to institutional standard. 
4.6.4 Surgical pathology report: Size of the breast tumor; number of lymph nodes examined 
and the number of positive by H&E staining; final tumor margins; and extent of surgery 
should be reported with submission of surgical and pathology reports. 
4.6.5 Required tissue sampling at surgery: Two core biopsies frozen in separate blocks 
and two formalin-fixed core biopsies should be obtained (preferred). Tumor samples 
may also be removed by dissection of the surgical specimen (not preferred) as long as 
the samples are frozen or fixed within 30 minutes of removal from the subject. In 
addition, slides for PEPI score will be collected from fixed surgical pathology tumor 
tissue blocks. 
4.7 
Postoperative chemotherapy: 
PEPI 0 Group: Adjuvant chemotherapy is not recommended. However, decision regarding use 
of adjuvant chemotherapy will be left to the discretion of treating physician. 
PEPI >0 Group: Adjuvant chemotherapy is recommended   at the discretion of treating 
physician and will be documented by online data submission. Subject may participate in other 
adjuvant clinical trials.  
4.7.1 Postoperative endocrine therapy 
In subjects who received adjuvant chemotherapy, adjuvant endocrine therapy is to be 
administered within 2-8 weeks of the completion of adjuvant chemotherapy based on 
evaluation of chemotherapy related toxicities. 
 
In subjects for whom adjuvant chemotherapy is not planned, adjuvant endocrine 
therapy is to be administered within 2-8 weeks postoperatively. 
 
 

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5.0 
Study Calendar: (Cycle length is 28 days) 
 
 
ScreeningA 
 
Prior to 
start of 
study 
treatment 
Day 14 
of 
Cycle 1 
(+7 
days) 
Day 1 
of 
Cycles 
2-6 
(+/-3 
days) 
Day 1 
of 
Cycle 3 
(+/- 7 
days) 
EOT 
Days 
8-22 of 
Cycle 6 
EOT  
(any 
reason 
other than 
treatment 
completion) 
SURGERY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 8-22 
of Cycle 6 
 
See 
section 5.1 
for post-op 
follow-up 
 
Research 
biopsies 
will be 
obtained at 
surgery (G) 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
Physical Exam 
(including vitals, height 
& weight) 
X 
 
 
X 
 
 
X 
Prior & Concomitant 
MedicationsJ 
X 
 
 
X 
 
 
X 
Performance Status 
X 
 
 
X 
 
 
X 
Adverse Event 
Assessment 
X 
 
 
X 
 
 
X 
CBC, CMP, PT/INR 
X 
 
 
X 
 
XI 
X 
Magnesium, 
Phosphorus 
X 
 
 
 
 
 
 
Fasting Lipid Profile 
X 
 
 
XE 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
X 
Measurement of breast 
lesionsB 
X 
 
 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Drug dispensing 
 
X 
 
X 
 
 
 
Drug compliance 
assessment 
(Participant Pill Diary 
Review) 
 
 
 
X 
 
 
X 
Mammogram, US of 
breast/axillary  masses 
XC 
 
 
 
 
X 
X 
MRI breast 
X 
 
 
 
X 
XH 
X 
ECG  
X 
 
 
X 
 
 
 
Echocardiogram 
 XF 
 
 
 
 
 
 
Tumor Biopsies 
XD 
 
XD 
 
 
XG 
XG 
Research blood 
samples 
XD 
 
 
 
 
X 
X 
 
See footnotes below 
 
 

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A. No more than 21 days prior to registration 
B. Using a standard cm calibrated caliper, measuring tape or ruler, the longest axis and the perpendicular axis 
of the tumor are to be measured and recorded in metric notation. Baseline evaluation should be done no 
more than 21 days prior to initiation of study therapy. 
C. Baseline mammogram, MRI and ultrasound of the diseased breast must be completed within 42 days of 
registration. MRI must include bi-dimensional breast tumor measurements. Mammogram of the contralateral 
breast is required to be within 12 months unless a mastectomy was performed. If a subject cannot have an 
MRI for any reason they will still be able to enroll.  US and mammogram alone will then be used for tumor 
assessments.  
D. Pre-treatment core biopsies and research blood sample for correlative studies are required prior to the 
initiation of protocol therapy. Samples obtained at the time of diagnosis before registration may be submitted 
if they were collected according to the tissue acquisition instructions outlined in protocol (Section 9). It is 
advised that the baseline samples are harvested during ultrasound guided clip placement (section 9).  A 
core biopsy will also be performed on day 14 and Ki67 will be calculated. If more than 10% of the cells 
express Ki67, subject will be removed from the study.  
E. Fasting Lipid Profile at Screen and Cycle 4 only. 
F. 
ECHO at screening and as clinically indicated throughout dose administration 
G. Required research tumor tissue biopsies will be obtained at the time of surgery. Sample submission for Ki67 
and correlative studies is required (Section 9). Calculation of PEPI score is described in Section 2.4) 
H. May be obtained at the discretion of the surgeon.  
I. 
CBC only 
J. 
Concomitant medications will be reviewed at each study visit, only prohibited concomitant medications will 
be entered into the CRFs 
 
5.1 Post-Operative Study Calendar 
 
Post-Op 
1-4 
weeks 
 
Post-Op 2-
8 weeks 
Every 6 
mo Years 
1-5F 
Once per 
year 
Years 1-5 
Medical 
History/Demographics 
X 
 
 
 
Clinical Breast Exam 
X 
 
X 
 
Physical Exam (including 
vitals, height & weight) 
X 
 
 
 
Prior & Concomitant 
MedicationsG 
X 
 
 
 
Performance Status 
X 
 
 
 
Adverse Event 
Assessment 
X 
 
 
 
Adjuvant Therapy 
 
XA, C 
 
 
Endocrine Therapy 
 
XB 
 
 
Adjuvant Radiation 
 
XD 
 
 
Mammogram 
 
 
 
XE 
 
A. Adjuvant therapy should begin 2-8 weeks following the last surgery date. 
B. Standard adjuvant endocrine therapy of treating physician’s choice is administered for 4.5 years. 
Participation in other adjuvant trials is permitted. 
C. The choice and regimen of adjuvant chemotherapy is at the discretion of the treating physician. Participation 
in other adjuvant trials is permitted 
D. Administration of whole breast radiation, rather than partial breast or brachytherapy, is recommended for 
patients in whom adjuvant radiation is indicated. 
E. Patients with breast tissue remaining will undergo annual mammograms of both breasts. 
F. 
The timing of the office visit and imaging is also documented if recurrence is suspected. 

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G. Concomitant medications will be reviewed at each study visit, only prohibited concomitant medications will 
be entered into the CRFs 
 
 

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6.0 
 STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures: 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening procedures include: 
6.1.1 Informed Consent 
6.1.2 Medical history 
Complete medical, surgical and oncology history is obtained at screening. Any changes from 
Screening (e.g. worsening severity or abnormal findings) are considered to be adverse events 
(AEs). 
6.1.3 Demographics 
Demographic profile will include date of birth, gender, race, and zip code. 
6.1.4 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for study 
entry. 
6.1.5 Review previous and concomitant medications 
All prior medication taken by the subject within 4 weeks before starting the study is to be 
recorded. Concomitant medications taken by the subject during the study are to be recorded up 
until 30-days after last study dose. If a reportable adverse event (see Section 7) occurs within 
30-days after last study dose, recording of concomitant medications should continue until 
resolution of the adverse event. 
6.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, blood pressure), height, weight 
6.1.7 Performance status (APPENDIX A):  Performance status evaluated prior to study entry 
6.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
6.1.9 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), and 
differential. 
6.1.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), 
glucose, total bilirubin, magnesium, and phosphorus. PT/INR. 
6.1.11 Serum fasting lipid panel 
6.1.12 Urinalysis 
6.1.13 Tumor Biopsies for research:  See Section 9.0 for details 

