Phase II, Randomized, Open-label, International, Multicenter Study to Compare Efficacy of Standard Chemotherapy vs. Letrozole Plus Abemaciclib as Neoadjuvant Therapy in HR-positive/HER2-negative High/Intermediate Risk Breast Cancer Patients
Phase: PHASE2
Conditions: Early Breast Cancer
Sponsor: Spanish Breast Cancer Research Group

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
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Protocol GEICAM/2019-01 
Phase II, randomized, open-label, international, multicenter study to compare 
efficacy of standard chemotherapy vs. letrozole plus abemaciclib as 
neoadjuvant therapy in HR-positive/HER2-negative high/intermediate risk 
breast cancer patients 
 
SPONSOR:  
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama) 
Avenida de los Pirineos 7, planta 1ª, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid), Spain 
Phone: 
 
 
Fax: 
 
Email: 
 
 
CHIEF INVESTIGATORs: 
Dr. Miguel Martin. H. General Universitario Gregorio Marañón, Madrid, Spain. 
Dr. Emilio Alba. H. Universitario Virgen de la Victoria. Málaga, Spain. 
Dr. Ángel Guerrero. Instituto Valenciano de Oncología. Valencia, Spain 
 
PATHOLOGY CENTRAL LABORATORY RESPONSIBLE:    
 H. Fundación Jiménez Díaz. Madrid, Spain 
Sponsor Study Code: GEICAM/2019-01 
EudraCT Number: 2019-002123-15  
Protocol reviewed by FECMA (Spanish Federation of Breast Cancer Patients)  
 
CONFIDENTIAL  
The information and data included in this protocol contain secrets and privileged or confidential information which is the property of 
GEICAM. No one is authorized to make this information public without the written permission of GEICAM. These limitations shall also be 
applied to all the information considered to be privileged or confidential and provided in the future. This material can be disclosed and used 
by its equipment and collaborators as necessary for conducting the clinical trial. 

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Protocol Number: GEICAM/2019-01
Protocol Tittle: Phase II, randomized, open-label, international, multicenter study to 
compare efficacy of standard chemotherapy vs. letrozole plus abemaciclib as 
neoadjuvant therapy in HR-positive/HER2-negative high/intermediate risk breast 
EudraCT Number: 2019-002123-15 Version: 2.0 Version Date: 29-Jun-2021 
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Chief Investigator: Dr. Miguel Martín                                                                Date (dd/mmm/yyyy)
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Chief Investigator: Dr. Emilio Alba                                                                    Date (dd/mmm/yyyy) 
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Chief Investigator: Dr. Ángel Guerrero                                                               Date (dd/mmm/yyyy) 
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Pathology Central Lab Responsible: 
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Medical Monitor: 
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Translational Monitor:
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Statistician:
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Protocol/Project Manager: 
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Chief Investigator: Dr. Ángel Gu
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EudraCT number: 2019-002123-15
 
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SUMMARY OF THE STUDY PROTOCOL 
Study Title: Phase II, randomized, open-label, international, multicenter study to compare 
efficacy of standard chemotherapy vs. letrozole plus abemaciclib as neoadjuvant therapy in 
HR-positive/HER2-
 
Sponsor Study Code: GEICAM/2019-01 
Sponsor: GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)   
Indication: High/intermediate risk hormone receptor (HR) positive/human epidermal 
growth factor receptor 2 (HER2) negative breast cancer patients with indication of 
neoadjuvant therapy. 
Countries and approximate number of sites: Approximately 34 sites in 2 European 
countries. 
Number of patients: Approximately 200 evaluable patients will be enrolled in the study. 
Study Rationale: 
Neoadjuvant chemotherapy (NACT) was introduced in the 1970s, aiming to downstage 
locally advanced (inoperable) disease and make it operable. NACT was subsequently 
extended to operable (early) breast cancer (BC), mainly to allow breast-conserving surgery, 
and is now widely used, particularly for human epidermal growth factor receptor 2 positive 
(HER2-positive),+), triple negative (TN) and high risk estrogen receptor positive (ER-
positive) and HER2- negative BC patients(1).  
Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery 
in BC(2) . A fundamental change in this paradigm happened in 2013 when the Food and 
Drug Administration (FDA)(3) approved the rate of pathological complete response (pCR) 
after NACT, that is absence of cancer in the breast and lymph nodes in the surgical 
specimen, as a surrogate marker of long term outcome in order to support accelerated 
approval. Nevertheless, the final full approval of such drugs is still dependent on 
demonstration of an improvement in event-free survival (EFS). 
Recently, an increasing number of neoadjuvant trials are testing new drugs in combination 
with endocrine therapy (ET) in patients with ER-positive breast cancer(2). There are 
several studies evaluating the addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) 
to ET versus CT in the NA setting:   
 NeoPalAna study (NCT01723774)(4): single-arm phase II trial to determine the 

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antiproliferative activity of palbociclib when added to anastrozole in pre- and 
postmenopausal women with newly diagnosed clinical stage II/II ER-positive 
(Allred score 6-8), HER2-negative (0 or 1+ by immunohistochemistry (IHC) or 
fluorescence in situ hybridization (FISH) negative) BC. The primary objective was 
to determine whether the addition of anastrozole to palbociclib induces a higher rate 
anastrozole alone as initial therapy at C1D15. The study was designed to ensure the 
sample size for the PIK3CA WT cohort and the overall population for the primary 
endpoint analysis. Fifty patients were enrolled, 16 in the PIK3CA MUT cohort, 32 
in the PIK3CA WT cohort, and 2 with unknown PIK3CA status. Thirty-nine 
patients completed NAT and underwent definitive breast and axillary surgery. The 
rates of CCCA with palbociclib plus anastrozole were significantly higher at C1D15 
than that at C1D1 with anastrozole monotherapy for all evaluable patients (87% vs. 
26%, P < 0.001), PIK3CA MUT (100% vs. 25%, P < 0.001), and PIK3CA WT 
(79%vs. 25%, P < 0.001) cohorts. There was a greater variability in Ki67 response 
among the PIK3CA WT tumors. Palbociclib enhanced cell-cycle control over 
anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA 
status with activity observed across a broad range of clinicopathologic and mutation 
profiles. 
 N007 study (NCT01709370)(5): The purpose of the study was to test the efficacy of 
neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and 
changes in EndoPredict (EP) scores before and after treatment. Postmenopausal 
women with histologically proven ER-
cm, were enrolled in an open-label, single-arm study. Twenty eligible patients were 
given letrozole 2.5 mg/day plus palbociclib 125 mg/day for 3 out of 4 weeks in 
repeated cycles for 16 weeks (4 cycles) before surgery. The primary end points were 
clinical response rates (cRR) and preoperative endocrine prognostic index (PEPI). 
Seventeen 
cant 
reduction in area (P < 0.0001) and volume (P = 0.017) of the cancer. Pathologic 
complete response (pCR) was achieved in 1 patient. Ki67 (P = 0.044) and EP scores 
(P < 0.0001) were significantly reduced after treatment. Only 8 of 20 (40%) patients 
had a Ki67 < 2.7 at the time of surgery after treatment. Three of 20 (15%) patients 
were determined to have Ki67 over 15% after treatment. 
 PALLET study (NCT02296801)(6): randomized phase II study to evaluate 
palbociclib in addition to letrozole as neoadjuvant therapy in ER-positive early BC. 
Postmenopausal women with tumor
letrozole 2.5 mg/day for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus 
letrozole for 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole 
to 14 weeks (C); or palbociclib plus letrozole for 14 weeks (D). Palbociclib 125 

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mg/day was administered orally on a 21-days-on, 7-days-off schedule. Co-primary 
endpoints for letrozole vs. palbociclib plus letrozole groups (A v B + C + D) were 
change in Ki67 between baseline and 14 weeks and clinical response after 14 
weeks. Complete cell-cycle arrest was defined as Ki67 
 2.7%. Three hundred 
seven patients were recruited. Clinical response was not significantly different 
between palbociclib plus letrozole and letrozole groups (P = 0.20; CR + PR, 54.3% 
vs. 49.5%). More patients on palbociclib plus letrozole achieved CCCA (90% vs. 
59%; P < 0.0001).  
 NeoPAL study(7)  (NCT02400567): randomized, parallel, non-comparative, proof-
of-concept, phase II study. Patients with ER-positive, HER2 negative, Prosigna®-
defined luminal B, or luminal A and nodal status (N) positive, stage II IIIA BC, not 
candidate for BCS (breast conserving surgery), were randomly assigned (1:1) to 
either letrozole (2.5 mg/day) and palbociclib (125 mg/day, 3 weeks on and 1 week 
off) during 19 weeks (4.8 months), or to 5-fluorouracil, epirubicin (100 mg/m2) and 
cyclophosphamide (FEC100) followed by docetaxel 100 mg/m2 with three 21-day 
courses. Sentinel lymph node (SLN) surgery was allowed only after completion of 
the NA therapy. One hundred and six randomized patients had a median Prosigna® 
score of 71 (22-
-
interim analysis mandated the accrual to be stopped early. The primary endpoint 
was RCB 0 1 rate on the ITT (intent to treat) population (locally assessed according 
to MDACC recommendations): letrozole/palbociclib 7.7% (95% confident interval 
(CI) 0.4 14.9) and CT 15.7% (95% CI 5.7 25.7). This study did not reach the 
primary endpoint of 20% RCB 0-I after 19 weeks of treatment (7.7%; 95% CI 0.4-
14.9).  
 CORALLEEN study(8) (NCT03248427): a parallel-arm, multicenter, randomized, 
open-label,  phase II clinical trial for postmenopausal women with stage I-IIIA, HR-
positive, HER2-negative, luminal B according to PAM50 intrinsic subtype, BC, 
sonance imaging (MRI). Patients were 
randomly assigned (1:1) to receive NACT (adryamicin/doxorubicin 60 mg/m2 plus 
cyclophosphamide 600 mg/m2 (AC) for 4 cycles followed by weekly paclitaxel 80 
mg/m2 for 12 weeks) vs. six 28-day cycles of letrozole 2.5 mg/day plus ribociclib 
600 mg/day for 3 weeks on, 1 week off, for 24 weeks. Primary endpoint was to 
evaluate the proportion of patients with PAM50 low risk of relapse (ROR) disease 
at surgery in the modified intention-to-treat (ITT) population including all randomly 
assigned patients who received study drug and had a baseline and at least one post-
baseline measurement of ROR score. One hundred and six patients were enrolled. 
At baseline, 92 (87%) had high ROR disease and 14 (13%) patients had 
intermediate-ROR disease. At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 
patients in the letrozole plus ribociclib group and 24 (46·1%; 32·9-61·5) of 52 

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patients in the CT group were low-ROR. 
 NEOLBC study(9) (NCT03283384): an ongoing randomized, multicenter, open-
label, phase II clinical trial in n = 100 postmenopausal patients with HR-positive 
HER2-negative, stages II/III BC. Based on Ki67 levels after two weeks of initial 
letrozole treatment, patients are advised to continue ET with letrozole (if Ki67 level 
<1%) or to be randomized between standard CT [2-weekly plus G-CSF 
(granulocyte colony stimulating factor) followed by a taxane (3-weekly docetaxel or 
aim of the study is to evaluate if CT could be replaced by the combination of 
letrozole plus ribociclib as a NA therapy for patients with non-metastatic primary 
luminal BC. The primary endpoint is to measure the difference in CCCA defined as 
Ki67 < 1% determined by IHC between letrozole plus ribociclib vs. CT in the 
surgical specimen (around seven months after starting the initial treatment with 
improvement in CCCA as compared to CT in the surgical specimen. 
PREDIX LumB study(10) (NCT02603679): an ongoing randomized phase II clinical trial 
in n=200 luminal A/B BC patients with regional lymph node metastases, comparing NA 
weekly paclitaxel vs. standard ET plus palbociclib for 12 weeks; after 12 weeks treatment 
is switched crossover. Choice of ET is for pre- and perimenopausal women and all men 
tamoxifen, alternatively for women in this age cohort, a luteinizing hormone-releasing 
hormone (LHRH) analogue in combination with an aromatase inhibitor (AI), for all 
postmenopausal women treatment with an AI. During the 24-weekly treatment period, 
clinical and radiological evaluations are performed repeatedly. Switch between the 
treatment groups is allowed in case of lack of response or toxicity. Postoperatively, patients 
receive 3-weekly courses of CT with a combination of epirubicin and cyclophosphamide 
(EC). The primary endpoint is Radiological Objective Response Rate after completion of 
the first 12-week treatment period. 
RCB as the only primary endpoint is not an adequate measure to capture the CDK4/6i 
mechanism of action, at least not if short duration, because these are drugs that rarely 
induce apoptosis in BC.  
These studies are optimized regarding the CT duration (4-6 months), but not for ET 
duration. 
The optimal length of ET in the NA setting is unknown, although there are data from a 
sequential cohort study showing a significantly higher clinical and pathological response 
with longer duration: cCR (clinical complete response) of 12.5%, 42.1% and 57.7% and 
pCR of 2.5%, 5% and 17.5% with 4, 8 and 12 months, respectively(11). 
In early BC (EBC), use of NA therapy is an attractive option to facilitate breast 
conservation and, critically, enables the assessment of in vivo biomarkers to identify proof-