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6.1.14 Blood draw for correlative studies:  See Section 9.0 for details. 
6.1.15 Tumor assessment 
• Using a standard cm calibrated caliper, measuring tape or ruler, the longest axis and 
the perpendicular axis of the tumor are to be measured and recorded in metric 
notation. Baseline evaluation should be done no more than 21 days prior to initiation 
of study therapy. 
• Baseline mammogram, MRI and ultrasound of the diseased breast must be 
completed within 42 days of registration. MRI must include bi-dimensional breast 
tumor measurements. Mammogram of the contralateral breast is required to be 
within 12 months unless a mastectomy was performed. 
6.1.16 Other:  ECG, Echocardiogram.  
6.2 
Day 14 (+7 days) of Cycle 1 (28 day cycle): Tumor Biopsies for research and 
calculation of Ki67. 
6.3 
Day 1 (+/-7 days) of Cycle 3 (28 day cycle): MRI of the breast for response 
assessment. 
6.4 
Days 1 (+/-3 days) of Cycle 2-6 (28 day cycle): 
6.4.1 Physical exam including vital signs, height and weight 
6.4.2 Performance status (APPENDIX A): Performance status evaluated at every cycle. 
6.4.3 Adverse event assessment:  See Section 7 for AE monitoring and reporting. 
6.4.4 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.4.5 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin. PT/INR 
6.4.6 Urinalysis 
6.4.7 Serum fasting lipid profile (Cycle 4 only) 
6.4.8 Tumor assessment 
Using a standard cm calibrated caliper, measuring tape or ruler, the longest axis and 
the perpendicular axis of the tumor are to be measured and recorded in metric notation.  
6.4.9 Drug compliance assessment (Participant Pill Diary Review): Letrozole and 
ribociclib/placebo medication diary is to be used.  
6.4.10 Echocardiogram, when clinically indicated 
6.4.11 Special consideration at the beginning of cycle 6: In order for the blood counts to be 
adequate for surgery and for the importance of continuing therapy until the last day prior 
to surgery (for accurate Ki67 assessment), ANC should be ≥1500/uL and platelet count 
should be ≥100,000/uL on day 1 of cycle 6. If ANC is <1500 and platelet count is < 
100,000 on day 1 of cycle 6, resumption of cycle 6 will be delayed until the recovery of 
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treating physician for ANC <1500 to help with the recovery of the counts at surgery.  
6.5 
At completion of study treatment – (Days 8-22 of Cycle 6): 
6.5.1 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.5.2 Tumor assessment 
Mammogram and ultrasound of the diseased breast. MRI may be obtained at the 
discretion of the surgeon and must include bi-dimensional breast tumor measurements. 
6.5.3 Tumor Biopsies at surgery for research and calculation of Ki67 and PEPI score 
See Section 9.0 for details. Required research tumor tissue biopsies can be obtained at 
the time of surgery. Sample submission for Ki67 and correlative studies is required. 
Calculation of PEPI score is described in Section 9. 
6.5.4 Blood draw for correlative studies:  See Section 9.0 for details. 
6.6 
Discontinuation of therapy for reasons other than treatment completion 
See Section 6.8 
6.6.1 Physical exam including vital signs, height and weight 
6.6.2 Performance Status 
6.6.3 Adverse event assessment:  See Section 7 for AE monitoring and reporting. 
6.6.4 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.6.5 Serum chemistries 
Comprehensive metabolic panel (CMP) to include:  albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin.  PT/INR. 
6.6.6 Urinalysis 
6.6.7 Tumor assessment 
Using a standard cm calibrated caliper, measuring tape or ruler, the longest axis and the 
perpendicular axis of the tumor are to be measured and recorded in metric notation. 
Mammogram, ultrasound, and MRI of the diseased breast.  MRI must include bi-
dimensional breast tumor measurements 
6.6.8 Drug compliance assessment (Subject Pill Diary Review):  letrozole and 
ribociclib/placebo.  Medication diary is to be used.  See APPENDIX F. 
6.6.9 Tumor Biopsies at surgery for research and calculation of Ki67 and PEPI score 
See Section 9.0 for details.  Required research tumor tissue biopsies can be obtained at 
the time of surgery.  Sample submission for Ki67 and correlative studies is required.  
Calculation of PEPI score is described in Section 9. 
6.6.11 Blood draw for correlative studies:  See Section 9.0 for details. 

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6.7 
Follow-Up: 
Subjects who have been registered to the study and signed a consent form, but have withdrawn 
consent prior to receiving any study therapy will be considered a cancellation. No further follow-
up is required. 
 
Subjects who discontinue their assigned neoadjuvant therapy due to progression, treatment 
refusal, intolerable toxicity, desire for alternative non-protocol therapy or other trials, or are 
unable/unwilling to undergo surgery will enter the follow-up phase of the study. 
 
After the completion of neoadjuvant endocrine therapy and surgery, subjects will enter the 
follow-up phase of the study, where they will undergo disease evaluations every 6 months of 
years 1-5. 
6.8 
Removal of Subjects from Study Treatment and Study: 
Subjects can be taken off the study treatment and/or study at any time by their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
6.8.1 Subject voluntarily withdraws from treatment (subject agrees to follow-up)  
6.8.2 Subject withdraws consent (termination of treatment and follow-up) 
6.8.3 Subject is unable to comply with protocol requirements 
6.8.4 Subject demonstrates disease progression  
6.8.5 Subject experiences toxicity that makes continuation in the protocol unsafe 
6.8.6 Treating physician judges continuation on the study would not be in the subject’s best 
interest 
6.8.7 Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
6.8.8 Lost to follow-up. 
If a research subject cannot be located to document survival after a period of 2 years, 
the subject may be considered “lost to follow-up.” All attempts to contact the subject 
during the two years must be documented. 
7.0 
ADVERSE EVENTS 
7.1 
Definitions: 
7.1.1 Adverse Event [21 CFR 312.32(a)]  
An adverse event means any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use 
in combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
 

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This study will use the descriptions and grading scales from Common Terminology 
Criteria for Adverse Events version 4.03 (CTCAE v4.03) for hematologic and non-
hematologic toxicities.  Detailed information may be found on the Cancer Therapy 
Evaluation Program (CTEP) website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Information for adverse events, whether reported by the subject, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported in the CRF as described in the following sections.  
 
Adverse events experienced by subjects will be collected and reported from initiation 
of study medication, throughout the study, and within 30 days of the last dose of 
protocol therapy.  Subjects who experience an ongoing adverse event related to a 
study procedure and/or study medication beyond 30 days will continue to be contacted 
by a member of the study team until the event is resolved, stabilized, or determined to 
be irreversible by the principal investigator. Study subjects should also be instructed to 
report any new serious post-study event(s) that might reasonably be related to 
participation in this study. 
 
Medical conditions/diseases, or cancer related symptoms present before starting study 
treatment are considered adverse events only if they worsen after initiation of study 
drug. Adverse clinical events occurring before starting study drug but after signing the 
informed consent form are to be recorded on the CRF where Medical History/Current 
Medical Conditions are recorded. All cancer-related symptoms that have occurred in 
the last 30 days prior to start of study drug must also be recorded on the CRF. 
  
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, or require therapy.  In this case they will be recorded on 
the Adverse Events CRF, along with the associated signs, symptoms or diagnosis. 
As far as possible, each adverse event will also be described by: 
• 
its duration (start and end dates) 
• 
grading of severity 
• 
its relationship to the study drug 
• 
the action(s) taken 
• 
outcome 
7.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.  
 
Suspected adverse reactions are the subset of all adverse events for which there is a 
reasonable possibility that the drug caused the event. Inherent in this definition, and in 
the requirement to report suspected adverse reactions, is the need for the sponsor to 
evaluate the available evidence and make a judgment about the likelihood that the 
drug actually caused the adverse event.  
 
Factors to be considered in assessing the relationship of the adverse event to study 
drug include: 

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• 
The temporal sequence from study drug administration: The event should occur 
after the study drug is given. The length of time from study drug exposure to 
event should be evaluated in the clinical context of the event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Subject’s response after drug discontinuation (de-challenge) or 
subject’s response after study drug re-introduction (re-challenge) should be 
considered in the view of the usual clinical course of the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated 
in the context of the natural history and course of the disease being treated and 
any other disease the subject may have. 
• 
Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of 
them may be suspected to cause the event in question. 
• 
The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test drug(s), 
coupled with the individual subject’s pharmacodynamics should be considered. 
 
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Possible – The AE may be related to the study treatment.  
• 
Probable – The AE is likely related to the study treatment. 
• 
Definite – The AE is clearly related to the study treatment. 
7.1.3 Unexpected [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected," as used in this definition, also 
refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
 
This definition relies entirely on a listing of the adverse events or suspected adverse 
reactions in the investigator brochure as the basis for determining whether newly 
acquired information generated from clinical trials or reported from other sources is 
unexpected. This means that events not listed for the particular drug under 
investigation in the investigator brochure are considered “unexpected” and those listed 
are considered “expected.”  When new adverse event information is received, it is the 
sponsor’s responsibility to determine whether the event is “unexpected” for safety 
reporting purposes. 
7.1.4 Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: Death, 
a life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 

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medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject or the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.5 Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
7.2 
Reporting Requirements for Adverse Events: 
7.2.1 Submitting Serious Adverse Events Reports to IRB 
For serious adverse events, the clinical research site will follow local IRB policies and 
procedures.  
7.2.2 Study Investigator Notification of Adverse Events 
All expected and unexpected serious adverse events occurring after the subject has 
signed the informed consent and has started protocol treatment must be reported to the 
study principal investigator within 24 hours of becoming aware of the event: 
PI Name: Qamar Khan 
Office Phone: 913-710-6387 
Fax: 913-588-4085 
Email: qkhan@kumc.edu 
7.2.3 DSMC Notification of SAEs 
All expected and unexpected serious adverse events occurring after the subject has 
signed the informed consent and has started protocol treatment must be reported by 
phone or email to the KUCC DSMC within 24 hours of becoming aware of the event to: 
KUCC DSMC 
Email: kucc-dsmc@kumc.edu 
 
A follow-up written report in the form of MEDWATCH Form FDA 3500A is required 
within 5 days. 
7.2.4 Reporting to Novartis:  To ensure subject safety, every SAE, regardless of suspected 
causality, occurring after the subject has provided informed consent and until at least 30 
days after the patient has stopped study treatment must be reported to Novartis within 
24 hours of learning of its occurrence. 
MEDWATCH Form FDA 3500A must be faxed to: 
Novartis Drug Safety and Epidemiology Safety Desk  
877-778-9739 
Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study treatment. Recurrent 
episodes, complications, or progression of the initial SAE must be reported as follow-up 
to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a 
new event. 