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of-principle activity or predict responsive or resistant subgroups of tumors. 
Some ER-positive breast tumors derive limited benefit from CT and might be treated with 
an exclusive ET-based approach(12). In the ACOSOG Z1031B study(13) , tumors resistant 
to NAET [defined by Ki67 > 10% after 2-week treatment with an aromatase inhibitor (AI), 
anastrozole, letrozole or exemestane] were also resistant to NACT. These highly 
proliferating endocrine resistant tumors treated with conventional CT had a pCR rate of 
5%, a pCR rate of > 20% was the predefined efficacy threshold.  
(14)  showed that resistant tumors in the 
ACOSOG Z1031B were enriched in an E2F4 signature. This signature is prognostic of 
poor outcomes and can be downregulated in patients by 2-week treatment with PAL (POP 
trial(15, 16). Interestingly, in BC cell lines resistant to estradiol deprivation, CDK4/6i but 
not paclitaxel or fulvestrant, were able to completely suppress the expression of all genes 
composing the E2F4 signature.  
In the neoMONARCH study(17) (NCT02441946), abemaciclib, alone or in combination 
with anastrozole as NA in EBC, reduced Ki67 expression after 2 weeks of treatment based 
on geometric mean change and patients with complete cell cycle arrest (Ki67 < 2.7%)(18, 
19). A total of 224 postmenopausal women with stage I IIIB HR-positive/HER2-negative 
BC were enrolled. The primary objective evaluated change in Ki67 from baseline to 2 
weeks of treatment. Of the 224 ITT patients, baseline tumor Ki67 expression was available 
at baseline and after 2 weeks of treatment in tumors from 75% of patients including 80% in 
the combination arm, 69% in the abemaciclib arm, and 76% in the anastrozole arm. 
Seventy-eight patients achieved a Ki67 < 2.7%: 67.8% patients treated with abemaciclib + 
anastrozole, 57.7% patients treated with abemaciclib and 14.3% patients treated with 
anastrozole (P < 0.001). The ORR (overall response rate) by radiologic assessment at the 
completion of the study treatment (16 weeks) was of 46.4% and the pCR rate was of 3.7%. 
These data support continued evaluation of abemaciclib in EBC patients. Abemaciclib will 
probably succeed in getting FDA/ European Medicines Agency (EMA) indication for EBC 
ER-positive/HER2 negative disease through the MONARCH-E trial in adjuvant setting. 
mostly after CT as standard of care (SoC). 
Recent results from TAILOR-Rx(20) and MINDACT(21) trials show that CT can be spared 
in patients with low or intermedium risk of recurrence. Patients with High-RS (Recurrence 
Score) (> 30) (Oncotype Dx®) benefit from CT, in part because those patients harbor 
tumors that are resistant to standard ET. The margin benefit of CT in high-RS ER-positive 
BC could be lower if compares to a more efficacious ET regimen (ET/abemaciclib). 
Neoadjuvant setting provides an ideal scenario to test this hypothesis and reach a go/no-go 
signal for an adjuvant study. Once new biological therapies in combination with ET are 

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available, an adequate patient selection for the different biological therapies is warranted. 
Study Treatment:  
Eligible patients will be randomized 1:1 to receive one of the following treatments: 
Control Arm (Arm A): 
 Doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 21 days for 4 
cycles followed by 
 weekly paclitaxel 80mg/m2 for 12 weeks or 3-weekly docetaxel 100mg/m2 for 4 
cycles. 
Approximately duration of 24 weeks (6 months). 
In Arm A, luteinizing hormone-releasing hormone (LHRH) analogs are not allowed in 
premenopausal women. 
Experimental Arm (Arm B): 
 Letrozole 2.5mg orally daily + abemaciclib 150mg orally every 12 hours on a 
continuous dosing schedule plus LHRH analogs in premenopausal women, up to 12 
months (±14 days), with study visits each 28 (±3) days from first study dose. 
After neoadjuvant treatment in each arm, patients will undergo breast surgery, with or 
without +/- regional lymph nodes surgery, of the primary breast cancer. Adjuvant CT will 
tumor response. 
Those patients who do not complete the neoadjuvant treatment according to the study 
protocol because of progression of the disease (PD), unacceptable toxicity or informed 
consent withdrawal, will be discontinued from the study treatment and treated as per 
 and only survival follow-up and death dates (if applicable) will be 
collected.  
Additionally, in those patients who experience recurrence during the follow-up period of 
the study, survival follow-up will also be collected. 
In survival follow-up, only dates on which the patient is alive or not will be collected. 
Study Design and Treatment: 
Study Design 
This is an international, multicenter, open-label, randomized phase II study in the 
neoadjuvant setting.  
Approximately 200 pre- and postmenopausal women with HR-positive/HER2 negative BC 

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centrally assessed, with indication of neoadjuvant treatment, will be included. Patients with 
EBC on stages II-III (T1c N1-2 M0 and tumor size (T) > 2cm  T3, T4a, T4b, and lymph 
node involvement (N) N0-2) according to the 8th edition of the UICC TNM 
Classification(22). The subgroup with tumors T2N0 will include high risk patients based on 
Ki67 index 
and/or histological grade 3. 
Patients will be stratified according to the disease stage (II vs. III), menopausal status 
 
Once the screening process (locally at site and at the central laboratory) is completed, fully 
eligible patients will be randomized in a 1:1 fashion to the control arm with standard CT 
based on anthracyclines and taxanes or to the experimental arm with letrozole + 
abemaciclib (+ LHRH analogs in premenopausal women). 
All patients will be treated according to the stipulations below, unless any of the following 
occur: unacceptable toxicity, progressive disease, or withdrawal of informed consent, 
whatever occurs first. 
After the last dose of any of the drugs in the neoadjuvant combinations, in both treatment 
arms definitive surgery will be performed. For Arm A not earlier than 21 days and not later 
than 42 days after the last dose of chemotherapy, and for Arm B within 7 days from the last 
dose of abemaciclib and/or letrozole, unless toxicities are not recovered completely in any 
treatment arm.  

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Primary Objective: 
 To assess the Residual Cancer Burden (RCB) 0-I rate in both treatment arms. 
Primary End-point: 
 Evaluation of the number of patients with a Residual Cancer Burden (RCB) 0-I 
index as a measure of efficacy. RCB(23) is a continuous variable derived from the 
primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. 
It is estimated from routine pathological sections of the primary breast tumor site 
and the regional lymph nodes after the completion of NA therapy. The pathological 
variables include bidimensional diameters of the primary tumor bed, the proportion 
of primary tumor area containing invasive carcinoma, the number of positive lymph 
nodes, and the diameter of the largest nodal metastasis. 
Secondary Objectives: 
 Changes in Ki67 index value after 2 weeks of treatment in both treatment arms. 
 RCB 0+I vs. RCB-II vs. RCB-III in both treatment arms (TNM downstaging). 
 Changes in RCB value between both treatment arms. 

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 Rate of PEPI score 0 at surgery in both treatment arms. 
 Clinical response measured by magnetic resonance imaging (MRI) according to 
RECIST v1.1 in both treatment arms. 
 Rate of breast conserving surgery (BCS) in both treatment arms. 
 iEFS (invasive Event Free Survival) in both treatment arms. 
 Assessment of safety profile by National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 5.0 classification. 
 To assess molecular downstaging for high risk genomic groups defined by a 
multigene expression panel. 
Secondary End-points: 
 Percentage of decrease in the geometric mean of Ki67 index value after 2 weeks of 
treatment in both treatments arms.  
Number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment 
in both treatment arms. 
 RCB is classified in four classes based on the residual disease (RD): 
o RCB-0 defined as pathological complete response. 
o RCB-I defined as minimal RD. 
o RCB-II defined as moderate RD. 
o RCB-III defined as extensive RD. 
 Variation of RCB value based on the RD between both treatment arms. 
 PEPI (Preoperative Endocrine Prognostic Index)(24) requires pathological stage 
(tumor size and nodal status), level of  Ki67 protein and Allred ER score measured 
Allred score > 2. 
 Clinical Response Rate (CRR) is defined as the proportion of subjects with 
complete or partial radiographic response. Complete response (CR) and partial 
response (PR) definitions are assessed by MRI at baseline and prior to breast 
surgery, with or without regional lymph nodes surgery, and categorized according 
to percent reduction in tumor size. 
 Rate of breast conserving surgery (BCS): defined as the proportion of patients who 
achieved BCS between both treatment arms. 
 Invasive event free survival (iEFS): defined as time from randomization to 
progressive disease (PD) or invasive disease recurrence (local, regional, distant, 

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or contralateral), or death from any cause. Invasive disease recurrence is defined as: 
o Ipsilateral invasive breast tumor recurrence (including second primary 
invasive breast cancer): an invasive breast cancer involving the same breast 
parenchyma as the original primary lesion.  
o Ipsilateral regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, other regional lymph nodes, chest wall, and/or skin of 
the ipsilateral breast). 
o Distant recurrence (i.e., evidence of breast cancer in any anatomic site 
outside local and/or regional location and that has been either histologically 
confirmed or clinically diagnosed as recurrent invasive breast cancer). 
o Contralateral invasive breast cancer. 
o Second primary invasive cancer of non-breast origin. 
 Safety will be assessed by standard clinical and laboratory tests (hematology, serum 
chemistry). AEs grade will be defined by the NCI-CTCAE version 5.0. AEs terms 
will be coded according to MedDRA dictionary. 
 Gene expression data provided by a multigene expression panel in sequential tumor 
biopsies. 
Exploratory Objectives: 
 Correlation of Ki67 protein level change after 2 weeks of treatment with some 
efficacy variables.   
 Genetic changes in sequential tumor samples and tumor evolution during NA 
therapy, and its correlation with some efficacy variables and surrogate endpoints for 
response. 
 To explore T-cell functional activation, immune suppression, neoantigens and 
cytokines production as well as other immune response biomarkers (such as 
CD4/CD8/FOXP3/PDL-1), in order to understand the activity of abemaciclib on the 
tumor microenvironment and the immune response. 
 Circulating tumor DNA (ctDNA) dynamics as a surrogate endpoint for response and 
prognostic implications. 
 Sequential genomic profiling and quantification of ctDNA samples to explore early 
response dynamics, minimal residual disease, tumor tracking, tumor mutational 
burden and clonal diversity along NA therapy and treatment follow up.  
 To investigate if ctDNA dynamics after 2-3 weeks of treatment predicts PEPI score, 

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molecular downstaging, and minimal residual disease in ctDNA samples, and its 
correlation with some efficacy variables. 
 To investigate if ctDNA dynamics after 3-4 weeks post-surgery predicts PEPI score 
and molecular downstaging, and its correlation with some efficacy variables. 
 Genetic changes in pre vs. post NA therapy tumor samples to identify potential 
genomic mechanisms of resistance.  
 To describe ctDNA mutation landscape in resistant tumors. 
 Generation and expansion of ex vivo organoid-based models and/or xenographs 
from post-therapy tumors and if possible, from baseline tumors to perform high-
throughput functional screening studies.  
 Identification of indirect biomarkers of tumor biology and treatment activity by 
metabolomic analysis (glutamine pathway).  
 To explore other possible biomarkers of clinical activity in tumor and blood 
samples. 
Exploratory End-points: 
 Variation of the Ki67 levels, determined by IHC, between pre-treatment and after 2 
weeks-treatment biopsies, and its correlation with some efficacy variables.  
 Mutational and copy number variation (CNV) data analyzed in pre-treatment and 
surgery tumor samples (large targeted gene panels including TP53 and MYC 
mutations and MYC CNVs) and its correlation with some efficacy variables.  
 Gene expression data provided by a multigene expression panel in sequential tumor 
biopsies and its correlation with some efficacy variables. 
 Monitoring of ctDNA abundance and specific tumoral mutation and genetic changes 
observed in ctDNA samples along treatment and follow up.  
 Mutations and CNV detected in ctDNA collected after recurrence. 
 Values of other proteins, metabolites, RNA or DNA alterations obtained from the 
tissue or blood samples and its correlation with efficacy variables could be used 
for assessment of biomarkers related to activity of abemaciclib and breast tumor 
sensitivity and/or resistance to treatment.   
Study population and main inclusion and exclusion criteria: 
Pre- and postmenopausal women with HR positive/HER2 negative intermediate/high risk 
ication of 

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neoadjuvant treatment will be included. 
Inclusion Criteria:  
Patients are eligible to be enrolled in the study only if they meet all of the following 
criteria: 
1. Written informed consent prior to any specific study procedures. 
2. 
years of age. 
3. Documentation of histologically confirmed primary invasive adenocarcinoma of the 
breast. Adenocarcinoma with another component of epithelial origin (for example,  
medullary or neuroendocrine) is allowed. 
4. Availability of a primary tumor tissue sample obtained during the diagnostic 
process before treatment for the central assessment of Ki67 index and biomarker 
exploratory analyses (following the specifications described in the Sample 
Management Manual of the study). 
5. Documentation of HR positive and HER2 negative BC based on local laboratory 
determination. 
a. HR positive is defined as more than or equal to 10% positive cells by IHC 
for ER and/or progesterone receptor (PgR). 
b. HER2 negative tumor is determined according to recommendations of 
ASCO/CAP 2018 guidelines.   
6. 
at a central laboratory. 
7. Patients should be in the following clinical stages of disease according to the 8th 
edition of the TNM Classification of Breast Cancer by the UICC (Union for 
International Cancer Control): T1c N1-2 M0 and T2 (> 2cm)  T3, T4a, T4b, N0  
N2, M0 (stages IIA, IIB, IIIA or IIIB). Subpopulation with tumors T2 N0 M0 will 
and < 30% if PgR negative and/or histological grade 3. 
8. Patients with diagnosis of suspicious for multifocal or multicentric breast cancer 
will be eligible for the study.. At least two tumor lesions should be biopsied. All 
histologically available tumor lesions must comply with the inclusion criterion no. 
5. 
a. If all lesions have similar morphological characteristics (i.e. based on local 
assessment of type, grade, Ki67 index 
largest tumor 
lesion will be assessed for central assessment of Ki67 index level. 

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b. If lesions have different morphological characteristics, discordant tumor 
lesions will be centrally evaluated for Ki67 index level. Patients will be 
eligible if at least one tumor lesion complies with criteria 6 and 7.  
9. Indication of neoadjuvant treatment. 
10. At the time of presentation, patients must be candidates for potentially curative 
 
11. Sentinel lymph node biopsy (SLNB) will be preferable after the neoadjuvant 
treatment. Those patients with SLNB before the neoadjuvant treatment will be 
eligible for the study only if the SLNB has a negative result (N0). One Step Nucleic 
Acid Amplification (OSNA) method is not allowed. 
12. Pre- and postmenopausal women. 
Postmenopausal status is defined as: 
 Patient underwent bilateral oophorectomy, or 
 
 
 Age < 60 years and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-
stimulating hormone (FSH) and plasma estradiol are in the postmenopausal 
ranges per local normal ranges. 
All women who do not meet the criteria for postmenopausal status are considered   
premenopausal for the purpose of this trial. 
13. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
14. Patients are able to swallow oral medications.  
15. Adequate organ and bone marrow function: 
 
3 (1.5x109/L); 
 
3 (100x109/L); 
 
initial treatment must not begin earlier than the day after the erythrocyte 
transfusion); 
 
normal limits if Gilbert´s disease); 
 
 
16. 
-gated 

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acquisition scan (MUGA) or echocardiogram (ECHO). 
17. For premenopausal women: agreement to remain abstinent or use single or 
combined non-hormonal contraceptive methods that result in a failure rate of  < 1% 
per year during the treatment period and for at least 3 weeks after the last dose of 
study treatment. Abstinence is only acceptable if it is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per 
year include tubal ligation, male sterilization, and certain intrauterine devices.  
Alternatively, two methods (e.g., two barrier methods such as a condom and a 
cervical cap) may be combined to achieve a failure rate of < 1% per year.  Barrier 
methods must always be supplemented with the use of a spermicide. 
18. Negative serum pregnancy test within 7 days of the first dose of abemaciclib or 
chemotherapy for premenopausal women, and for women who have experienced 
menopause onset < 12 months prior to first dose of therapy. 
19. Patients consent to biological sample provision for biomarker exploratory analyses.  
20. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests and other study procedures. 
Exclusion Criteria:   
Patients will be excluded from the study if they meet any of the following criteria: 
1. Previous anti-cancer treatment with therapeutic intent for current breast cancer is 
not allowed. 
2. Patients with inflammatory breast cancer or synchronous bilateral invasive breast 
cancers are not eligible.  
3. Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment 
of the investigator, would preclude participation in this study (for example, 
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe 
renal impairment [e.g. estimated creatinine clearance < 30ml/min], history of major 
disease or ulcerative colitis or a preexisting chronic condition resulting in baseline 
Grade 2 or higher diarrhea). 
4. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose- galactose malabsorption. 

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5. Females who are pregnant or lactating. 
6. Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of 
initiating study treatment), fungal infection, or detectable viral infection (such as 
known human immunodeficiency virus positivity or with known active hepatitis B 
or C [for example, hepatitis B surface antigen positive].  Screening is not required 
for enrollment.  
7. Personal history of any of the following conditions: syncope of cardiovascular 
etiology, ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.  
8. Diagnosis of any other malignancy within 5 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the cervix, breast or colorectal. 
9. Prior hematopoietic stem cell or bone marrow transplantation.  
10. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
Justification of Sample size determination and interim analysis: 
A Bayesian design has been used to define the most appropriate sample size. The major 
advantage of this Bayesian approach is to allow us to evaluate how similar response rates 
between both treatment arms are, without using a very large non-inferiority study.  
Comparability of RCB0/1 will be declared if the following Bayesian criterion is achieved in 
the primary RCB0/1 analysis:  
Posterior P(true RCB0/1Chemo  true RCB0/1Abema+AI < 5%) > 80% 
Full detail regarding the Bayesian model for ORR (including prior specifications) will be 
provided in the statistical analysis plan (SAP).  
Simulations were conducted to evaluate probability of declaring comparability based on 
various scenarios of underlying true RCB0/1 values. Different underlying true RCB0/1 
values for abemaciclib plus an AI were considered in the scenarios. 
Three scenarios were explored (n=150, n=200, and n=250) and it is considered that the 2nd 
scenario with a sample size of 200 patients is the best option. Simulation results are shown 
in the table below: 

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Statistical analyses: 
 Demographics and baseline characteristics: 
o Standard descriptive statistics, such as the mean, median, range and 
proportion, will be used to summarize the patient sample and to estimate 
parameters of interest. Ninety-five percent confidence intervals will be 
provided for estimates of interest wherever possible. 
 Safety analyses: 
o Adverse events data and serious adverse events will be reported in frequency 
tables (overall and by intensity). The safety analysis will be performed in the 
safety population. Serious AE and deaths will be provided in a listing. All 
AEs resulting in discontinuation, dose modification, dosing interruption, 
and/or treatment delay of medicinal product will also be listed. 
 
 Efficacy analyses:  
The final efficacy analyses will be performed in the ITT. The primary endpoint is 
the Residual Cancer Burden (RCB) 0-I rate in both treatment arms. Comparability 
between the two treatment arms will be assessed using the following Bayesian 
criterion: 
Posterior P(true RCB0/1Chemo  true RCB0/1Abema+AI < 5%) > 80% 
Posterior medians and Bayesian credible intervals will be reported for the RCB0/1 
rate for each arm. In addition, arms will be compared using a Cochran-Mantel-
Haenszel (CMH) test using the stratification factors. The accompanying 2-sided 
95% confidence intervals (CIs) in each arm and the difference between arms will be 
computed.   
 Biomarker analyses: 
o Biomarker exploratory analyses would include at least gene expression 
analysis to determine intrinsic subtypes and gene signatures of interest in 
sequential tumor samples, characterization of mutational genetic profiles and 
monitoring residual disease and tumor burden in tumor and ctDNA samples 

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along the study, as well as proteomics and metabolomics analyses. All 
biomarkers will be correlated with efficacy endpoints, as feasible.  
Study Duration: 
The start date of study is the date of the first site activation. 
Recruitment period will occur during approximately 2 years from first patient in (FPI). 
There would be a follow-up period of 10 years. 
The end date of study is the date of the last visit of the last patient (LPLV) including 
follow-up. 
Performing exploratory analyses will be independent of the date of the end of the study. 
 
 
 

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Table of Contents  
Section                                                                                                          Page 
1. 
Introduction .......................................................................................... 30 
1.1. 
Overview of Breast Cancer ............................................................. 30 
1.2. 
Neoadjuvant Treatment for HR-positive Breast Cancer ................. 31 
1.3.  Role of Abemaciclib in the Treatment of Breast Cancer ................ 32 
1.3.1 Abemaciclib in Advanced Breast Cancer ...................................... 32 
1.3.2 Abemaciclib in Early Stage Breast Cancer ................................... 38 
1.4. 
Overview of Abemaciclib ............................................................... 40 
1.4.1 
Preclinical Data ....................................................................... 40 
1.4.2 
Human Pharmacokinetic (PK) Data ....................................... 44 
1.4.3 
Pharmacodynamic and Biomarker Analyses .......................... 48 
1.4.4 
QTc Evaluation Data .............................................................. 49 
1.4.5 Abemaciclib Dose Rationale ......................................................... 49 
1.5.  Study Rationale ............................................................................... 50 
2. 
Objectives ............................................................................................. 60 
2.1. 
Primary Objective ........................................................................... 60 
2.2.  Primary End-point ........................................................................... 60 
2.3. 
Secondary Objectives ...................................................................... 60 
2.4.  Secondary End-points ..................................................................... 60 
2.5.  Exploratory Objectives.................................................................... 62 
2.6.  Exploratory End-points ................................................................... 63 
3. 
Investigational Plan .............................................................................. 64 
3.1. 
Study Design ................................................................................... 64 
3.2. 
Duration of the study ....................................................................... 66 
4. 
Study Population .................................................................................. 68 
4.1. 
Inclusion Criteria ............................................................................. 68 
4.2. 
Exclusion Criteria............................................................................ 70 
4.3. 
Discontinuations .............................................................................. 71 
4.3.1. 
Discontinuation of Study Treatment ....................................... 71 
4.3.2. 
Discontinuation of Study Sites ............................................... 72 
4.3.3. 
Discontinuation of Study ........................................................ 72 
5. 
Treatment ............................................................................................. 73 
5.1. 
Treatments Administered ................................................................ 73 
5.1.1. 
Study Treatment Arm A ......................................................... 73 

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5.1.2. 
Study Treatment Arm B .......................................................... 73 
5.2. 
Materials and Supplies .................................................................... 73 
5.2.1.  
Storage, preparation and administration ................................. 74 
5.2.1.1. 
Abemaciclib ...................................................................... 74 
5.2.1.2. 
Letrozole ........................................................................... 75 
5.2.1.3.  
Doxorubicin, Cyclophosphamide and Paclitaxel or 
Docetaxel .......................................................................... 75 
5.2.2. 
 Accountability ........................................................................ 75 
5.3. 
Method of Assigning a Patient to a Treatment................................ 76 
5.4. 
Special Treatment Considerations. Dose Adjustments of 
Study Treatment .............................................................................. 76 
5.4.1.  
Abemaciclib ............................................................................ 77 
5.4.1.1. 
Dose Adjustements ........................................................... 78 
5.4.1.2 Guidelines for Diarrhea Management ..................................... 78 
5.4.1.3 General Guidance for Increases in Serum Creatinine 
and Assessment of Renal Insufficiency ............................ 79 
5.4.1.4 General Guidance for Interstitial Lung Disease 
(ILD)/Pneumonitis Events ................................................ 79 
5.4.1.5 General Guidance for Hepatic Monitoring .............................. 80 
5.4.1.6 General Guidance for Hematology Toxicity and Dose 
Modification ...................................................................... 82 
5.4.1.7 General Guidance for Non-hematologic Toxicities 
(excluding diarrhea, increased ALT/AST and 
Venous Thromboembolic Events) Monitoring ................. 83 
5.4.2. 
Letrozole ................................................................................. 84 
5.4.3.  Doxorubicin, Cyclophosphamide and Paclitaxel or 
Docetaxel ................................................................................ 84 
5.5. 
Medication Errors and Overdose .................................................... 84 
5.6. 
General Concomitant Medication and Supportive Care 
Guidelines ....................................................................................... 85 
5.6.1. 
Prohibited Medications ........................................................... 85 
5.6.2. 
Medications Not Recommended............................................. 86 
5.6.3. 
Permitted Medications ............................................................ 87 
5.6.4. 
General Guidance for Women of Child Bearing 
Potential and/or Use of Contraceptive Methods ..................... 88 
5.7. 
Treatment Compliance .................................................................... 88 
6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of 
Assessments ......................................................................................... 90 

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6.1. 
Efficacy Assessments ...................................................................... 90 
6.1.1. 
Primary Efficacy Assessments ............................................... 90 
6.1.2. 
Secondary Efficacy Assessments ........................................... 90 
6.2. 
Safety Assessments ......................................................................... 92 
6.2.1. 
Timing of Assessments ........................................................... 93 
6.2.2. 
Definitions .............................................................................. 94 
6.2.3 
Management, Timing and Assessment of Adverse 
Events ..................................................................................... 96 
6.2.4. 
Management, Timing and Assessment of 
SAEs/pregnancies ................................................................... 99 
6.2.5. 
Management, Timing and Assessment of SUSARs ............. 102 
6.3. 
Other Assessments ........................................................................ 104 
6.3.1. 
Biomarker Assessments ........................................................ 104 
7. 
Data Quality Assurance ...................................................................... 108 
7.1. 
Data Management and Registries file ........................................... 108 
8. 
Sample Size and Statistical Methods ................................................. 110 
8.1. 
Determination of Sample Size ...................................................... 110 
8.1.1. 
Sample Size determination ................................................... 110 
8.2. 
Statistical and Analytical Plans ..................................................... 110 
8.2.1. 
General Considerations ......................................................... 110 
8.2.1.1. 
Patient Populations .......................................................... 111 
8.2.2. 
Patient Disposition ................................................................ 111 
8.2.3. 
Patient Characteristics .......................................................... 111 
8.2.4. 
Concomitant Therapy ........................................................... 112 
8.2.5. 
Treatment Compliance .......................................................... 112 
8.2.6. 
Efficacy Analyses ................................................................. 112 
8.2.6.1. 
Analyses of Primary Endpoint ........................................ 112 
8.2.6.2. 
Analysis of Secondary Endpoints ................................... 113 
8.2.7. 
Safety Analyses .................................................................... 115 
8.2.8. 
Other Analyses ...................................................................... 116 
8.2.8.2. 
Biomarker Analyses ........................................................ 116 
8.2.9. 
Subgroup Analyses ............................................................... 117 
8.2.12. 
Criteria for End of Study ...................................................... 117 
9. 
Informed Consent, Confidentiality, Responsibility Insurance 
and Regulatory Considerations .......................................................... 118 
9.1. 
Informed Consent .......................................................................... 118 
9.2. 
Respect of Confidentiality............................................................. 118 

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9.3. 
Insurance and Compensation for Injury ........................................ 119 
9.4. 
Regulatory Considerations ............................................................ 119 
9.4.1. 
Investigator Information ....................................................... 119 
9.4.2. 
Protocol Signatures ............................................................... 119 
10. Practical Considerations ..................................................................... 120 
10.1.  Monitoring, Audit and Inspections .............................................. 120 
10.2 Protocol Deviations ....................................................................... 120 
10.3.  Preservation of Study Documentation ......................................... 120 
10.4.  Protocol Modification .................................................................. 120 
10.5.  Use of the Information and Publication ....................................... 121 
10.5.1 
Clinical Trial Registration .................................................... 121 
10.5.2 
Clinical Trial Results Disclosure .......................................... 122 
10.6.  Ethics Committees and/or IRBs ................................................... 122 
11. References .......................................................................................... 123 
Protocol Attachment 1. Study Schedule ..................................................... 128 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status ............................................................................. 134 
Protocol Attachment 3. Adverse event (AE) non defined in CTCAE ........ 135 
Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide .............................................................................. 136 
Protocol Attachment 5. List of inducers and strong inhibitors of 
CYP3A ............................................................................................... 137 

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AE 
Adverse Event 
AEMPS 
Spanish Agency for Medicines and Health Products 
AESI 
Adverse Event of Special Interest 
AI 
Aromatase Inhibitor 
ALT/ALAT (SGPT) 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
AR 
Adverse Reaction 
AST/ASAT (SGOT) 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BC 
BCS 
Breast Cancer 
Breast Conservative Surgery 
BID 
CBP 
 
cCR 
Twice A Day 
Child Bearing Potential: premenopausal women, and for women who have 
experienced menopause onset < 12 month prior to first dose of therapy. 
Clinical Complete Response 
CDK 
Cyclin-Dependent Kinase 
ctDNA 
Circulating tumoral  DNA 
CI 
Confidence Interval 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
CR 
CT 
Complete Response 
Chemotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DDI 
Drug-Drug Interaction 