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If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, an 
oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may 
urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
7.2.5 Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the Novartis study treatment of 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
7.2.6 Recording Adverse Events and Documentation in eVELOS 
All expected and unexpected adverse events and serious adverse events occurring 
after the subject has signed the informed consent and has started protocol treatment 
must be fully recorded in the subject’s case record form. 
 
All AEs and SAEs regardless of causality must be entered in the KU implementation of 
eVELOS, (also often called the Comprehensive Research Information System [CRIS]).  
All SAEs regardless of causality must be entered into eVELOS within 24 hours.  
Unexpected and expected adverse events must be entered within 15 days and include:  
new unexpected adverse events; worsening baseline conditions; clinically significant 
laboratory findings; disease-related signs and symptoms that were not present at 
baseline, and any event or findings that the Investigator feels is clinically significant. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator, should be reported as an adverse event.  Each event 
should be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
7.2.7 Reporting of Unexpected, Related SAEs for Concomitant Medications 
For concomitant medications, all unexpected, related serious adverse experiences will 
be forwarded to the product manufacturer by the investigator using the Voluntary 
MEDWATCH Form FDA 3500A. 

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7.2.8 Summary of Expedited Serious Adverse Event Reporting 
 
Relationship 
to Study 
Drug 
KUCC 
DSMC 
 
IRB 
Novartis 
PI 
Velos 
Unexpected 
SAE 
Related 
24 hrs 
Follow local 
IRB reporting 
requirements 
24 hrs 
24 hrs 24 hrs 
Unexpected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 24 hrs 
Expected 
SAE 
Related 
24 hrs 
24 hrs 
24 hrs 24 hrs 
Expected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 24 hrs 
 
8.0 
DRUG INFORMATION 
8.1 
Letrozole (Please refer to package insert for more comprehensive information): 
• 
Other names for the drug(s): Femara 
• 
Classification - type of agent: Non-steroidal aromatase inhibitor 
• 
Mode of action: In postmenopausal women, the principal source of circulating estrogen 
(primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by 
aromatase in peripheral tissues, such as adipose tissue, with further conversion of 
estrone to estradiol. Many breast cancers also contain aromatase; the importance of 
tumor-generated estrogens is uncertain.  
• 
Letrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly    
lowers serum estradiol concentrations and has no detectable effect on formation of 
adrenal corticosteroids or aldosterone. 
• 
Storage and stability: Controlled room temperature 
• 
How supplied: 2.5 mg tablet 
• 
Route of administration for this study: Oral (non-liquid only). Take with or without food. 
• 
Potential drug interactions: Letrozole is generally safe to administer with other 
medicines. However, concomitant use of agents and herbal products that alter ER 
function are specifically not allowed. 
• 
Availability: Provided by Novartis 
• 
Side effects: Hot flashes, asthenia, arthritis, pain, pharyngitis, HTN, depression, nausea, 
vomiting, rash, osteoporosis, fractures, headache, bone pain. 
8.2 
Ribociclib: 
Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that 
potently induces G1 arrest with sub-micromolar IC50’s in a variety of pRb-positive cancer cells. 
• 
Other names for the drug(s): LEE011 
• 
Classification: CDK4/6 inhibitor 
• 
Non-clinical pharmacology: 
• 
In Jeko-1 MCL cells that overexpress cyclin D1 as a result of the t (11; 14) chromosomal 
translocation, ribociclib inhibits the phosphorylation of pRb at CDK4/6-specific sites with 
an average IC50 of 60 nM. In nude rats bearing Jeko-1 subcutaneous xenografts, 
ribociclib demonstrates dose-dependent target inhibition in the tumors. Ribociclib doses 
that induce >75% inhibition of pRb phosphorylation in this model are associated with 
complete tumor regression. Ribociclib also inhibits the growth of many other tumor cell 
types in vitro and in vivo, including liposarcoma, melanoma, rhabdoid cancer, and 

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carcinomas of the esophagus, breast, lung and pancreas. 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 pRb. Refer to Ribociclib (LEE011) 
Investigators Brochure for more details.  
• 
Preclinical data with ribociclib in a primary model of ER+ breast cancer demonstrated 
synergy when given in combination with letrozole, showing complete and sustained 
inhibition of tumor growth (Figure below). 
 
Figure: Ribociclib in combination with letrozole in an ER+ primary breast cancer model 
 
 
Mean tumor volumes in mice treated at clinically relevant doses for 56 days with ribociclib (75 
mg/kg qd) alone; letrozole (2.5 mg/kg qd) alone; ribociclib (75 mg/kg qd) plus letrozole (2.5 
mg/kg qd); or vehicle. The combination arm shows complete inhibition of tumor growth that was 
sustained for more than 30 days of post-treatment observation. 
 
Nonclinical pharmacokinetics and metabolism: 
The pharmacokinetics (PK) of ribociclib was investigated in mouse, rat, dog and monkey. The 
absorption of ribociclib after oral administration was moderate for rats (48-84%). Oral 
bioavailability (BA) ranged between 10% and 65% across animal species. Time to maximum 
plasma drug concentration (Tmax) was between 2 and 4 hours. Terminal half-life (T1/2) of 
ribociclib was moderate in rodents and monkeys (~2-5 hours), and was longer in dogs (18 
hours). Ribociclib is moderately bound to plasma proteins in all animal species with unbound 
fractions in plasma (fu) ranging from 20-34% (human fu = 30%). [3H]Ribociclib and metabolites 
were extensively distributed to tissues in male rats, but there was no uptake into the brain. In 
vitro metabolism studies showed that oxidative metabolism of ribociclib is dominated by 
CYP3A4 with a minor contribution of about 20% by flavin-containing monooxygenase 3 (FMO3). 
In rat ADME studies, ribociclib was predominantly excreted in the bile as metabolites, with 
limited excretion of unchanged drug in urine. The bulk of the administered dose (87%) was 
excreted within 24 hours. LEQ803 (N-demethylation) is a prominent metabolite in rat, monkey, 
and human hepatocytes, and the only metabolite in dog hepatocytes. LEQ803 is weakly 
pharmacologically active; however, it interacts with hERG channels in vitro. 
 

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Ribociclib is a time-dependent CYP3A4 inhibitor (KI = 5.1 μM, kinact = 0.0245 min-1) and a 
reversible inhibitor of CYP1A2 at higher concentrations (Ki = 16 μM). Ribociclib is a low affinity 
substrate of P-glycoprotein (P-gp/MDR1). Ribociclib inhibits MDR1 (IC50 = 143 μM), 
mitoxantrone-resistant protein (MXR/BCRP) (IC50 = 24 μM) and human bile salt export pump 
(BSEP) (IC50 = 4.7 μM), but not rat or dog BSEP. Additionally, ribociclib has been found to 
inhibit OCT1 (Ki = 17.3 μM), OATP1B1 (Ki = 42.9 μM), OCT2 (Ki = 1.9 μM), MATE1 (Ki = 1.7 
μM) and MATE2K (Ki = 31 μM). Overall, the elimination of ribociclib may potentially be affected 
by co-administered drugs that inhibit or induce CYP3A4. Ribociclib may inhibit substrates of 
CYP3A4, CYP1A2, BSEP, OCT2, and MATE1 if sufficiently high concentrations are achieved in 
vivo. At the recommended dose for future development (600 mg), steady-state plasma Cmax 
ranges from 859-5860 ng/mL (geometric mean = 1940 ng/mL or 4.46 μM) [Ribociclib 
Investigator’s Brochure]. 
 