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DFS 
 
DLT 
Disease-Free Survival 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DSUR 
EBC 
Development Safety Update Report 
Early Breast Cancer 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). An 
required by the protocol. 
ECG 
ECHO 
Electrocardiogram 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
End of Study (Trial) 
The end of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active patient in the study, including follow-up  
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned a registration number and treatment.  
ER 
Estrogen Receptor 
ER1 
Estrogen Receptor 1 
ER-LBD 
Estrogen Receptor-Ligand Binding Domain 
EC/IRB 
Ethics Committee/Institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical trial are protected. 
ESR 
ET 
Expedited Safety Report 
Endocrine Thearapy 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GEICAM 
Spanish Breast Cancer Group 

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G-CSF 
Granulocyte Colony-Stimulating Factor 
GI 
GastroIntestinal 
HER2 
Human Epidermal Growth Factor Receptor 2 
Hgb 
Hemoglobin 
HR 
Hormone Receptor or Hazard Ratio depending on the context 
IA 
Interim Analysis 
ICD 
Informed Consent Document  
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 
ISH 
In Situ Hybridization 
ITT 
Intent To Treat 
Legal Representative 
An individual, judicial, or other body authorized under applicable law to consent, on 
 
LLN 
Lower Limit of Normal 
LFT 
Liver Function test 
MBC 
Metastatic Breast Cancer 
MID 
Minimally important difference 
MRI 
Magnetic Resonance Imaging 
mRNA 
 
MUGA 
Messenger Ribonucleic Acid 
 
Multigated Acquisition Scan 
NA 
Neoadjuvant 
NCI 
National Cancer Institute 
NACT 
Neoadjuvant Chemotherapy  

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NAET 
Neoadjuvant Endocrine Therapy 
NSAI 
Non-Steroidal Aromatase Inhibitor 
OR 
 
ORR 
Objective Response 
 
Objective Response Rate 
OS 
Overall Survival 
Patient 
A subject with a defined disease 
pCR 
Pathological Complete Response 
PD 
Progressive Disease or Pharmacodynamic depending on the context 
PEPI 
Preoperative Endocrine Prognostic Index 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Perfomance Status 
QD 
Once A Day 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCB 
Residual Cancer Burden 
RR 
Response Rate 
RS 
Recurrence Score 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAI 
Steroidal aromatase inhibitor 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 

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Screen 
 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
screened into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives. 
SD 
Stable Disease 
SGOT 
Serum Glutamate-Oxoloacetate Transaminase 
SGPT 
Serum Glutamate-Pyruvate Transaminase 
SLN 
Sentinel Lymph Node 
SMM 
Sample Management Manual 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TN 
Triple Negative 
TNM 
Tumor, Node, Metastasis, for the purpose of staging 
TTP 
Time To Progression 
ULN 
 
US 
Upper Limit of Normal 
 
Ultrasound 
VTE 
Venous Thromboembolism 
WNL 
Within Normal Limits 
 
 
 
 
 
 
 
 
 
 

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Protocol GEICAM/2019-01 
Phase II, randomized, open-label, international, multicenter study to 
compare efficacy of standard chemotherapy vs. letrozole plus abemaciclib 
as neoadjuvant therapy in HR-positive/HER2-negative high/intermediate 
risk breast cancer patients 
 

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1. Introduction 
1.1. 
Overview of Breast Cancer 
Breast cancer is the most commonly diagnosed cancer and the leading cause of 
cancer death among women, with an estimation of 2 million new cases and more than 
600,000 deaths in 2018, worldwide(25).  Breast cancer is a heterogeneous disease with 
multiple clinical, histopathological and genomics characteristics(26, 27). The hormone 
receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative 
(HER2-negative) is the more common subtype and accounts for approximately 70% of all 
breast cancers(28). Gene expression profiling studies have classified breast tumors into 
several distinct biological subtypes with prognostic and therapeutic implications. According 
to this classification, four main molecular subtypes have been identified: Luminal A, 
Luminal B, HER2-enriched, and Basal. The molecular subtypes of breast cancer correspond 
reasonably well to a classification based on immunohistochemistry (IHC) markers on the 
basis of  HR status , HER2 status  and proliferation markers (ie, Ki67)(29).  The most 
common subtypes are HR-positive (ER-positive and/or PgR-positive)/HER2-negative, 
comprising Luminal A-like and Luminal B-
low PgR (< 20%) value may be used to distinguish between  Luminal A-like (more 
endocrine sensitive, indolent, better prognosis) and Luminal B-like (less endocrine 
sensitive, more aggressive, worse prognosis) tumors(30, 31). Luminal A like tumors are 
ER-positive and HER2-negative with low Ki67 expression (< 14%) or with intermediate 
Ki67 expression (14% to 19%) and high PgR levels (> 20%).  Luminal B like  tumors are 
ER-positive and HER2-negative with intermediate Ki67 expression (14% to 19%) and low 
(32). The vast majority of  
patients with luminal breast cancer are diagnosed at an early stage of their disease which 
are potentially curable with locoregional treatments  such as surgery and radiation(33). 
After surgery, HR-positive early breast cancer (EBC) is usually treated with adjuvant 
endocrine therapy (ET) and, depending on the estimated individual risk of disease 
recurrence, adjuvant chemotherapy (CT)(34).  Most validated clinical and pathological 
features that may indicate a higher risk of disease recurrence, and therefore the need for 
adjuvant CT, include large primary tumor size and involvement of axillary lymph nodes. 
Other prognostic factors are, histopathological grade, PgR expression, Ki67 expression, 
multi-gene testing recurrence scores, age and comorbidities. Using these factors, EBC can 
be classified as having low, intermediate/moderate or high risk for recurrence after 
surgery(35). Patients with smaller tumors, no axillary involvement and Luminal A-like 
characteristics or low recurrence genomic score, derive little benefit, if any, from the 
addition of adjuvant CT to ET. On the other hand, patients with metastases in multiple 
axillary lymph nodes, Luminal B-like tumors or high recurrence genomic score have a 
higher risk of recurrence and are usually considered for adjuvant CT, in addition to ET(20, 

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21). With current standard of care adjuvant therapy, approximately 25-30% of women with 
high risk early stage HR-positive breast cancer experience recurrence(36, 37). 
Consequently, there is a critical need for more optimal adjuvant therapy in patients with 
early HR-positive breast cancer who have a high likelihood of distant recurrence. 
1.2. 
Neoadjuvant Treatment for HR-positive Breast Cancer 
Neoadjuvant treatment of breast cancer is increasingly used to improve the chance 
of breast conservation and as a platform for the development of investigational drugs, 
triaging of novel combinations, biomarker validation, and discovery of mechanisms of drug 
resistance. In contrast to adjuvant setting, neoadjuvant CT (NACT) remains the first 
treatment option for most HR-positive/HER2-negative breast cancer patients and 
neoadjuvant endocrine therapy (NAET) is commonly relegated for elderly patients who are 
unsuitable for CT. The efficacy of NACT depends on the regimens used. Anthracyclines 
and taxanes are the most active group of CT regimens used for BC patients(38). Currently 
only 3% of eligible patients in the United States receive NAET treatment(37). However, 
two randomized phase II trials of NAET vs. NACT showed a similar response and rate of 
breast conservation for both treatment arms, with substantially less toxicity with ET. 
Although 3 to 4 months has been the standard 
seem to be a consensus that this length of treatment is insufficient to reach maximal tumor 
response. Non-randomized studies suggest that some tumors benefit from a longer duration 
(6 12 months) of anti-ER treatment(39-41). 
 Recently, an increasing number of NAET are testing new drugs in combination 
with ET in patients with HR-positive BC(2). Conducting these trials are more challenging 
than trials of NACT and/or anti-HER2 therapy in patients with triple negative (TN) or 
HER2-positive BC, respectively. A main limitation is that pathological complete response 
(pCR), a well-stablished biomarker in TN and HER2-positive BC(3), is uncommon after 3 
to 4 months of NAET and not an effective surrogate of long-term outcome in patients with 
HR-positive/HER2-negative BC(42, 43).  Therapy-induced changes in the proliferation 
marker Ki67 and the preoperative endocrine prognostic index (PEPI), a composite score of 
post-treatment ER, Ki67, tumor size, and axillary nodal status, are widely used markers of 
response to antiestrogens in NAET trials. A high post-treatment Ki67 score and a high 
PEPI score have been shown to correlate with an increased risk of recurrence(13, 24, 44, 
45). The Residual Cancer Burden (RCB) index is another biomarker of response to NACT 
that is increasingly used in NAET studies. The RCB index evaluates 5 post-treatment 
variables: two-dimensional tumor bed, cellularity, percentage of carcinoma in situ (CIS), 
number of metastatic lymph nodes, and the diameter of the largest nodal metastases. It 
classifies the surgical specimen into four categories: RCB-0 (pCR), RCB-I (minimal 
residual disease), RCB-II (moderate residual disease), and RCB-III (extensive residual 
disease). RCB is able to predict risk of recurrence after NACT, which is highest for RCB-

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III (53.6%) and similar for RCB-0 and RCB-I (2.4% and 5.4%, respectively)(23, 46). 
Interestingly, the incorporation of Ki67 into RCB improved the prognostic ability of either 
Ki67 and RCB alone(47). 
The preoperative therapy setting is an excellent clinical research platform where 
treatment can be compared and triaged using endpoints that correlate with long-term 
outcome. There are multiples examples where NAET trials results predicts outcome from 
adjuvant and metastatic studies(2). An illustrative example supporting the value of the NA 
platform for clinical trial prioritization is provided by IMPACT trial(45) comparing 
anastrozole, tamoxifen, or the combination for 12 weeks. In IMPACT, following 2 and 12 
weeks of treatment, anastrozole suppressed Ki67 by 76% and 82%, respectively, compared 
with tamoxifen by 59% and 62%, and the combination of both drugs by 64% and 61%. 
These differences paralleled the outcome of the same three treatment arms in the large 
adjuvant ATAC trial which enrolled more than 9,000 women(48). After a median follow-up 
of 30 months, anastrozole significantly improved disease-free survival (DFS) over 
tamoxifen and the combination, whereas DFS was similar in the tamoxifen and 
combination arms. It can be argued that had the results of IMPACT been known before the 
ATAC trial, these data would have provided a rationale for elimination of the combination 
arm in ATAC trial, thus significantly reducing the size, duration, and cost of the adjuvant 
study. 
1.3.  Role of Abemaciclib in the Treatment of Breast Cancer 
1.3.1 Abemaciclib in Advanced Breast Cancer 
The treatment of metastatic HR-positive/HER2-negative BC has changed since the 
approval of cyclin-dependent kinases (CDK) 4 and 6 inhibitors (CDK4/6i). These drugs, in 
combination with ET, have consistently and homogeneously demonstrated doubling the 
progression free survival (PFS) interval (from approximately 14 to 28 months in the first 
line), increase of response rates and delay in the start of CT. All these benefits are achieved 
with minimal toxicity and an excellent quality of life perceived by patients(20, 21, 36, 37, 
39, 40). 
Abemaciclib is a potent and selective small-molecule CDK4/6i administrated orally 
on a twice daily continuous schedule. Abemaciclib is structurally distinct from other 
CDK4/6i (such as ribociclib and palbociclib) and is 14 times more potent against cyclin 
D1/CDK4 than against cyclin D3/CDK6 in enzymatic assays(49). Currently, abemaciclib is 
FDA-EMA approved for the treatment of advanced HR-positive/HER2-negative BC in 
three scenarios: 
1) As first line treatment, based on MONARCH-3 trial(50): a randomized (2:1), double-
blinded, placebo-controlled, multicenter clinical trial in postmenopausal women with 

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HR-positive/HER2-negative BC. A total of 493 patients were randomized to receive 
either abemaciclib 150mg 
letrozole or anastrozole. The estimated median PFS was 28.2 months (95% CI: 23.5, 
not reached) for patients receiving abemaciclib and 14.8 months (95% CI: 11.2, 19.2) 
for those receiving placebo (HR 0.540; 95% CI: 0.418, 0.698; p < 0.0001).  
2) As second line treatment, based on MONARCH-2 trial(51) : a randomized, placebo-
controlled, multicenter trial in women with HR-positive/HER2-negative metastatic 
breast cancer (MBC), disease progression following ET and who had not received CT 
in the metastatic setting. A total of 669 patients received either abemaciclib or placebo 
orally twice daily plus fulvestrant 500mg on days 1 and 15 of cycle 1 and then on day 1 
of cycle 2 and beyond (28-day cycles). Median PFS for patients taking fulvestrant with 
abemaciclib was 16.4 months compared with 9.3 months for those taking fulvestrant 
with placebo (HR 0.553; 95% CI: 0.449, 0.681; p < 0.0001). The objective response 
rate (ORR) in patients with measurable disease taking fulvestrant with abemaciclib was 
48.1% (95% CI: 42.6, 53.6) compared to 21.3% (95% CI 15.1, 27.6) in the fulvestrant 
with placebo treated patients. 
3) As third or greater line, based on MONARCH-1 trial(52): a single-arm, open-label, 
multicenter study in women with measurable HR-positive/HER2-negative MBC whose 
disease progressed during or after ET, had received a taxane in any setting, and one or 
two prior CT regimens in the metastatic setting. A total of 132 patients received 
abemaciclib 200mg orally twice daily on a continuous schedule until PD or 
unmanageable toxicity. Objective response rate was 19.7 percent (95% CI: 13.3, 27.5) 
with a median response duration of 8.6 months (95% CI: 5.8, 10.2). This indication is 
only included in the FDA approval. 
 
Abemaciclib is indicated for the treatment of HR-positive, HER2-negative advanced 
or metastatic BC: 
 in combination with an AI, 
 in combination with fulvestrant, and  
 as a single agent following progressive disease (PD) after ET and CT 
regimens. 
Refer to the local label for information regarding the precise indications approved in a 
specific country or region. 
The recommended dose of abemaciclib in combination with ET is 150 mg orally, BID on a 
continuous dosing schedule. The recommended dose of abemaciclib as a single agent is 200 
mg orally, BID on a continuous dosing schedule. It is recommended that treatment be 
continued until PD or unacceptable toxicity.  Abemaciclib may be taken with or without 
food. Abemaciclib is available as 50-, 100-, 150-, and 200-mg tablets. 

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Management of some adverse reactions may require dose interruption and/or dose 
reduction.  If dose reduction is necessary, decrease the dose by 50 mg at a time.  
Discontinue abemaciclib for patients unable to tolerate 50 mg BID.  
Three registration studies (MONARCH 3, MONARCH 2, and MONARCH 1) 
provide the primary safety data supporting abemaciclib use in combination with endocrine 
therapies and as a single agent.  Adverse events of special interests (AESIs) were 
determined to be events that were:  
 of clinical significance  
 potentially associated with other agents that inhibit CDK4 and CDK6, or  
 observed in preclinical evaluation or earlier clinical studies of abemaciclib, although in 
some instances a causal association with abemaciclib could not be clearly established.   
The following AEs are considered to be AESIs for abemaciclib:   
 neutropenia,  
 infections,  
 diarrhea,  
 hepatic events, including increases in AST and ALT,  
 venous thromboembolic events (VTEs), and  
 ILD/pneumonitis.   
 
Overall, the safety profile of the three registration studies was generally consistent 
in terms of adverse event (AE) incidence and severity. The most frequent toxicities were of 
low grade (grade 1 or 2), generally predictable, manageable, and reversible. The most 
commonly reported treatment-emergent adverse events (TEAE) included diarrhea, 
neutropenia, fatigue, nausea, vomiting, abdominal pain, decreased appetite, and anemia. 
The most common AEs leading to dose reductions, dose omissions, or discontinuation of 
abemaciclib included diarrhea and neutropenia. Overall, the safety profile of abemaciclib 
remains unchanged based on the completed and ongoing studies. 
 Diarrhea was the most commonly treatment-emergent adverse event (TEAE) with 
abemaciclib in the reported studies. Incidence was greatest during the first month of 
abemaciclib treatment and was lower subsequently. The median time to onset of the 
first diarrhea event was approximately 6 to 8 days across studies, and the median 
duration of diarrhea was 9 to 12 days (Grade 2) and 6 to 8 days (Grade 3) across 
abemaciclib studies in combination with ET. Exposure-response analyses demonstrated 
that dose was the most important factor related to diarrhea. There was 1 Grade 5 (fatal) 
event of diarrhea reported in the EBC Study JPCF which occurred in the setting of 
acute intra-abdominal sepsis. Diarrhea returned to baseline or lesser grade with 
supportive treatment such as loperamide and/or dose adjustment. At the first sign of 

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loose stools, treatment with antidiarrheal agents, such as loperamide, should be 
initiated. 
 Neutropenia has been observed in studies with single-agent abemaciclib and when 
combined with ET and was predominantly of low-grade severity. It was reported 
frequently (45.1%) and a Grade 3 or 4 decrease in neutrophil counts (based on 
laboratory findings) was reported in 28.2% of patients receiving abemaciclib in 
combination with aromatase inhibitors (AIs) or fulvestrant. The median time to onset of 
Grade 3 or 4 neutropenia was 29 to 33 days, and median time to resolution was 11 to 15 
days. On central laboratory analysis, neutrophil count decrease from the baseline visit 
was observed; mean neutrophil counts generally remained stable at the later visits and 
were reversible once patients discontinued the treatment. Febrile neutropenia was 
reported in 0.9% patients. Dose modification is recommended for patients who develop 
Grade 3 or 4 neutropenia. 
 Increased aminotransferases in patients receiving abemaciclib in combination with AIs 
or fulvestrant, ALT and AST elevations were reported frequently (15.1% and 14.2%, 
respectively). Elevations in ALT/AST were predominantly of Grade 1 or Grade 2 
severity, and a concurrent increase in blood bilirubin was infrequent. Generally, ALT 
and AST increases were manageable by dose reduction or dose omission and resolved 
upon discontinuation of study treatment.  Several patients had isolated episodes of 
elevated ALT and AST that resolved without dose adjustment. Grade 3 or 4 ALT or 
AST elevations (based on laboratory findings) were reported in 6.1% and 4.2% patients. 
The median time to onset of Grade 3 or 4 ALT elevation was 57 to 61 days, and median 
time to resolution was 14 days. The median time to onset of Grade 3 or 4 AST elevation 
was 71 to 185 days, and median time to resolution was 13 to 15 days. Dose 
modification is recommended for patients who develop ALT or AST increase of Grade 
3 or 4 or experience persistent or recurrent Grade 2. 
 Venous thromboembolic events (VTE): in randomized Phase 3 studies in patients with 
ABC or EBC treated with abemaciclib in combination with ET, a greater number of 
patients experienced VTE events in the abemaciclib plus ET arm than in the placebo 
plus ET arme or ET alone arm. Patients were treated with low molecular weight heparin 
(LMWH) and generally, these events did not result in discontinuation of the study 
treatment. At this time, the mechanism underlying the association between abemaciclib 
and the occurrence of VTEs is not known.  Venous thromboembolic events have been 
reported with other CDK4 and 6 inhibitors, and ETendocrine therapy is known to be 
associated with the occurrence of VTEs. 
 Interstitial lung disease (ILD)/Pneumonitis: in randomized Phase 3 studies, in patients 
with ABC, EBC, and in patients with stage IV non-small cell lung cancer, 
ILD/pneumonitis events, including ILD, pneumonitis, organizing pneumonia, and 
pulmonary fibrosis, were reported. The majority of events were Grade 1 or Grade 2, 

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with serious cases and fatal events reported in each study.  Most of the events were 
confounded due to factors such as lung metastases, prior exposure to radiation, presence 
of infection, and/or administration of other medication (e.g., prior chemotherapeutic 
agents known to cause pneumonitis).  Patients who develop new or worsening 
pulmonary symptoms such as dyspnea, cough, and fever should be investigated and 
treated as per local clinical practice and/or guidelines.  Investigations may include 
imaging, such as high resolution computed tomography (HRCT), broncheoalveolar 
lavage (BAL), and biopsy as clinically indicated.  Discontinue abemaciclib in cases of 
severe (Grade 3 or 4) ILD/pneumonitis.  In cases of non-severe ILD/pneumonitis, the 
benefit of resuming abemaciclib treatment must be carefully evaluated.   
 Ocular effects: in rodents, cataracts/lens fiber degeneration and retinal atrophy have 
been observed at clinically relevant abemaciclib exposure levels. Patients who 
experience changes in vision should undergo ophthalmological investigations as 
clinically indicated. 
 Creatinine: although not an AR, abemaciclib has been shown to increase serum 
creatinine in 98.3% of patients (based on laboratory findings), 1.9% Grade 3 or 4 (based 
on laboratory findings). In patients receiving an AI or fulvestrant alone, 78.4% reported 
an increase in serum creatinine (all laboratory grades).  
 Carcinogenicity: in a 2-year carcinogenicity study in rats, interstitial (Leydig) cell 
hyperplasia and benign interstitial (Leydig) cell adenomas in the testes were observed at 
clinically relevant exposure levels. Male patients should be instructed to conduct 
regular self-examination of their testicles and report any new symptoms or changes. 
 Reproductive safety: abemaciclib has not been studied in pregnant or lactating women; 
therefore, no clinical data are available.  Animal studies indicate that abemaciclib has 
the potential to cause fetal harm when administered to a pregnant woman. Male animals 
given abemaciclib had injury to their testes; therefore, male patients should be advised 
about the possibility of infertility. 
 
Table 1. Tabulated List of Adverse Reactions 
In the following table, adverse reactions (ARs) are listed in order of MedDRA body 
system 
1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available 
data). Within each frequency grouping, ARs are presented in order of decreasing 
seriousness. 
 
 

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System organ 
class 
Frequency 
Preferred term 
Abemaciclib plus ETa 
All Grades 
Toxicity (%) 
Grade 3 
Toxicity (%) 
Grade 4 
Toxicity (%) 
Infections and infestations 
Very common 
  Infectionsb 
 
 
43.6 
 
 
5.2 
 
 
1.0 
Blood and lymphatic system disorders 
Very common 
  Neutropenia 
  Leukopenia 
  Anemia 
  Thrombocytopenia 
Common 
  Lymphopenia 
Uncommon 
     Febrile neutropenia 
 
 
45.1 
25.7 
30.1 
14.3 
 
7.3 
 
0.9 
 
 
22.9 
8.5 
7.0 
2.2 
 
3.0 
 
0.7 
 
 
2.5 
0.3 
0.1 
1.0 
 
0.1 
 
0.1 
Metabolism and nutrition disorders 
Very common 
  Decreased appetite 
 
 
26.4 
 
 
1.3 
 
 
0 
Nervous system disorders 
Very common 
  Dysgeusia 
  Dizziness 
 
 
14.3 
12.9 
 
 
0 
0.5 
 
 
0 
0 
Eye disorders 
Common 
Lacrimation increased 
 
 
6.8 
 
 
0.1 
 
 
0 
Vascular disorders 
Common 
Venous thromboembolismc 
 
 
5.3 
 
 
1.7 
 
 
0.3 
Gastrointestinal disorders 
Very common 
  Diarrhea 
  Vomiting 
  Nausea 
 
 
84.6 
27.7 
43.5 
 
 
11.7 
1.2 
2.1 
 
 
0 
0 
0 
Skin and subcutaneous tissue disorders 
Very common 
  Alopecia Pruritus 
  Rash 
Common 
  Dry 
skin
 
 
20.7 
13.5 
12.9 
 
9.0
 
 
0 
0 
1.0 
 
0 
 
 
0 
0 
0 
 
0 
Musculoskeletal and connective tissue 
disorders 
Common 
    Muscular weakness 
 
 
 
8.3 
 
 
 
0.5 
 
 
 
0 

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System organ 
class 
Frequency 
Preferred term 
Abemaciclib plus ETa 
All Grades 
Toxicity (%) 
Grade 3 
Toxicity (%) 
Grade 4 
Toxicity (%) 
General disorders and administration site 
Conditions 
  Very common  
    Fatigue 
    Pyrexia 
 
 
 
40.5 
10.7 
 
 
 
2.3 
0.1 
 
 
 
0 
0 
Investigations 
Very common 
  Alanine aminotransferase increased 
  Aspartate aminotransferase increased 
 
 
15.1 
14.2 
 
 
4.8 
2.9 
 
 
0.3 
0 
a. 
Abemaciclib in combination with letrozole, anastrozole, or fulvestrant. 
b. Infections include all preferred terms (PTs) that are part of the System Organ Class Infections and 
infestations. 
c. 
Venous thromboembolic events include deep venous thrombosis (DVT), pulmonary embolism, cerebral 
venous sinus thrombosis, subclavian, axillary vein thrombosis, DVT inferior vena cava and pelvic venous 
thrombosis. 
 
1.3.2 Abemaciclib in Early Stage Breast Cancer 
The exciting results observed with CDK4/6i in the treatment of advanced HR-
positive/HER2-negative BC patients have activated the evaluation of these agents in the 
early-stage setting. Several studies have explored the efficacy of CDK4/6i and ET over ET 
alone as preoperative treatment. In all of them, the combination induced a more potent cell 
cycle arrest than ET alone(6, 19, 53, 54). 
NeoMONARCH (NCT02441946) was a multicenter, randomized, open-label, phase 
2 study comparing the biological effects of abemaciclib in combination with anastrozole to 
those of abemaciclib monotherapy and anastrozole monotherapy for women with early-
stage HR-positive/HER2-negative BC. The study met its primary endpoint demonstrating 
that abemaciclib alone and in combination with anastrozole significantly reduced Ki67 
expression after 2 weeks of treatment compared to anastrozole alone. Complete cell cycle 
arrest (Ki67 < 2.7%) after two weeks of treatment was 68% for abemaciclib and 
anastrozole and 14% for anastrozole monotherapy. After 16 weeks of treatment with the 
combination, 53% of patients achieved a radiological response (partial or complete 
response) and 7 patients (3.7%) obtained a pCR. Subgroup analyses demonstrated that 
abemaciclib efficacy was not associated with disease stage, baseline lymph node 
involvement, tumor grade, tumor size, or PIK3CA mutation status. The high activity of 
abemaciclib in the NA setting supports a large ongoing phase III adjuvant trial (monarchE) 
that evaluates the potential for abemaciclib to enhance adjuvant ET. MonarchE is a 

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multicenter, randomized, open-label, phase III study assessing the efficacy of twice-daily 
intake of 150mg abemaciclib for 2 years plus adjuvant ET (5-10 years) vs. adjuvant ET 
alone (5-10 years), in terms of invasive disease-free survival (iDFS).  
MonarchE (NCT03155997) is an ongoing study including high risk early stage BC 
defined as: pathological tumor 
profile of abemaciclib plus ET in this Phase 3 study was acceptable, monitorable, 
manageable, and generally consistent with that previously reported for abemaciclib and ET. 
ET treated patients, with diminishing frequencies over time. The overall incidence of all 
population.The efficacy results described here are based on the second efficacy interim 
analysis using a data cut-off date of 16 March 2020. The primary objective of monarchE 
was invasive disease-free survival (iDFS). At the time of the second efficacy IA, monarchE 
met the primary objective of the study, with abemaciclib plus ET achieving statistically 
significant and clinically meaningful improvement in iDFS compared to ET alone in the 
overall ITT population (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.598, 
0.932, p=0.0096). There was also a clinically meaningful improvement in 2-year iDFS rates 
for patients treated with abemaciclib plus ET. At the time of the second efficacy IA, iDFS 
in patients with high Ki-67 was tested sequentially after iDFS in ITT population being 
statistically significant, with a pre-specified 2-sided alpha level of 0.02. Statistical 
significance was not met for iDFS in the high Ki-67 population and will be tested again at 
the time of the final iDFS analysis.  
Distant relapse-free survival (DRFS): at the time of the second efficacy IA, abemaciclib 
plus ET demonstrated a numerical benefit in DRFS compared to ET alone, with a clinically 
meaningful 2-year DRFS rate improvement in the ITT population. The DRFS results 
indicated the treatment benefit in terms of delaying metastatic disease by 28.3% compared 
to ET alone and were consistent with the statistically significant iDFS results in the ITT 
population.  
Overall survival: at the time of the second efficacy IA, OS was immature, with 
large variability on the OS HR estimate. Overall survival will be re-evaluated at further 
analysis time points. 