In GLP toxicology studies, ribociclib and LEQ803 exposure (Cmax and AUC0-24h) generally 
increased in a dose proportional manner in rats and dogs. Gender-differences in PK were 
observed in rats, with higher exposure (Cmax and AUC) to ribociclib and LEQ803 in males as 
compared to females, however no gender differences were identified in dogs. 
Clinical experience with Ribociclib: 
Ribociclib is being evaluated as a single agent in an ongoing phase I study in adult patients with 
solid tumors and lymphoma [CLEE011X2101], in pediatric patients [CLEE011X2102], and in 
adult Japanese patients with solid tumors [CLEE011X1101]. In addition, several combination 
studies (with investigational and/or approved drugs) [CLEE011X2105, CMEK162X2114] are 
ongoing or in study start-up phase. More specifically, several studies are ongoing or planned for 
investigating the safety and efficacy of ribociclib in combination with various hormonal agents 
such as letrozole [CLEE011X2107, CLEE011A2201, CLEE011A2301], fulvestrant 
[CLEE011X2108], and exemestane [CLEE011X2106] in patients with ER+ HER2-negative 
breast cancer. 
Clinical safety of LEE011 plus Letrozole: 
Study CLEE011X2107 is a phase Ib/II, multicenter study of the combination of LEE011 and 
BYL719 with letrozole in adult patients with advanced ER+ breast cancer. Three arms (LEE011 
+ letrozole, BYL719 + letrozole, LEE011 + BYL719 + letrozole) are included in this study. The 
primary endpoints of the study are to estimate the MTD(s) and/or RP2D(s) for the 3 
combinations. The phase Ib part is followed by a phase II part to compare the clinical efficacy of 
LEE011 + BYL719 + letrozole compared with LEE011 + letrozole or BYL719 + letrozole. The 
study is currently in the dose escalation part in phase Ib.  
 
As of 28-Mar-2014, 17 patients have been enrolled: 10 have been treated with at least one 
LEE011 dose (600 mg LEE011 (3-weeks-on/1-week-off) + 2.5 mg letrozole once-daily). The 
median age of 10 patients treated with LEE011 was 59 (range: 45–67) years, all the patients 
were female, and the distribution of ECOG performance status of 0/1 at baseline was 5/5 
patients, respectively. Among 10 patients treated with LEE011, 2 patients were discontinued 
from the study (2 due to progressive disease) and 8 patients were still ongoing. Among 10 
patients treated with LEE011, all patients experienced at least one AE. The most frequent AEs 
(≥10%), regardless of grade, causality and LEE011 dose, were neutropenia (90.0%); nausea 
(40.0%); fatigue (30.0%); leukopenia (20.0%); diarrhea, decreased appetite, weight decreased, 
anemia, constipation, headache, lymphopenia, rash, dyspnea, fever, flushing, increased 
creatinine, pleural effusion, urinary tract infection and visual impairment (10.0% each). 
 
• 
How supplied: Ribociclib 200mg and matching placebo will be supplied by Novartis as 
hard gelatin capsules in bottles of 28 capsules per bottle. 

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• 
Route of administration for this study: Oral (Non-liquid only). Can be taken without 
regard to food.   
• 
Storage and stability: The shelf life of the drug product is established based on ongoing 
stability studies and may be extended during the clinical study. The capsules are stored 
in HDPE bottles. According to drug label, storage for the capsules is listed as follows:  
“Do not store above 25 °C, protect from moisture”. However, the drug manufacturer, 
Novartis, has provided additional stability information, which approves the drug storage 
methods at ambient temperatures, which are to be used at the University of Kansas (KU) 
Hospital, Investigational Drug Services (IDS).  Documentation of Novartis approval will 
be kept on file by the University of Kansas (KU) Hospital, Investigational Drug Services 
(IDS).” 
• 
Potential drug interactions between ribociclib, letrozole and goserelin:  
• 
Letrozole is not expected to affect the metabolism ribociclib, which is mainly metabolized 
by CYP3A4 with a minor contribution by FMO3 based on in vitro data. Letrozole inhibits 
CYP2A6 (Ki = 4.6 μM) and CYP2C19 (Ki = 42 μM) in vitro. Letrozole is not an inhibitor of 
CYP3A4 or FMO3 and is therefore not expected to affect ribociclib metabolism. The 
metabolism of goserelin is not CYP-mediated; rather hydrolysis of C-terminal amino 
acids is the major clearance mechanism. No formal clinical DDI studies have been 
conducted or reported with goserelin. Based on the available information, goserelin is 
not expected to affect the metabolism of nor be affected by co-administered drugs 
(Zoladex® Prescribing Information). 
• 
Side effects: Based on its mechanism of action, the results of the preclinical toxicology 
studies and available clinical safety data as of September 10, 2014, the following are 
identified as the main adverse reactions for ribociclib: bone marrow suppression 
including leukopenia, neutropenia, anemia, and thrombocytopenia, renal toxicity, fatigue, 
nausea, vomiting, abdominal pain, diarrhea, pneumonia and prolongation of the QT 
interval. The risk of these toxicities may be amplified by concomitant administration of 
strong inhibitors of CYP3A4 or other combination treatments.  
• 
Permitted concomitant therapy – See Appendix D 
• 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are 
allowed. 
• 
The patient must be told to notify the investigational site about any new medications she 
takes after the start of the study treatment.  All medications (other than study drugs) and 
significant non-drug therapies (including vitamins, herbal medications, physical therapy 
and blood transfusions) administered within 30 days of study entry and during the study 
must be listed on the Concomitant medications/Significant non-drug therapies section of 
the patient record. 
• 
Bisphosphonates and denosumab 
• 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and 
prevention of skeletal related events for patients with bone metastases. Hematopoietic 
growth factors 
• 
Hematopoietic growth factors may be used according to ASCO guidelines. 
• 
Palliative radiotherapy 
• 
Palliative radiation for bone pain relief is not permitted because metastasis in not 
permitted in this study. Refer to the ribociclib (LEE011) Investigator’s Brochure [If 
applicable: and other drug package insert], Table 1, and Table 2 for information on 
possible interactions with other drugs. 

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8.3 
Permitted concomitant therapy requiring caution: 
• 
Medications to be used with caution during ribociclib and letrozole treatment in this study 
are listed in Appendix C. This list is not comprehensive and is only meant to be used as 
a guide. These medications should be excluded from patient use if possible. If they must 
be given, then use with caution and consider a ribociclib interruption if the concomitant 
medication is only needed for a short time (APPENDIX C): 
• 
Moderate inhibitors or inducers of CYP3A4/5 
• 
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index 
• 
Strong inhibitors of BSEP 
• 
Sensitive substrates of the renal transporters, MATE1 and OCT2 
• 
Sensitive substrates of BCRP 
• 
Medications that carry a possible risk for QT prolongation 
8.4 Prohibited concomitant therapy: 
The following medications are prohibited during study treatment in the study (APPENDIX B). 
This list is not comprehensive and is only meant to be used as a guide: 
• 
Strong inhibitors or inducers of CYP3A4/5 
• 
Substrates of CYP3A4/5 with a narrow therapeutic index 
• 
Medications that carry a known risk for QT prolongation 
• 
Herbal medications/preparations, dietary supplements (unless approved for participant 
use by PI). 
• 
Other investigational and antineoplastic therapies not part of the study 
8.5 
Study Drug Packaging and Labeling: 
Study Treatment 
Packaging 
Labeling 
Ribociclib /Placebo 
Capsules in bottles 
Labeled as 
‘LEE011/placebo’ 
Study treatments must be received by designated personnel at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, the study 
treatment should be stored according to the instructions specified on the medication 
label. Medication labels will comply with the legal requirements of each country and be 
printed in the local language.   
 
NOTE – per agreement with representatives of the manufacturer, Novartis and their 
provision of additional stability information, drug storage methods at ambient 
temperatures is approved.  These methods are to be used at the University of Kansas 
(KU) Hospital, Investigational Drug Services (IDS).  Documentation of Novartis approval 
will be kept on file by the University of Kansas (KU) Hospital, Investigational Drug 
Services (IDS).  Affiliate sites will follow the same guidelines for study drug storage as 
the University of Kansas (KU) Hospital, Investigational Drug Services (IDS), and 
documentation of the agreement with the drug manufacturer, Novartis regarding drug 
storage methods will be provided to the affiliate sites upon request. 
8.6 
Return and Retention of Study Drug: 
Remaining drug is to be destroyed, according to University of Kansas Investigational Drug 
Services or affiliate site’s destruction policy.  

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8.7 
Drug Accountability/Subject Compliance: 
Records of study medications used, dosages administered, and intervals between visits will be 
kept during the study.  Subjects will be asked to fill out a pill diary and bring with them for review 
after each cycle of study treatment. 
Drug accountability will be noted at the completion of the trial.  Subjects must return all unused 
medication at each visit and end of study. 
9.0 
Sample collection and storage for future correlative studies 
 
Tissue samples will be collected and stored as below, at baseline, Day 14 (+7) of Cycle 1, and 
at the time of surgery for biomarker analysis including ER and Ki67 and for future correlative 
studies. In addition, blood will be collected for serum, plasma, and germ-line and cell free DNA 
and stored at baseline for future correlative studies. The correlative studies will be performed in 
collaboration with Dr. Cynthia Ma at the Siteman Cancer Center and Dr. Yuan Yuan and Dr. 
Shiuan Chen at the City of Hope Comprehensive Cancer Center. 
 
Sample Collection/Shipment Kit 
 
The kit is a two-chamber kit in which it is possible to ship both frozen and ambient specimens.  
The kit is stocked with necessary items needed for blood and tumor sample collection.  It also 
contains the necessary materials used to process and prepare specimens for shipment in 
accordance to IATA regulations. 
 