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1.4. 
Overview of Abemaciclib 
1.4.1 
Preclinical Data 
The cell cycle is the process by which mammalian cells replicate their 
deoxyribonucleic acid (DNA) and undergo cellular division. The mammalian cell cycle has 
4 phases: S phase, in which DNA replication occurs; M (mitosis) phase, in which the 
replicated DNA and cellular components are divided to form 2 daughter cells; G2 phase 
(after S phase), in which the cell prepares for mitosis; and G1 phase (after mitosis), in 
which cells commit to another round of DNA and cellular replication. Defects in the 
pathways that regulate cell proliferation in response to mitogenic signaling and other 
extracellular stimuli such as cell density and nutrients are a hallmark of cancer cells(55) and 
the G1 restriction point (R) is believed to be essential to maintain control of cell 
proliferation(56, 57). A primary mechanism controlling cellcycle progression through the 
restriction point is the CDK4 and CDK6 pathway (CDK4 and CDK6-cyclin D-INK4-Rb) 
and the importance of this pathway in regulating cell proliferation is highlighted by 
inactivation of restriction point control in a majority (> 85%) of human tumors(58) . CDK4 
and CDK6 regulate the G1 restriction point through phosphorylation of the Rb protein, 
which allows subsequent expression of genes required to complete transition through G1 
and initiate DNA replication. Selective inhibition of CDK4 and CDK6 results in a 
reversible arrest of cancer cells at the restriction point when used as a single agent in cells 
containing functional Rb protein. Abemaciclib mesylate is a potent inhibitor of CDK4 and 
CDK6 that is selective over other CDKs at the enzyme and cellular level. This is 
demonstrated in Colo-205 cells by potent cellular inhibition of Rb phosphorylation 
(pSer780, 50% inhibition concentration [IC50] = 120 ± 36 nM) and by exclusive G1 cell 
cycle arrest (indicated by accumulation of cells with 2N DNA content) up to 6 µM 
concentration. Other studies have confirmed and demonstrated that abemaciclib mesylate 
inhibits CDK4 and CDK6 to induce G1 arrest specifically in Rb-proficient tumors. Using in 
vitro kinase panel screening, abemaciclib mesylate also demonstrates inhibition (IC50 < 0.3 
µM) of the human protein kinases hCDK9, hPIM1, hPIM2, hHIPK2, hDYRK2,GSK3ß, 
hCDK5/P35, and CK2; however, the reversible G1 arrest seen in vitro and in vivo  indicates 
that the inhibition of CDK4 and CDK6 by abemaciclib mesylate predominates over these 
other activities. Notably, an analysis of the human circulating metabolites  showed that 3 of 
them had activity against the target that was nearly equivalent to the parent compound. In 
particular, metabolites M2 and M20 were evaluated in vitro in biochemical enzyme assays 
and cell-based functional assays. In biochemical assays,both metabolites showed nearly 
identical potency (IC50 between 1 and 3 nM) as that of abemaciclib. Likewise, both 
metabolites inhibited cell growth and cell cycle progression in a concentration-dependent 
manner that was consistent with the inhibition of CDK4 and CDK6. In the cancer cell lines 
evaluated, metabolite LSN3106726 consistently showed potencies nearly identical to 

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abemaciclib while LSN2839567 was approximately 2- to 3-fold less potent. Like 
abemaciclib, both LSN2839567 and LSN3106726 also induced senescence in addition to 
growth inhibition in breast cancer cell lines at similar concentrations. Metabolite 
LSN3106729 (M18) is a minor metabolite and also active, but its potency in functional 
assays was 3- to 20-fold lower than abemaciclib. The evaluation of abemaciclib in animal 
models shows that the phenotypic selectivity for G1 arrest, which is observed in cell culture 
studies, is also observed in the in vivo xenograft tumors. For such studies, direct 
biochemical inhibition of CDK4 and CDK6 as well as the phenotypic inhibition of cell 
cycle progression can be assessed in tumor explants by measuring Rb phosphorylation at 
serine 780 (pRb), since Rb is a direct target of CDK4 and CDK6 activity. Reduced pRb 
expression is also a phenotypic marker for G1 arrest at the restriction point (R). The 
inhibition of TopoIIa and phospho-histone H3 (pHH3) provides additional measures for the 
inhibition of cell cycle progression through the S and M phases, respectively. The 
inhibition of CDK4 and CDK6 and cell cycle progression in vivo by abemaciclib mesylate 
is evident by the dose-dependent reduction of pRb in the Colo-205 xenografts. These 
effects on Rb also correlate with similar dose-dependent reductions in the other cell 
markers TopoIIa and pHH3, indicating that inhibition of CDK4 and CDK6 activity by 
abemaciclib mesylate results in the inhibition of cell cycle progression in the Colo-205 
xenograft tumors. This inhibition of pRb and the cell cycle also shows a time-dependency, 
whereby abemaciclib mesylate treatment results in a sustained pharmacodynamic response 
in a mouse Colo-205 xenograft model. Specifically, a 50mg/kg oral dose resulted in =50% 
inhibition of Rb phosphorylation for 1 to 24 hours after dosing. This effect also correlated 
with an inhibition of cell cycle progression as indicated by the potent suppression of pRb, 
TopoIIa, and pHH3 observed at 24 hours following dosing. A dose response for inhibition 
was observed in these studies such that the threshold effective doses for 70% inhibition for 
pRb and TopoIIa inhibition 24 hours after oral dosing were 14.1 and 14.3mg/kg, 
respectively. Abemaciclib mesylate demonstrates significant inhibition of tumor growth in 
multiple murine xenograft models of human cancer including Colo-205 (colorectal cancer), 
NCI-H460 (non n.small-cell lung cancer [NSCLC]), U87 MG (glioblastoma), and JeKo-1 
(mantle cell lymphoma [MCL]). Although characterized by a different constellation of 
genomic mutations, each of these 4 human xenografts has an intact, functional Rb tumor-
suppressor protein. Xenograft growth inhibition was in general dose-dependent from 15 to 
100mg/kg following daily oral administration for 21 days. Consistent with the mechanism 
of action of abemaciclib, the antitumor activity in Colo-205 was associated with a sustained 
inhibition of pRb, TopoIIa, and pHH3. As a result of its brain exposure, treatment with 
abemaciclib mesylate produces a statistically significant and dose-dependent improvement 
in survival when assessed in a rat orthotropic brain tumor model. Tumor cells were 
implanted intracerebrally and compound treatment started 4 days after implantation (20, 40, 
or 80mg/kg daily for 21 days). Efficacy was assessed using Kaplan-Meier survival analysis. 
Statistically significant improved survival was observed after treatment at 40 and 80mg/kg. 

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The results in the JeKo-1 MCL model demonstrate the potential value for targeting specific 
cancers with known alterations in the CDK4- and CDK6-cyclin D-INK4-Rb pathways. 
This model is typical of MCLs that overexpress cyclin D1 as a result of a specific 
chromosomal translocation [t(11;14)(q13;q32)]. The overexpression of cyclin D1, which 
leads to activation of CDK4 and CDK6, is an important driver for the disease and correlates 
with the sensitivity of this xenograft model to inhibition of CDK4 and CDK6 by 
abemaciclib mesylate. In particular, complete growth inhibition was observed at a dose as 
low as 15mg/kg, with a decrease in baseline tumor burden (ie, regressions) occurring when 
the dose was increased to 25 and 50mg/kg. The sustainability of the antitumor response was 
also dose-dependent in that the delay for tumor regrowth following the cessation of dosing 
increased as the dose of abemaciclib mesylate was increased. In particular, no tumor 
regrowth was observed during the entire 3-week period following cessation of treatment at 
50mg/kg. Studies in breast cancer cell lines have elucidated potential tailoring strategies 
based on histological and genetic characteristics associated with human breast cancer. 
These particular studies, which evaluated in vitro growth inhibition across a diverse panel 
of 46 breast cell lines representing the known molecular subgroups of breast cancer, 
indicated that sensitivity to abemaciclib was greater in estrogen receptor-positive (ER-
positive) lines with luminal histology. In accordance with the known biology for CDK4 and 
CDK6, the results also indicated that many of these sensitive cell lines are also 
characterized as having amplification of CCND1, which is the gene that encodes cyclin D1. 
Moreover, the cell lines that showed the least sensitivity to abemaciclib were those that had 
either homozygous deletions of RB1, the gene which encodes Rb, or copy number 
amplifications in E2F3. Both of these alterations presumably mitigate the effects of CDK4 
and CDK6 inhibition, since both Rb and E2F3 are regulatory nodes for the G1 to S 
transition that are downstream from CDK4 and CDK6. These cell culture observations 
were further validated by studies in vivo in mice bearing human breast cancer xenografts 
such as ZR-75-1, which is a xenograft model for ER-positive and CCND1-amplified breast 
cancer. Specifically, the treatment of mice bearing ZR-75-1 xenograft tumors with either 50 
or 75mg/kg resulted in either a complete inhibition of tumor growth or reductions in tumor 
size (regression). Notably, these effects on tumor growth correlated with the dose-
dependent inhibition of CDK4 and CDK6 and cell cycle progression, as indicated by the 
-clinical studies 
also show that abemaciclib can be used effectively in combination with standard cytotoxic 
or targeted therapies to improve the efficacy of these agents. In these studies, the 
combination therapies, compared to the single-agent treatments, resulted in either a greater 
inhibition of tumor growth during therapy or in a longer duration of growth inhibition 
following the cessation of treatment. Additionally, studies in ER-positive human breast 
cancer xenograft models show that abemaciclib can combine effectively with endocrine 
treatments such as tamoxifen or fulvestrant to attain greater inhibition of tumor growth 
when compared to monotherapy with any of these agents. 

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To support human clinical studies, the toxicity profile of abemaciclib has been 
effectively characterized in mice, rats, and dogs through a package of repeat-dose 
toxicology, 
safety 
pharmacology, 
developmental 
and 
reproductive 
toxicology, 
carcinogenicity, phototoxicity, and genetic toxicology studies.  These studies demonstrate 
an acceptable safety profile with toxicities that are generally considered to be monitorable 
and reversible. The safety profile of abemaciclib in non-clinical toxicology studies is 
generally consistent with the adverse effects (AEs) observed to date in humans. 
Primary target organs: 
 
The primary target organs associated with daily dosing of abemaciclib observed in at 
least 2 species (rats and dogs) are bone marrow, pancytopenia and hypocellularity 
 
gastrointestinal tract  crypt necrosis/hyperplasia and villous atrophy 
 
eye  cataracts and retinopathy 
 
lymphoid tissues  lymphoid depletion, and 
 
male reproductive tract  hypospermatogenesis and atrophy in the testes.   
With the exception of eye effects, these effects were consistent with antiproliferative effects 
in rapidly dividing cells.   
Eye effects have only been observed in rodents. After 3 months of treatment in mice, eye 
effects were observed only in female mice at a dose level that exceeded the maximum 
tolerated dose (MTD). In rats, the eye effects were observed in studies which were 6 
months in duration or longer. The effects were generally more severe in male rats, but do 
appear in female rats as well. 
Other general toxicity findings: 
In rats, the lung was also identified as a target organ for toxicity, characterized by 
multifocal macrophage accumulation with or without reversible bronchoalveolar 
inflammation. Only in the 6 month rat study, minimal inflammation, observed concurrently 
with vacuolated macrophages, within heart valves was observed in male rats treated at 30 
mg/kg/day. 
Reproductive effects: 
In pregnant rats exposed to abemaciclib, skeletal and cardiac variations and malformations 
were observed along with decreased fetal weights; thus, abemaciclib is teratogenic in rats. 
Despite the lack of effects on fertility in male rats, abemaciclib may impair fertility in men 
based on testicular injury observed in mice, rats, and dogs treated with abemaciclib. 
Abemaciclib had no effects on fertility in female rats nor any effects on female 
reproductive organs. 
Carcinogenic effects: 
Benign interstitial (Leydig) cell tumors were observed in the testes of rats treated for up to 
95 weeks with abemaciclib. These findings were accompanied by interstitial cell 
hyperplasia; however, interstitial cell hyperplasia has not been observed in rats treated for 6 
months or less.   

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1.4.2 
Human Pharmacokinetic (PK) Data 
The PK profile of abemaciclib was studied using data available from a total of 222 
patients enrolled in study I3Y-MC-JPBA (JPBA). In the dose range of 50 to 275 mg, 
abemaciclib absorption is slow, with a Tmax ranging from 4 to 6 hours and AUC and Cmax 
generally increased in a dose-proportional manner after a single dose and also with multiple 
twice-daily doses. With repeated administration of 200 mg twice daily, which was 
identified as the maximum tolerated dose (MTD) in study JPBA, abemaciclib accumulated 
with a geometric mean accumulation ratio of 2.5 (67% coefficient of variation [CV]). At 
steady state (SS), after repeated oral Q12H dosing of 200 mg, the mean minimum plasma 
concentration at steady state (Cmin,ss) and maximum observed plasma concentration at 
steady state (Cmax,ss) were 197 and 298 ng/mL, respectively. The mean area under the 
steady state plasma concentration time curve over a dosing interval (AUC0-
approximately 3000 
-MC-JPBS 
[JPBS]) of abemaciclib after a single oral dose of 200 mg is 45%. In a study (I3Y-MC-
JPBU [JPBU]) of the effect of a high-fat meal using the 25% w/w capsule formulation, 
abemaciclib exposure increased by 27% (90% confidence interval [CI] 1.18, 1.36) based on 
AUC, and by 35% (90% CI 1.25, 1.46) based on Cmax. A similar result was observed in 
study JPCC, in which the effect of food on the PK of the tablet formulation was evaluated. 
Abemaciclib exposure increased by 13% (90% CI 1.05, 1.22) based on AUC, and by 30% 
(90% CI 1.20, 1.40) based on Cmax. Although the change in AUC and Cmax in both 
studies was statistically significant, it was small relative to the variability in exposure in the 
cancer patient population, and therefore not considered to be clinically relevant. In both 
studies, a high-fat meal did not change the interindividual variability in PK. Therefore, 
abemaciclib can be taken without regard to meals. New protocols no longer contain 
requirements regarding food restrictions.  
Summary 
After single and multiple BID twice-daily 50- to 275 mg doses of abemaciclib,  
 abemaciclib absorption was slow 
 Tmax ranged from 4 to 6 hours  
 t1/2 ranged from 17 to 38 hours, and 
 area under the concentration versus time curve (AUC) and Cmax generally 
increased in a dose-proportional manner.   
At 200 mg twice daily (BID), the maximum tolerated dose (MTD) for abemaciclib 
monotherapy when dosed BID, abemaciclib achieved 
 a mean minimum plasma concentration at steady state (Cmin,ss) of 197 ng/mL 

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 a mean maximum observed plasma concentration at steady state (Cmax,ss) of 298 
ng/mL, and 
 a mean area under the steady-state plasma concentration time curve over a dosing 
interval (AUC0-
 
The mean absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45%. 
The relative bioavailability of the 25% w/w capsule formulation used in clinical 
development was compared to the commercially available tablet formulation. In 85 
subjects, the PK after a single dose of 3 × 50-mg tablets was bioequivalent to the PK of a 
single dose of 3 × 50-mg capsules, with 
 an AUC0-
 
 a Cmax ratio of 1.03 (90% CI:  0.986, 1.08). 
In a study of the effect of a high-fat meal using the 25% w/w capsule formulation, 
abemaciclib  
 AUC increased by 27% (90% CI:  1.18, 1.36) and 
 Cmax increased by 35% (90% CI:  1.25, 1.46). 
Similarly, for the tablet formulation (Study JPCC), a high-fat meal 
 increased AUC by 13% (90% CI:  1.05, 1.22) and 
 increased Cmax by 30% (90% CI:  1.20, 1.40).   
Although these changes were statistically significant, they were small relative to exposure 
variability in the cancer patient population and therefore not considered to be clinically 
relevant. In both studies, a high-fat meal did not change the interindividual variability in 
PK. Therefore, abemaciclib can be taken with or without food. New protocols no longer 
specifycontain requirements regarding food restrictions. 
Distribution 
In humans, Abemaciclib was highly bound to plasma proteins, serum albumin and alpha-1-
acid glycoprotein  with a mean bound fraction was approximately 96% to 98%, which was 
independent of concentration from 152 to 5066 ng/mL. The active metabolites were 
approximately 89% to 94% bound to plasma proteins. The geometric mean apparent 
volume of distribution at steady state (Vss/F) for abemaciclib was approximately 1300 L 
(96% CV). 
Distribution to the Central Nervous System 
Distribution of abemaciclib to the central nervous system in patients with brain metastases 
has been clinically evaluated by collection of  
 cerebrospinal fluid (CSF) samples in Studies I3Y-MC-JPBA (JPBA) (N=10) and 
I3Y-MC-JPBO (Part C N=6; Part F N=3), and 
 brain tumor tissues in Study JPBO (Part C N=8). 
 

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Abemaciclib demonstrated penetration of the blood brain barrier in cancer patients with 
detectable concentrations in brain tumor tissues and CSF. 
These brain tumor tissue and CSF concentrations were  
 consistently above the IC50 for CDK4 and CDK6, and  
 comparable with plasma concentrations which are associated with clinical efficacy 
in the MONARCH metastatic breast cancer (mBC) studies. 
 
Metabolism 
In vitro and in vivo studies indicated that metabolism was the main route of elimination for 
abemaciclib. It is metabolized to several oxidative metabolites primarily by cytochrome 
P450 (CYP) 3A, with formation of LSN2839567 (M2) representing the major elimination 
pathway. Following oral administration of a single 150mg dose of [14C]abemaciclib to 
healthy subjects, abemaciclib was the major drug-derived entity in plasma (34%), with the 
metabolites LSN3106726 (M20), LSN2839567 (M2), and LSN3106729 (M18) accounting 
for approximately 26%, 13%, and 5%, respectively. Abemaciclib was extensively 
metabolized, with 7% of the dose recovered in the feces as unchanged drug. In vitro, the 
major metabolites LSN3106726 and LSN2839567 were active with similar potency as 
abemaciclib. The active metabolites were eliminated via biliary excretion directly and/or 
further metabolized and eliminated via biliary excretion. The elimination t1/2 of 
LSN2839567 and LSN3106726 in cancer patients at a dose of 200mg was 36 and 32 hours, 
respectively. Across a dose range of 50 to 200 mg, the elimination t1/2 and metabolite-to-
parent drug ratio remained stable with dose for LSN2839567 and LSN3106726, suggesting 
that metabolism of abemaciclib does not change with dose. 
Elimination 
The geometric mean apparent oral clearance (CL/F) of abemaciclib was 38.3 L/hour (105% 
CV), and the mean (range) plasma elimination t1/2 for abemaciclib in patients at a dose of 
200mg was 21 (12-63) hours. The mean t1/2 ranged from 17 to 38 hours, with no consistent 
trends related to dose, suggesting no dose-dependent change in CL. After a single oral dose 
of [14C]abemaciclib in 6 healthy subjects, approximately 81% of the dose was excreted in 
the feces and 3.4% excreted in urine. The majority (52%) of the dose excreted in feces 
constituted metabolites, indicating that abemaciclib is highly metabolized. Only 7% was 
recovered in the feces as unchanged drug. 
CYP3A Inducers and Inhibitors 
Please, refer to Section 5.6.1. of this document. 
Abemaciclib is predominantly cleared by oxidative metabolism via CYP3A. Co-
administration of abemaciclib with rifampin, a strong CYP3A inducer, decreased the 
potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 77%.and may 

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lead to reduced activity. The percentage reduction in the potency-adjusted unbound AUC of 
abemaciclib plus its active metabolites in the presence of moderate CYP3A4 inducers 
modafinil, efavirenz, and bosentan was predicted to be 29%, 53%, and 41%, respectively, 
using physiologically based PK modeling.  
As a result, concomitant use of CYP3A inducers may reduce the activity of abemaciclib. 
At a minimum, it is recommended to avoid concomitant use of CYP3A inducers and 
consider alternative agents.   
Co-administration of a strong CYP3A inhibitor (clarithromycin) resulted in a 2.5-fold 
increase in the potency-adjusted unbound AUC of abemaciclib plus its active metabolites in 
patients with advanced and/or metastatic cancer. The potency-adjusted unbound AUC of 
abemaciclib plus its active metabolites is predicted to increase by 7.1-fold, 3.8-fold, and 
2.4-fold in the presence of CYP3A inhibitors ketoconazole, itraconazole, and diltiazem, 
respectively, using physiologically based PK modeling.  
As a result, concomitant use of strong and moderate CYP3A inhibitors may increase the 
likelihood of AEs related to abemaciclib. 
At a minimum, it is recommended to avoid concomitant use of strong CYP3A inhibitors. 
Combinations with Endocrine Therapy and Anti-Cancer Agents 
Abemaciclib has been studied in combination with fulvestrant, anastrozole, letrozole, 
tamoxifen, exemestane, everolimus, trastuzumab, pemetrexed, gemcitabine, LY3023414, 
galunisertib and ramucirumab(59, 60). No clinically significant PK drug interaction was 
observed with these agents. Overall, the safety results in the Phase 2 study (I3Y-MC-JPBO) 
was consistent with the known safety profile of abemaciclib with no new safety signals 
identified. Most TEAEs were of mild or moderate severity. Diarrhoea, fatigue, and nausea 
were the most common AEs for abemaciclib. 
Hepatic Impairment 
Abemaciclib is metabolized in the liver. The effect of hepatic impairment as defined by 
Child-Pugh on abemaciclib PK was evaluated in the Phase 1 study I3Y-MC-JPBV (JPBV). 
In subjects with severe hepatic impairment, the abemaciclib t1/2 increased from 24 to 55 
hours. No dosage adjustement is required for patients with mild or moderate hepatic 
impairment, but changing the dosing frequency to once daily may be required for patients 
with severe hepatic impairment. 
Renal impairment 
The influence of baseline creatinine clearance on abemaciclib disposition was evaluated 
with 233 patients with normal renal function (Cockcroft Gault creatinine clearance 
[CGCL] > 90 mL/min), 186 patients with mild renal impairment (60 mL/m

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creatinine clearance was not a significant covariate on abemaciclib disposition. No dose 
adjustment is necessary for patients with mild or moderate renal impairment. There are no 
data in patients with severe renal impairment or in patients on dialysis to provide any dose 
adjustment recommendation. 
1.4.3 
Pharmacodynamic and Biomarker Analyses 
Pharmacodynamic assessments for CDK4 and CDK6 inhibition and cell cycle arrest 
downstream of the G1 restriction point were performed on skin biopsies collected from 180 
patients enrolled in Study JPBA. The skin biopsies were collected immediately before dose 
and 4 hours after dose on Day 15 of Cycle 1 (i.e., at steady state after repeated every 24 
hours and/or every 12 hours (Q12H) oral dosing of abemaciclib). The CDK4 and CDK6 
inhibition and cell cycle arrest downstream of the G1 restriction point were explored by 
 
Skin biopsies collected both before dose and 4 hours after dose show a decrease in the level 
of pRb expression with increasing plasma concentration. More specifically, more robust 
and more consistent CDK4 and CDK6 inhibition seems to be associated with abemaciclib 
plasma concentration levels exceeding 200 ng/mL. These findings were confirmed when 
pRb levels were expressed as a percentage of the baseline value measured before treatment 
initiation. 
Likewise, a decrease in cell density in the S phase, as measured by a decrease in the level of 
expression fell below its baseline value measured pretreatment for abemaciclib steady-state 
plasma concentration levels exceeding 200 ng/mL. 
Altogether, these findings suggest that abemaciclib-mediated CDK4 and CDK6 inhibition 
and subsequent cell cycle arrest upstream of the G1 restriction point are time dependent and 
are associated with a minimum abemaciclib Cmin,ss of approximately 200 ng/mL. 
It is notable that these findings are consistent with previous PK/pharmacodynamic analyses 
performed in Colo-205 xenograft tumors, wherein constant CDK4 and CDK6 inhibition 
and constant cell cycle arrest were associated with a similar abemaciclib plasma 
concentration level of approximately 200 ng/mL. 
In 
Studies 
MONARCH 
2 
and 
MONARCH 
3, 
a 
dynamic 
population 
PK 
(PopPK)/pharmacodynamic model incorporating individual dosing history, fluctuating 
concentrations, change in tumor size, and progression-free survival (PFS) was built to 
describe the relationship among dose, concentrations, and efficacy. There was a positive 
linear relationship identified between abemaciclib exposure and tumor shrinkage and also 
PFS. Larger tumor reductions and longer PFS were associated with higher abemaciclib 
concentrations within the concentration range observed in MONARCH 2 and MONARCH 
3. 

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1.4.4 
QTc Evaluation Data 
Relationship between Plasma Concentrations of Abemaciclib and Metabolites and QT 
Interval 
In Study JPCA, single ascending oral doses of 200, 300, 400, or 600 mg abemaciclib or 
placebo were administered to healthy subjects to determine the relationship between plasma 
concentrations of abemaciclib, its major active metabolites M2 and M20, and QT interval. 
Exposure-response analysis revealed that abemaciclib does not cause clinically significant 
bounds of the 2-sided 90% CI of the predicted baseline- and placebo-corrected change-
from-baseline QTcF were below 10 ms at the highest observed abemaciclib, M2, M20, and 
total analyte concentrations. 
1.4.5 Abemaciclib Dose Rationale 
The following Phase 1 studies in advanced cancer and/or metastatic cancer (solid tumors) 
were conducted. Refer to Table 5.1 of the IB December 2018 for details of the below listed 
studies. 
 I3Y-MC-JPBA: in the first part of this dose-escalation Phase 1 study (Part A), 
patients were treated with either 50, 100, 150, or 225 mg abemaciclib Q24H or 75, 
100, 150, 200, and 275 mg abemaciclib Q12H to determine the MTD of 
abemaciclib. The MTD for the once-daily dose was not established. At abemaciclib 
275 mg Q12H dose level, 2 of the 3 patients experienced dose-limiting toxicities 
(DLTs) of Grade 3 fatigue. Therefore, the identified MTD for the twice-daily dosing 
schedule was 200mg Q12H. This study demonstrated acceptable safety and 
tolerability for abemaciclib in patients with advanced cancers. 
 I3Y-JE-JPBC: safety data from Study JPBC were similar in Japanese patients for 
single agent abemaciclib as those observed in Study JPBA. The MTD of 200mg 
Q12H was confirmed in Study JPBC. 
 I3Y-MC-JPBE: this study assessed the effect of clarithromycin on the PK of 
abemaciclib and its metabolites. Single doses of 50mg abemaciclib administered 
during the drug-interaction phase of the study were generally well tolerated when 
administered alone or co-administered with 500mg clarithromycin Q12H and the 
TEAE profile was similar for each treatment. 
 I3Y-MC-JPCP (abemaciclib monotherapy and impact of food on tolerability): 
overall, the safety and tolerability profile of abemaciclib 200 mg BID administered 
in various feeding states were acceptable in this patient population with no new 
safety signals identified. This study did not demonstrate any impact of food on the 
tolerability of abemaciclib in relation to the incidence of diarrhea and associated 
dose modifications. The incidence of severe diarrhea (Grade 3 and above severity) 

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observed in this study (4.2%) was lower compared to that reported in the 
MONARCH 1 (19.7%), MONARCH 2 (14.5%), and MONARCH 3 (9.5%) studies. 
Prolonged Grade 2 diarrhea was reported for 2 patients (8.3%) in Arm 1, 4 patients 
(17.4%) in Arm 2, and 5 patients (20.8%) in Arm 3. 
 