Washington University Tissue Procurement Core Facility (WUTPC) 
 
425 S. Euclid Ave, Room 5120 
St. Louis, MO  63110-1005 
Phone: 314-454-7615 
Email: tbank@wudosis.wustl.edu 
 
Sample collection/shipment kits are available for institutions by sending the request to Email: 
tbank@wudosis.wustl.edu with the subject “FELINE Trial Biopsy Kit Request”. 
9.1 
Required pre-treatment core biopsy for biomarker and correlative studies: 
Samples collection is mandatory for all patients prior to initiating study therapy. 
 
Core biopsy should be performed with image guidance using a 14 gauge needle.  
The required biopsies include two core biopsies placed in 10% buffered formalin (a single pre-
filled formalin container to hold both cores) and two core biopsies frozen immediately at 
bedside in separate OCT blocks.  The cryo kits, formalin containing cup and blood collection 
tubes will be provided in the sample collection/shipment kits to the sites and are funded by this 
study. 
 
Tissue may be obtained concurrent with another procedure (clip placement, axillary node 
biopsy, port placement) or as a separate procedure. 
9.2 
Required Day 14 (+7) core biopsy for biomarker and correlative studies: 
Core biopsy should be performed with image guidance using a 14 gauge needle.  
The required biopsies include two core biopsies placed in 10% buffered formalin (a single pre-
filled formalin container to hold both cores) and two core biopsies frozen immediately at bedside 
in separate OCT blocks.  The cryo kits, formalin containing cup and blood collection tubes will 
be provided in the sample collection/shipment kits to the sites and are funded by this study. 

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9.3 
Required post-treatment core biopsy at time of surgery for all patients after the 
completion of neoadjuvant therapy for correlative studies 
Following completion of neoadjuvant therapy, an intra-operative core biopsy of residual tumor 
prior to its resection is required. 
 
The required biopsies include: Two core biopsies placed in 10% buffered formalin (a single pre-
filled formalin container to hold both cores) and two core biopsies frozen immediately at 
bedside in separate OCT blocks to preserve the proteome and transcriptome of the tumor.  
Biopsy kits will be provided to the sites and are funded by this study. 
 
If an intra-operative core biopsy is not practical, the site pathologist can remove the tumor 
samples during the dissection of the surgical specimen (using a 5-mm skin punch biopsy 
device) and samples frozen or fixed within 30 minutes of removal from the patient. 
 
In addition to the above, after the pathological tumor analysis is complete, 10 unstained 
Superfrost Plus slides cut at 4 microns thickness from the most representative and tumor cell 
enriched block, and the corresponding pathology report should be submitted for central Ki67 
calculation to be used for PEPI assessment.  Each research site will be responsible for 
calculating the PEPI scores for its own specimens. 
9.4 
Pre and post treatment blood specimen collection and storage: 
Blood samples will be collected pre-treatment, at discovery of disease progression or at end of 
treatment, whichever occurs first.  Please see study calendar. 
 
One 10mL lavender top EDTA vacutainer tube (for plasma and buffy coat cell pellet), 1 8.5mL 
red/black marble top tube (for serum) and 2 10mL Streck BCT tubes (for cell free plasma DNA) 
will be collected. Sample processing for serum, plasma, and viable buffy coat sections are 
performed at the participating site and stored at -80ºC before shipment.  Streck BCT tube blood 
is not processed but shipped ambient overnight via the specimen collection/shipment kits with 
all other samples to the Washington University Tissue Procurement Core Facility (WUTPC) for 
further processing to cell free plasma. 
 
All samples will be appropriately labeled (study number, subject number and date of collection) 
before being stored.  These samples are going to be used in future studies to assess 
biomarkers such as tumor markers, cell free tumor DNA, SNPs, genetic changes, etc. 
 
If a subject withdraws from the main study participation and future use of specimens is 
withdrawn by the subject (submitted in writing to the investigator), best efforts will be made to 
stop any ongoing studies and to destroy the specimens. 
 
All specimens are to be processed and stored in the WUTPC for a period of 20 years or until 
used up for future research. 
 
Upon the approval of the study PI, de-identified blood specimens may be shared with potential 
research collaborators outside of the University of Kansas for biomarker work related only to the 
hypothesis of this study. Collaborators will be required to complete an agreement (Material 
Transfer Agreement or recharge agreement) that states specimens will only be released for use 
in disclosed research. Any data obtained from the use of clinical specimen will be the property 
of the University of Kansas for publication and any licensing agreement will be strictly enforced. 
 

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The following information may be provided to research collaborators when specimens are made 
available:  
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data (which does not include any protected health information) 
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that there is 
the potential for financial gain by the University of Kansas, the investigator or a collaborating 
researcher or entity. 
9.5 
Shipping instructions for all research samples (tissue and blood): 
The Washington University Tissue Procurement Core Facility (WUTPC) will store the research 
samples.  The formalin fixed cores in the formalin cup received from the shipment will be further 
processed for tumor Ki67 at the CLIA certified Anatomic and Molecular Pathology Core Labs 
(AMP) at Barnes Jewish Hospital at St. Louis (CLIA number 26D2013203).  Slides and blocks 
from AMP will be returned to WU TPC for storage after completion of analysis and reporting. 
 
Specimens collected and preserved from outside sites will be shipped overnight (may use the 
two-chamber kit to ship both frozen specimens (OCT embedded frozen tumor biopsy cores, 
serum, plasma and cell pellet) on dry ice and ambient specimens (formalin cup with biopsy 
cores). A completed shipping manifest will be completed, emailed to the Wash U TPC (Email: 
tbank@wudosis.wustl.edu), and included in the specimen shipment. 
 
Arrange for Federal Express pick-up through your usual institutional procedure. Ship 
specimens to the address below: 
 
Washington University Tissue Procurement Core 
425 S. Euclid Ave, Room 5120 
St. Louis, MO 63110-1005 
Phone: (314) 454-7615 
E-mail:  tbank@wudosis.wustl.edu 
 
On the day that specimens are sent to the specimen bank, please contact the bank by 
phone, fax, or e-mail to notify what is being sent and when the shipment is expected to 
arrive. 
9.6 
Tissue Processing and Ki67: 
9.6.1 Baseline and Day 14 (+7d) 
Upon receipt of the specimen, the 2 fixed biopsy specimens at baseline and 2-week 
will be further processed for tumor Ki67 analysis at the CLIA certified Anatomic and 
Molecular Pathology Core Labs at Barnes Jewish Hospital at St. Louis (CLIA number 
26D2013203). After embedding in paraffin, one section from the tumor block will be 
stained with H&E to assess biopsy adequacy. Another section from the block will be 
incubated with antibody against Ki67 (clone 30-9) and then assayed using the Ventana 
Benchmark platform.  The block and any remaining sections will be returned to the 
Tissue Procurement Core Facility at the completion of testing. Both cores will be 
reviewed and will be taken into account for the scoring.   
 

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Ki67 scoring is reported as a quantitative/continuously distributed value. The Ki67 data 
for Day 14 biopsy is available real time to the treating physician and the patients. 
Patients will be continued on protocol therapy while awaiting analysis results. Results 
of tumor Ki67 will be reported within 10 working days upon receipt of the samples. 
Wash U Coordinator will email and fax the results to both the CRA listed on Specimen 
Submission CRF that is sent with the tissue samples and Wash U CRA. Contact Wash 
U coordinator for questions related to the Ki67 result. 
 
Note: If the biopsy yielded no tumor cells, the patient may continue on study drug 
therapy or proceed with a second biopsy for Ki67 determination. 
9.6.2 Surgery 
Ki67 on surgical specimen will be performed on one of the 10 unstained slides cut at 4 
microns thickness from tumor rich block obtained after breast surgery. 
 
The 2 fixed biopsy cores obtained at surgery time point will be further processed to 
FFPE core at the CLIA certified Anatomic and Molecular Pathology Core Labs at 
Barnes Jewish Hospital at St. Louis (CLIA number 26D2013203).  After embedding in 
paraffin, the block will be stored at the Wash U TPC unless Ki67 could not be obtained 
on the surgical slides, in which case, further sectioning and staining for Ki67 will be 
performed. 
9.7 
Correlative studies:  See Appendix E. 
10.0 
Measurement of Effect 
10.1 
Response Criteria: 
10.1.1   Clinical responses will be based on the WHO criteria 
Prior to each cycle of neoadjuvant treatment and at the completion of neoadjuvant 
treatment, the longest axis and the perpendicular axis of the measurable lesion should 
be measured and recorded in metric notation by bi-dimensional tape, ruler or caliper 
technique.  
 
Complete Response (CR) is defined as the disappearance of all known disease based 
on a comparison between the pre-treatment measurements and the measurements 
taken at the completion of neoadjuvant therapy (that is, at the end of cycle 6 
neoadjuvant endocrine therapy).  In addition, there is no appearance of new lesions.  
 
Partial Response (PR) is defined as a 50% or greater decrease in the product of the 
bi-dimensional measurements of the lesion (total tumor size) between the clinical pre-
treatment measurements and the clinical measurements taken at the completion of 
neoadjuvant therapy.  In addition, there can be no appearance of new lesions or 
progression of any lesion.  
 
No Change (NC) occurs when a 50% decrease in total tumor size cannot be 
established, nor has a 25% increase in the size of the lesion been demonstrated. 
10.2 
Definition of pathologic response and events during follow up: 
• 
A pathologic complete response is defined as no histology evidence of invasive tumor 
cells in the surgical breast specimen and sentinel or axillary lymph nodes. 
• 
Following surgery, diagnosis of breast cancer recurrence and other cancer events: 

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o Local recurrence - Local recurrence is defined as histologic evidence of ductal 
carcinoma in situ or invasive breast cancer in the ipsilateral breast or chest wall. 
o Regional recurrence - Regional recurrence is defined as the cytologic or 
histologic evidence of disease in the ipsilateral internal mammary, ipsilateral 
supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes or soft 
tissue of the ipsilateral axilla. 
o Distant recurrence - Distant recurrence is defined as the cytologic, histologic, 
and/or radiographic evidence of disease in the skin, subcutaneous tissue, lymph 
nodes (other than local or regional metastasis), lung, bone narrow, central 
nervous system or histologic and/or radiographic evidence of skeletal or liver 
metastasis. 
o Second primary breast cancer - Second primary breast cancer is defined as 
histologic evidence of ductal carcinoma in situ or invasive breast cancer in the 
contralateral breast or chest wall. 
o Second primary cancer (non-breast) - Any non-breast second primary cancer 
other than squamous or basal cell carcinoma of the skin, melanoma in situ, or 
carcinoma in situ of the cervix is to be reported and should be confirmed 
histologically whenever possible. 
o Death - Underlying cause of death is to be reported. 
10.3 Safety/Tolerability 
Analyses will be performed for all subjects having received at least one dose of study drug. The 
study will use the CTCAE version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
adverse events. 
 
10.4 
Central MRI Assessment 
Radiographic disease response will be assessed by centralized, blinded group of Breast 
Radiology experts at KUCC.  MRI images performed at baseline and Cycle 3 will be submitted 
to KUCC.  The blinded radiology team will perform an independent review of the MRI images.  
 
11.0 
DATA AND SAFETY MONITORING 
11.1 Oversight and Monitoring Plan: 
The DSMC of the KUCC is responsible for monitoring subject safety for this trial. The DSMC is 
responsible for: 
• Review of all clinical trials conducted by the KUCC for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Submission of recommendations for corrective action to the PI and the Deputy Director 
of the KUCC or designee. 
• Notification of external sites participating in multiple-institutional clinical trials 
coordinated by the KUCC of adverse events requiring expedited reporting and 
subsequent committee recommendations for study modifications.  
11.2 
Review and Oversight Requirements: 
a) Serious Adverse Event  
Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or 
designee who will determine if immediate action is required.  Refer to Section 7.2.  If determined 

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to be necessary by the DSMC, all participating sites will be notified of the event and any 
resulting action within one working day of this determination. 
b) Review of Serious Adverse Event Rates  
Once per month, serious adverse event rates will be monitored by the DSMC Coordinator. If any 
study has had 2 or more of the same SAE reported within one month, or more than 6 of the 
same SAE in 6 months, the DSMC will review summaries of SAEs, and discuss events in detail 
with the PI. The DSMC chair or designee determines whether further action is required.  The 
DSMC Coordinator ensures that collaborating investigators and IRBs for all Participating sites 
are notified of any resulting action. 
c) Study Safety and Progress  
The multidisciplinary KUCC Data and Safety Monitoring Committee (DSMC) is charged with 
overseeing the monitoring of participant safety, conduct and scientific progress of research 
protocols, and the validity and integrity of the data for clinical trials. The KUCC DSMC has the 
authority to require amendments, suspend, or terminate any research activities that fall within its 
jurisdiction, and can institute other appropriate actions as needed to protect participant safety. 
 
The study will be monitored at appropriate intervals, no less than those assigned by the KUCC 
Protocol Review and Monitoring Committee, to assure compliance to GCP and to assess the 
data quality and study integrity. The frequency of monitoring may vary depending on enrollment 
rate and the quality of data collected. 
 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. The study monitor will have 
direct access to source data for data verification. Data verification will be conducted by 
comparing the data entered into the CRFs with source data 
 
12.0 
REGULATORY CONSIDERATIONS 
12.1 Protocol Review and Amendments: 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by a properly constituted IRB governing each study 
location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. 
The Principal Investigator will disseminate protocol amendment information to all participating 
investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
12.2 Informed Consent: 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 

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consent document. The original signed copy of the consent document must be retained in the 
medical record or research file. 
12.3 Ethics and Good Clinical Practice (GCP): 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice: 
 
1. 
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm  
2. 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
- 
Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
- 
Title 21 Part 50 – Protection of Human Patients 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
- 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
- 
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
- 
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
3. 
State laws 
4. 
Institutional research policies and procedures 
http://www2.kumc.edu/researchcompliance/hscpolicies.htm 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy. 
13.0 
REGISTRATION PROCEDURES 
13.1 
General Guidelines for KUCC and Other Participating Organizations: 
Institutions will register eligible subjects through the KUCC Clinical Research Office central 
registration process.  Registration must occur prior to the initiation of therapy.  Any subject not 
registered to the protocol before treatment begins will be considered ineligible and registration 
will be denied.  
 
The completed source documentation provided for eligibility verification and registration must be 
kept in the subject binder for monitoring purposes and documentation of subject eligibility. 
 
Issues that would cause treatment delays should be discussed with the Principal Investigator. If 
a subject does not receive protocol therapy following registration, notify the KU Cancer Center 
Project Director or designee and change the subject’s status in the eVELOS system. 
13.2 
Registration Process for KUCC and Other Participating Centers: 
The Coordinating Center (KUCC), specifically the Project Director or designee is accessible for 
registration Monday through Friday from 8:00 AM to 5:00 PM Central Time.  
 
The registration procedures are as follows: 
 

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1. Obtain written informed consent from the subject prior to the performance of any study 
related procedures or assessments. 
 
2. Complete the appropriate baseline demographic information in eVELOS and the 
required registration form and inclusion/exclusion criteria checklist using the eligibility 
assessment documented in the subject’s medical/research record.  To be eligible for 
registration to the study, the subject must meet each inclusion and none of the exclusion 
criteria listed in Section 3.0 of this protocol.  The KU department of biostatistics will grant 
access to eVelos for this study for access to study documents, patient enrollment and 
data entry into eCRFs. 
 
3. Submit the registration form and inclusion/exclusion criteria checklist to KUMC via email.  
The KU Project Director or designee will send an email confirmation stating whether or 
not the subject may enroll. 
 
4. The unblinded pharmacist or designee will assign the subject to a treatment group using 
sequential assignment of predetermined block randomized 1:1:1 treatment assignments 
provided by the study statistician prior to activation. 
13.3 
Unblinding: 
Due to the objectives of the study, treatment assignments will not be known to investigators, 
research staff, or participants.  The study blind will be broken on completion of the clinical study 
and after the study database has been locked. 
 
During the study, the blind may be broken only in medical emergencies when knowledge of the 
participant’s treatment group is necessary for further patient management.  When possible, the 
investigator should discuss the emergency with the Sponsor-Investigator prior to unblinding. 
 
If the decision is made to unblind a participant’s treatment in a medical emergency, the following 
steps should be taken: 
1. Contact the investigational pharmacy to request unblinding of the participant, providing 
the pharmacist with the rationale for unblinding. 
2. Document the date, time, and reason for the unblinding.  This documentation should be 
archived in the Investigator Site File, the participant’s medical records, and in the eCRF. 
3. Notify the Sponsor-Investigator and DSMC of the unblinding event. 
 
If a serious adverse reaction is judged reportable on an expedited basis, it is recommended that 
the blind be broken only for that specific participant by the Sponsor-Investigator even if the 
investigator has not broken the blind.  In the case of a SUSAR, the DSMC may be involved to 
ensure that the study team remains blinded. 
 
If the blind must be broken for a participant, the case should be unblinded only to a limited 
number of people and access to the case should be limited so that the blind can be maintained 
as much as possible.  It is also recommended that, when possible and appropriate, the blind be 
maintained for those persons responsible for the analysis and interpretation of results at the 
study’s conclusion. 
 
Reporting of the event will be followed according to FDA and local IRB guidelines depending 
upon the details of the specific event. 
 
 

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14.0 
STUDY MANAGEMENT 
14.1 Investigator Files and Retention of Documents: 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. Original source documents supporting entries in the case report forms include but are 
not limited to hospital records and clinic charts, laboratory and pharmacy records, ECG, signed 
ICFs, subject diaries and pathology reports. All study-related documents must be retained for 
the maximum period required by applicable federal regulations and guidelines or institutional 
policies.  
14.2 Case Report Forms: 
Case report forms (CRFs) will be completed for each subject enrolled.  All CRFs will be 
complete and accurate. The medical chart and any other clinical worksheets, procedural 
reports, etc. are the source of verification of the data captured into the study database.   
14.3 Study Monitoring: 
The study will be monitored at appropriate intervals to assure compliance to GCP and to assess 
the data quality and study integrity. The frequency of monitoring may vary depending on 
enrollment rate and the quality of data collected. 
 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit. The study monitor will have direct access to source 
data for data verification. Data verification will be conducted by comparing the data entered into 
the CRFs with source data. 
15.0 
STATISTICAL CONSIDERATIONS 
15.1 Study Design/Study Endpoints: 
This is a prospective randomized phase II, multi-center study. Refer to protocol Section 2 for 
study endpoints. 
16.0 
SAMPLE SIZE JUSTIFICATION AND INTERIM ANALYSIS FOR FUTILITY 
 
In the ACOSOG Z1031 study, 16% of the patients in the letrozole alone arm had a PEPI score 
of 0. The sample size of this trial was determined with the assumption that 16% of the patients 
letrozole will have a PEPI 0 score. Assuming that addition of LEE011, either 600 mg for 21/7 
scheme (Arm B) or 400mg for 28/28 scheme (Arm C), will increase the rate of PEPI 0 by 20%, 
and setting Type I error rate of 10% and Type II error rates at 20%  (Rubinstein et al., 2005) in 
the final analysis with an interim analysis at 0.5 information time for futility, a sample size of 80 
women in the treatment arms (40 in each arm) and 40 women in the control arm are needed to 
achieve 80% power in a 1-sided unpooled z-test with continuity correction for Ha: 36% vs.H0: 
16%.  This calculation was performed on nQuery + nTerim 3.0 using the O’Brian-Fleming 
spending function, and finds the drift parameter value of 2.224 and the futility lower bound of 
0.0876. 
 
Because the total sample size is estimated to be 80 + 40 = 120 patients, the planned 0.5 
information time for futility requires 120x0.5 = 60 patients. If the z-statistic is below the 
aforementioned lower bound 0.0876, the study will be stopped early for futility.   

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16.1 Accrual rate and study duration: 
It is anticipated that 6 subjects per month will be enrolled. Accrual will be completed in 19 
months. Pathology data will be available on the last subject 6 months after the accrual is 
complete. The trial should be completed for the primary endpoint analysis in 26 months after 
accrual is initiated. 
16.2 Data Analysis Plans: 
Although the trial is designed with 3 arms, the hypotheses concern about the comparisons of 
the two treatment arms combined vs. the control, hence 2-sample methods are planned. 
 
The primary endpoint 
The frequency and proportion of patients with PEPI score 0 at surgery will be reported for each 
arm.  The 1-sided 90% confidence intervals (CI) will also be computed for the difference of 
proportions.  The proportions will be compared between treatment (Letrozole with 2 ribociclib 
arms combined) and control by 1-sided unpooled z-test with continuity correction for both the 
interim futility and the final analyses at 0.02 and 0.094 significance level, respectively, to retain a 
cumulative 0.10 significance level.  The trial will be stopped early if the z-value in the futility 
analysis is below the boundary of 0.0876.  
 
The secondary endpoints 
The secondary objectives concern about four endpoints.  Among them, the three binary 
endpoints (Complete cell cycle arrest, pCR, cCR) will be analyzed in the same way as the 
primary endpoint described above but they will not be analyzed for futility.   
 
The Ki-67 level is often skewed in its distribution and will be summarized by median and 
corresponding 95% CI (use e.g. the CIPCTLDF option in PROC UNIVARIATE, SAS) for each 
arm.  The Ki-67 may take zero values and will be square-root transformed, and compared 
between arms by 1-sied 2-sample t-test, or by Wilcoxon rank-sum test if transformations fail to 
make distributions approximately normal. 
 
The 5-year relapse-free survival and corresponding confidence interval will be estimated by 
Kaplan-Mayer estimator for each arm, and compared between treatment arms combined vs. 
control by 1-sided log-rank test.  
 
Significance for the secondary endpoints will be assessed at 0.05 significance level. 
 
In addition, we will explore differences between the two treatment doses by 2-sided Fisher’s 
exact test, 2-sided t- or Wilcoxon test, and 2-sided log-rank test at 0.05 significance level. 
 
Interim analysis 
Since the patient accrual was almost complete by the time first 60 patients had complete 
information regarding PEPI scores, interim analysis will not be performed.  
 
 
 

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17.0 
REFERENCES 
 
1. Howlader, N., et al., SEER Cancer Statistics Review, 1975-2008, National Cancer 
Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 
2010 SEER data submission, posted to the SEER web site, 2011. 2011. 
2. Anderson, W.F., et al., Estrogen receptor breast cancer phenotypes in the Surveillance, 
Epidemiology, and End Results database. Breast Cancer Res Treat, 2002. 76(1): p. 27-
36. 
3. Early Breast Cancer Trialists' Collaborative, G., Relevance of breast cancer hormone 
receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-
analysis of randomized trials. The Lancet, 2011. 378(9793): p. 771-784.  
4. Cuzick, J., et al., Effect of anastrozole and tamoxifen as adjuvant treatment for early-
stage breast cancer: 10-year analysis of the ATAC trial. The Lancet Oncology, 2010. 
11(12): p. 1135-1141. 
5. Ellis, M.J., Neoadjuvant endocrine therapy as a drug development strategy. Clin Cancer 
Res, 2004. 10(1 Pt 2): p. 391S-5S. 
6. Chia, Y.H., M.J. Ellis, and C.X. Ma, Neoadjuvant endocrine therapy in primary breast 
cancer: indications and use as a research tool. Br J Cancer, 2010. 103(6): p. 759-64. 
7. Pagani, O., et al. (2014). "Adjuvant exemestane with ovarian suppression in 
premenopausal breast cancer." N Engl J Med 371(2): 107-118. 
8. Paik, S, Shak, S, Tang, G, et al. A multigene assay to predict recurrence of tamoxifen 
treated, node-negative breast cancer. N Engl J Med 2004; 351:2817. 
9. Paik, S, Tang, G, Shak, S, et al. Gene expression and benefit of chemotherapy in 
women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 
24:3726. 
10. Albain K, Barlow W, Shak S, Hortobagyi G, Livingston R, Yeh I, Ravdin P, Yoshizawa C, 
Baehner F, Davidson N, Sledge G, Winer E, Hudis C, Ingle J, Perez E, Pritchard K, 
Shepherd L, Allred C, Osborne K, Hayes D.: Prognostic and predictive value of the 21-
gene recurrence score assay in postmenopausal, node-positive, ER+ breast cancer 
(S8814,INT0100). Abstract 10, SABCS 2007. 
11. Eiermann, W., et al., Preoperative treatment of postmenopausal breast cancer patients 
with letrozole: A randomized double-blind multicenter study. Ann Oncol, 2001. 12(11): p. 
1527-32.  
12. Smith, I.E., et al., Neoadjuvant treatment of postmenopausal breast cancer with 
anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, 
Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized 
trial. J Clin Oncol, 2005. 23(22): p. 5108-16.  
13. Cataliotti, L., et al., Comparison of anastrozole versus tamoxifen as preoperative therapy 
in postmenopausal women with hormone receptor-positive breast cancer: the Pre-
Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer, 2006. 106(10): p. 
2095-103.  
14. Finn RS, et al: AACR Annual Meeting. Abstract CT101. Presented April 6, 2014. 
15. Olson, J.A., Jr., et al., Improved surgical outcomes for breast cancer patients receiving 
neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. J Am 
Coll Surg, 2009. 208(5): p. 906-14; discussion 915-6. 

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16. Colleoni M, Viale G, Zahrieh D, et al. Chemotherapy is more effective in patients with 
breast cancer not expressing steroid hormone receptors: a study of preoperative 
treatment. Clin Cancer Res 2004;10:6622-6628 
17. Dowsett, M., et al., Prognostic value of Ki67 expression after short-term presurgical 
endocrine therapy for primary breast cancer. J Natl Cancer Inst, 2007. 99(2): p. 167-70. 
 
 

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18.0 
APPENDICES 
Appendix A:  Performance Status 
 
Zubrod (ECOG) Performance Scale 
 
POINT 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
 
 

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Appendix B:  List of prohibited medications during study drug treatment5 
 
Category 
Drug Name 
Strong CYP3A inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, 
indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandomycin, voriconazole 
Strong CYP3A inducers 
Avasimibe3,, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin) 3, St. John's wort (hypericum 
perforatum) 3 
Medications with a 
known risk for QT 
prolongation4 
Amiodarone, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, droperidol, erythromycin, 
flecainide, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, 
probucol, procainamide, quinidine, sotalol, sparfloxacin, terfenadine, 
thioridazine, vavdetanib 
CYP3A substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine 
Other investigational and 
antineoplastic therapies  
Other investigational therapies must not be used while the patient is 
on the study. Anticancer therapy (chemotherapy, biologic or radiation 
therapy, and surgery) other than the study treatments must not be 
given to patients while the patient is on the study medication. If such 
agents are required for a patient then the patient must be 
discontinued from the study drug. 
Herbal preparations/ 
medications 
Herbal preparations/medications are prohibited throughout the study. 
These herbal medications include, but are not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, black cohosh, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. Patients should stop using these herbal medications 7 days 
prior to first dose of study drug. 
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). 
2 Herbal product 
3 P-gp inducer 
4 Source: www.crediblemeds.org  
5 Topical preparations are allowed 
 
 
 

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Appendix C:  List of medications to be used with caution during study drug treatment 
 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, 
ciprofloxacin, darunavir, diltiazem, dronedarone, fluconazole, 
fosamprenavir, grapefruit juice (citrus paradisi fruit juice), 
imatinib, Schisandra sphenanthera1, tofisopam, verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, 
talviraline, thioridazine 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine, aplaviroc, aprepitant, atorvastatin, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, 
casopitant, , darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, eplerenone, everolimus, felodipine, 
fluticasone, , lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, neratinib, nisoldipine, perospirone, quetiapine, 
ridaforolimus, , sildenafil, simvastatin, , ticagrelor, , tolvaptan, 
triazolam, vardenafil, vicriviroc 
Strong BSEP inhibitors 
Bosentan, fusidate, glibenclamide, lovastatin, , sulindac, 
troglitazone (TGZ- sulfate) 
 Mate1 and OCT2 
substrates3 
Acyclovir, amantadine, amiloride, cephalexin, cephradine, 
cimetidine, famotidine, fexofenadine, memantine, metformin 
(also a substrate for OCT1, MATE1, and MATE2K), pindolol, 
procainamide, ranitidine, and varencicline 
BCRP substrates 
Daunorubicin doxorubicin, rosuvastatin, sulfasalazine, 
topotecan 
Medications that carry a 
possible risk for QT 
prolongation 
Alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, dronedarone, eribulin, escitalopram, famotidine, 
felbamate, fingolimod, foscarnet, fosphenytoin, gatifloxacin, 
gemifloxacin, granisertron, iloperidone, indapamide, 
isradipine, lapatinib, levofloxacin, lithium, moexipril, 
nicardipine, nilotinib, octreotide, ofloxacin, ondansetron, 
oxytocin, paliperidone, pasireotide, quetiapine, ranolazine, 
risperidone, roxithromycin, sertindole, sunitinib, tacrolimus, 
tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, 
voriconazole,  ziprasidone 
1  Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor. 
2  Source: www.crediblemeds.org  
3 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and implications for Dosing and Labeling (February 2012) and Yonezawa and Inui 
(2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to 
pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J 
Pharmacology 164:1817-25 
 
 
 

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Appendix D:  Concomitant Medications 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration of 
study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or ribociclib. 
 
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Oncology Clinical Pharmacology Drug-Drug Interaction Database (release 
date: 29 Oct 2012), which was compiled from the Indiana University School of Medicine’s P450 
Drug Interaction Table (http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented 
with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and Implications for Dosing and Labeling (February 2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
292362.pdf), and the University of Washington’s Drug Interaction Database 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(https://crediblemeds.org/). Please contact the medical monitor or the PI with any questions. 
 
 

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Appendix E:  Correlative Studies for the Feline Trial (Chen/Yuan/Ma) 
While CDK4/6 inhibitors such as palbociclib have been approved by FDA for the use in 
combination with letrozole for the treatment of patients with ER+ breast cancer, at the present 
time, no response/predictive markers have been identified. Therefore, correlative studies will be 
performed to identify potential markers associated with the combination treatment of letrozole 
and LEE011. Four sets of correlative studies will be conducted.  The objectives of these studies 
are: 
 
a) To determine whether treatment with letrozole and LEE011 will be affected by gene 
mutation in the cancer by Exome Sequencing of tumors.  
b) To perform RNA Sequencing and reverse phase protein array (RPPA) analyses to 
search for potential markers associated to the treatment outcome. 
c) To define potential markers, identified through our preclinical studies, related to the 
activity of letrozole and LEE011 by IHC. 
d) To determine whether miRNA and lncRNA in peripheral blood can be used as 
markers of the activity of letrozole and LEE011.  
 
1. Exome sequencing 
 
We will perform Exome Sequencing analysis on 40 tumor specimens (20 patients who have 
complete or very good partial response and 20 patients who had stable disease and or partial 
response) collected prior to treatment (diagnostic tumor biopsy specimens) to determine 
whether any somatic mutations in the tumors that affect the treatment outcome. Mutation status, 
allelic imbalance, and/or copy number variations of cancer-related genes (including, but not 
limited to:  RB1, CCND1, CDKN2A, CDK4, CDK6, etc.) will be analyzed. Note that a gene will 
be considered as amplified if six (6) or greater copies of a given gene are present in the sample. 
Loss will be defined if zero (0) copies of a given gene are present in the sample. For this 
purpose, the results of this analysis will be correlated with clinical efficacy data. As these data 
are extensive and complex, only those markers that show at least 5% alteration frequency will 
be shown, as well as genes associated with the key pathway of interest. 
 
2. RNA Sequencing and RPPA 
 
As non-biased approaches, RNA Sequencing and RPPA will be performed on fresh frozen 
specimens collected before and six months after treatment of letrozole + LEE011 (36 pairs). 
These analyses will provide gene and protein expression signatures in the collected tissue. 
Expression changes before and after treatment will be correlated to the response of the 
combination treatment. In tumor tissue samples, an evaluation of the expression of 
genes/proteins related to the mechanism of action of CDK4/6, Rb pathway, cell cycle pathways 
or downstream effects, and cancer pathobiology may be evaluated (for example, loss of 
CDKN2A and/or RB1, amplification of CCND1, FOXM1; Cyclin B etc.) to assess any potential 
correlation with response to LEE011.   
 
3. Immunohistochemical analysis 
 
Pretreatment formalin-fixed paraffin-embedded tumor tissue should be in a whole block or 
unstained slides.  Tissue will also be obtained following completion of study drugs (breast-
conserving surgery or mastectomy) or at the time of progression (core biopsy).  Tumor 
specimens submitted as a FFPE tissue block will be returned to the sites by end of study or 
upon request. Tumor samples will be analyzed by IHC of proteins associated with response or 
resistance to LEE011 therapy.  IHC markers, e.g. pRB and PTEN, will be listed by marker and 

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treatment group and summarized using summary statistics (mean, standard deviation, median, 
minimum, maximum). 
 
4. Peripheral blood 
 
Blood will be collected prior to treatment, at discovery of disease progression or at end of 
treatment, whichever occurs first.  In addition, paraffin blocks of formalin-fixed diagnostic tumor 
biopsy specimens before treatment will be requested from each patient.  
 
Gene expression profile analysis will be performed to determine how LEE011 + letrozole 
treatment affects gene expression, including aromatase.  The processing of the tumor for gene 
expression profiling of the samples will be carried out at the Wash U TPC or City of Hope 
Functional Genomics core facility.  These facilities have experienced laboratories for expression 
profiling that are highly automated and that have extensive quality control procedures.  
Processing the samples will ensure consistent sample handling and high quality gene 
expression data. Collection of tumor samples for expression profiling is an important part of this 
study and whenever possible should be collected at the time points indicated below. 
 
Exome Sequencing and Gene Expression Profiling of Tumor Samples 
 
Molecular studies of clinical samples obtained from patients with cancer can provide rich clinical 
and biological information.  For example, gene expression profiling of diagnostic breast cancer 
samples has been used to identify expression profiles associated with risk of metastasis (van de 
Veer et al., 2002; van de Vijver et al., 2002). In this protocol, pretreatment and on-treatment 
samples of tumor (in patients with accessible tumor) will be collected for correlative molecular 
studies. These samples will be used to search for (1) somatic gene mutations that affect the 
response to letrozole + LEE011, (2) gene expression profiles that predict response to letrozole + 
LEE011 and (3) expression changes that occur after exposure to letrozole + LEE011.  In 
addition, off-treatment samples will be requested. These samples will be used to search for 
gene expression changes that occur after acquired resistance to letrozole + LEE011.  The 
samples will also be used for confirmatory studies based on the gene expression results.  
Results from these gene expression studies may provide important information regarding the 
mechanisms of response and the mechanisms of resistance to letrozole + LEE011. Ultimately, 
these results could guide the selection of patients for treatment with letrozole + LEE011 and 
guide strategies for preventing or overcoming resistance to these drugs. In addition, paraffin 
blocks of formalin-fixed diagnostic tumor biopsy specimens will be requested from each patient. 
If more recent paraffin blocks of tumor biopsy specimens from the same patient are available, 
these will also be requested. These blocks will be used to identify molecular markers that are 
associated with response to letrozole + LEE011. 
 
 

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Appendix F:  Drug Compliance Assessment Tool (Sample Participant Pill Diary) 
 
 

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