1.5.  Study Rationale 
Currently chemotherapy (CT) is one of the standard neoadjuvant (NA) therapies in 
high risk luminal breast cancer (BC) patients. Nowadays there are several NA studies 
comparing CT vs. CDK4/6i + ET.   
 NeoPalAna study(53) (NCT01723774): single-arm phase II trial to determine the 
antiproliferative activity of palbociclib when added to anastrozole in pre- and 
postmenopausal women with newly diagnosed clinical stage II/II ER-positive 
(Allred score 6-8), HER2-negative (0 or 1+ by immunohistochemistry (IHC) or 
fluorescence in situ hybridization (FISH) negative) BC. The primary objective was 
to determine whether the addition of anastrozole to palbociclib induces a higher rate 
hieved by 
anastrozole alone as initial therapy at C1D15. The primary endpoint was chosen 
based on the long-term follow-up data of several neoadjuvant endocrine therapy 
(NAET) trials which demonstrated that the 2.7% Ki67 cut-point (natural log of one) 
during NAET is associated with favorable BC relapse free and overall survival 
(OS). The added effect of palbociclib over that of anastrozole was determined by 
analysis of tumor biopsies collected at C1D1 following 4 weeks of cycle 0 
anastrozole monotherapy, and at C1D15, 2 weeks after the addition of palbociclib to 
anastrozole. CCCA and Ki67 responses were assessed by PIK3CA mutation status 
because of the alternative strategy of PIK3CA-targeted therapy in the mutation-
positive population. Secondary objectives included analysis of CCCA and Ki67 
response by baseline PAM50-based intrinsic subtypes, and assessment of clinical, 
radiological, and pathologic response and safety profiles. Exploratory biomarker 
studies included gene expression and somatic mutation profiling. The study was 
designed to ensure the sample size for the PIK3CA WT cohort and the overall 
population for the primary endpoint analysis. A sample size of 33 in the PIK3CA 
WT cohort was chosen based on the Fleming's single-stage phase II design to test 
the hypothesis that palbociclib plus anastrozole leads to at least 50% improvement 
over anastrozole alone in CCCA rates [44% with anastrozole based on historical 
data vs. 66% with palbociclib plus anastrozole, power 0.8, alpha 0.05]. The primary 
endpoint was met if more than 20 of 33 patients achieved CCCA. 
Between April 2013 and April 2015, 50 patients (18 pre- and 32 postmenopausal),    
median age 57.5 (range, 34.1 79.6) years, with clinical stage II/III ER-positive, 

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HER2-negative BC enrolled to the study, which included 16 in the PIK3CA Mut, 32 
in the PIK3CA WT cohort, and 2 with unknown PIK3CA status. Thirty-nine 
patients completed NAT and underwent definitive breast and axillary surgery. 
Following the protocol amendment that added cycle 5 prior to surgery, 10 patients 
received cycle 5 palbociclib and all underwent surgery as scheduled. The rates of 
CCCA with palbociclib plus anastrozole were significantly higher at C1D15 than 
that at C1D1 with anastrozole monotherapy for all evaluable patients (87% vs. 26%, 
P < 0.001), PIK3CA Mut (100% vs. 25%, P < 0.001), and PIK3CA WT (79%vs. 
25%, P < 0.001) cohorts. The CCCA rates at C1D15 exceeded the predefined cut-
point for meeting the primary endpoint of at least 66% in the overall, PIK3CA WT, 
and Mut cohorts. Of the 31 patients resistant to anastrozole (non-CCCA at C1D1), 
26 (84%) responded to palbociclib (CCCA at C1D15). When considered as a 
continuous variable, Ki67 levels were significantly reduced from baseline C0D1 to 
C1D1 following anastrozole monotherapy (P < 0.01) and from C1D1 to C1D15 
after adding palbociclib (P < 0.01) for both PIK3CA WT and Mut cohorts. There 
was a greater variability in Ki67 response among the PIK3CA WT tumors. 
Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of 
luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad 
range of clinicopathologic and mutation profiles. 
 N007 study(5) (NCT01709370): The purpose of the study was to test the efficacy of 
neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and 
changes in EndoPredict (EP) scores before and after treatment. Postmenopausal 
women with histologically proven ER-
cm, were enrolled in an open-label, single-arm study. Twenty eligible patients were 
given letrozole 2.5 mg per day together with palbociclib 125 mg per day for 3 out of 
4 weeks in repeated cycles for 16 weeks (4 cycles) before surgery. Palbociclib was 
stopped 1 week before surgery, whereas letrozole was continued till day of surgery. 
The primary end points were clinical response rates (cRR) and preoperative 
endocrine prognostic index (PEPI). The secondary end points were pathologic 
response and gene expression testing with EP test on collected tumor samples. 
The following results were obtained: 17 patients showed a clinical response of 
50%, including 8 complete responses (CRs) and 9 partial responses (PRs). There 
was significant reduction in area (P < 0.0001) and volume (P = 0.017) of the cancer. 
Pathologic complete response (pCR) was achieved in one patient; all cancers were 
downgraded after treatment. Ki67 (P = 0.044) and EP scores (P < 0.0001) were 
significantly reduced after treatment. The mean value of Ki67 before treatment was 
21.7%; after treatment it was 11.4% (P = 0.044). Core biopsy was performed on 7 
patients on day 15 of cycle 1 for the evaluation of Ki67. It was less than 2.7 in five 
of seven (71.4%) patients. However, only eight of 20 (40%) patients had a Ki67 less 

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than 2.7 at the time of surgery after treatment. Except for 3 patients with elevation 
after treatment, the other 17 patients showed a significant drop in value. Eight of 17 
(47.1%) patients had a high proliferation fraction (Ki67 > 15%) before treatment but 
only three of 20 (15%) patients were determined to have Ki67 over 15% after 
treatment. 
Analysis of the relative gene expression levels showed that all proliferative genes, 
IL6ST and RBBP8 were decreased after palbociclib treatment. 6 patients with 
intermediate and three patients with high PEPI risk scores were found to have low 
EPclin scores. All patients with high PEPI relapse risk score had high EPclin score. 
In conclusion, effective clinical response was demonstrated by neoadjuvant 
letrozole in combination with palbociclib. Compared with PEPI, EPclin might be a 
better parameter to estimate prognosis after neoadjuvant therapy. 
 PALLET study(6) (NCT02296801): randomized phase II study to evaluate 
palbociclib in addition to letrozole as neoadjuvant therapy in ER-positive early BC. 
letrozole 2.5 mg/d for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus 
letrozole for 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole 
to 14 weeks (C); or palbociclib plus letrozole for 14 weeks (D). Palbociclib 125 
mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut 
biopsies were taken at baseline and 2 and 14 weeks. Co-primary end points for 
letrozole vs. palbociclib plus letrozole groups (A v B + C + D) were change in Ki67 
(protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 
14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete 
cell-cycle arrest was defined as Ki67 less than or equal to 2.7%. Apoptosis was 
characterized by cleaved poly (ADP-ribose) polymerase. 
Three hundred seven patients were recruited. Clinical response was not significantly 
different between palbociclib plus letrozole and letrozole groups (P = 0.20; CR + 
PR, 54.3% vs. 49.5%), and PD was 3.2% vs. 5.4%, respectively. Median log-fold 
change in Ki67 was greater with palbociclib plus letrozole compared with letrozole 
(-4.1 vs. -2.2; P < 0.001) in the 190 evaluable patients (61.9%), corresponding to a 
geometric mean change of -97.4% vs. -88.5%. More patients on palbociclib                             
plus letrozole achieved CCCA (90% vs. 59%; P < 0.001). Median log-fold change 
(suppression) of cleaved poly (ADP-ribose) polymerase was greater with 
palbociclib plus letrozole vs. letrozole (-0.80 vs. -0.42; P < 0.001). More patients 
mainly because of asymptomatic neutropenia. 
 NeoPAL study(7)  (NCT02400567): randomized, parallel, non-comparative, proof-
of-concept, phase II study. Patients with ER-positive, HER2 negative, Prosigna®-
defined luminal B, or luminal A and nodal status (N) positive, stage II IIIA BC, not 

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candidate for BCS (breast conserving surgery), were randomly assigned (1:1) to 
either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks on and 1 
week off) during 19 weeks (4.8 months), or to CT (5-fluorouracil, epirubicin (100 
mg/m2) and cyclophosphamide (FEC100) with three 21-day courses followed by 
docetaxel 100 mg/m2 with three 21-day courses). Breast surgery was carried out at 
day 1 of week 20. Sentinel lymph node (SLN) surgery was allowed only after 
completion of the NA therapy. Patients with pN0, pN0iþ, or pN1mi SLN were 
classified as pN0 for residual cancer burden (RCB) calculation. Patients who did not 
achieve RCB 0 I in letrozole/palbociclib arm were recommended to receive 
adjuvant CT. One hundred and six randomized patients had a median Prosigna® 
score of 71 (22-
-
interim analysis mandated the accrual to be stopped early. The primary end point 
was RCB 0-1 rate on the ITT (intent to treat) population (locally assessed according 
to MDACC recommendations for which pathologists of participating centers were 
specifically trained): letrozole/palbociclib 7.7% (95% confident interval (CI) 0.4
14.9) and CT 15.7% (95% CI 5.7 25.7). This study did not reach the primary 
endpoint of 20% RCB 0-I after 19 weeks of treatment (7.7%; 95% CI 0.4-14.9). 
Other results of the study include: a) pCR: letrozole/palbociclib 3.8% and CT 5.9%; 
b) clinical response (75%) and BCS rates (69%) were similar in both arms; c) Ki67 
index: baseline [median (range): 25% (1-80) on letrozole/palbociclib and 30% (2-
80) on CT; geometric mean 24.1% vs. 27.7%] and final [median (range): 3% (1-40) 
on letrozole/palbociclib and 9% (2-15) on CT; geometric mean 1.17% vs. 3.7%]; d) 
PEPI (Preoperative Endocrine Prognostic Index) 0 score: letrozole/palbociclib 
17.6% and 8% CT. 
 CORALLEEN study(8) (NCT03248427): a parallel-arm, multicenter, randomized, 
open-label,  phase II clinical trial for postmenopausal women with stage I-IIIA, HR-
positive, HER2-negative, luminal B according to PAM50 intrinsic subtype, BC, 
randomly assigned (1:1) to receive NACT (adriamycin/doxorubicin 60 mg/m2 plus 
cyclophosphamide 600 mg/m2 (AC) for 4 cycles followed by weekly paclitaxel 80 
mg/m2 for 12 weeks) vs. six 28-day cycles of letrozole 2.5 mg/day plus ribociclib 
600 mg once daily for 3 weeks on, 1 week off, for 24 weeks. Primary endpoint was 
to evaluate the proportion of patients with PAM50 low risk of relapse (ROR) 
disease at surgery in the modified intention-to-treat (ITT) population including all 
randomly assigned patients who received study drug and had a baseline and at least 
one post-baseline measurement of ROR score. The PAM50 ROR risk class 
integrated gene expression data, tumor size, and nodal status to define prognosis. 
Between July 2017 to December 2018, 106 patients were enrolled. At baseline, of 
the 106 patients, 92 (87%) had high ROR disease (44 [85%] of 52 in the letrozole 

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plus ribociclib group and 48 [89%] of 54 in the CT group) and 14 (13%) patients 
had intermediate-ROR disease (eight [15%] and six [11%]). Median follow up was 
200·0 days (IQR 191·2 206·0). At surgery, 23 (46·9%; 95% CI 32·5 61·7) of 49 
patients in the letrozole plus ribociclib group and 24 (46·1%; 32·9 61·5) of 52 
patients in the CT group were low-ROR. The most common Grade 3 4 adverse 
events (AEs) in the letrozole plus ribociclib group were neutropenia (22 [43%] of 51 
patients) and elevated alanine aminotransferase (ALT) concentrations (ten [20%]). 
The most common Grade 3 4 AEs in the CT group were neutropenia (31 [60%] of 
52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during 
the study in either group. 
Chemotherapy seemed to be superior to CDK4/6i in terms of objective response rate 
(ORR) assessed by MRI. However, more patients in the letrozole plus ribociclib 
arm received breast conserving surgery (BCS) compared to the CT arm. No 
differences between the two arms were suggested when ORR was evaluated by 
physical examination. Pathologic complete response (pCR) and residual cancer 
burden (RCB) of 0 I were low, with patients treated with CT appearing more likely 
to achieve pCR and RCB 0 I compared to the ones treated with the letrozole plus 
ribociclib arm. 
Moving to biological response, the trial showed greater reduction in Ki67 
expression levels with the cyclins-dependent kinase (CDK)4/6 inhibitor than with 
CT. Of note, this decrease in Ki67 could be underestimated due to Ki67 rebound 
occurring when the CDK4/6 inhibitor are suspended some days before surgery, as 
the NeoPalAna study previously showed. This issue is applicable to the 
CORALLEEN trial where 13.1 (standard deviation [SD] 14.6) was the mean 
number of days between the last dose of ribociclib and surgery. 
The conversion to luminal A subtype assessed by PAM50 at surgery was evaluated 
in this study, a numerically higher percentage of conversion to luminal A subtype 
was observed in the letrozole plus ribociclib arm compared to the CT arm. 
Additionally, similar rates of low-ROR score at surgery were found in both arms. 
 NEOLBC study(9) (NCT03283384): an ongoing randomized, multicenter, open-
label, phase II clinical trial in n=100 postmenopausal patients with HR-positive 
HER2-negative, stages II/III BC. Based on Ki67 levels after two weeks of initial 
letrozole treatment, patients are advised to continue ET with letrozole (if Ki67 level 
< 1%) or to be randomized between standard CT [2-weekly plus G-CSF 
(granulocyte colony stimulating factor) followed by a taxane (3-weekly docetaxel or 
 1%). The 
aim of the study is to evaluate if CT could be replaced by the combination of 
letrozole plus ribociclib as a NA therapy for patients with non-metastatic primary 
luminal BC. The primary endpoint is to measure the difference in complete cell 

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cycle arrest (CCCA) defined as Ki67 < 1% determined by immunohistochemistry 
(IHC) between letrozole plus ribociclib vs. CT in the surgical specimen (around 
seven months after starting the initial treatment with letrozole) and to determine if 
compared to CT in the surgical specimen. 
 PREDIX LumB study(10) (NCT02603679): an ongoing randomized phase II 
clinical trial in n = 200 luminal A/B BC patients with regional lymph node 
metastases, comparing NA weekly paclitaxel vs. standard ET plus palbociclib for 12 
weeks; after 12 weeks treatment is switched crossover. Choice of ET is for pre- and 
perimenopausal women and all men tamoxifen, alternatively for women in this age 
cohort, a luteinizing hormone-releasing hormone (LHRH) analogue in combination 
with an aromatase inhibitor (AI), for all postmenopausal women treatment with an 
AI. During the 24-weekly treatment period, clinical and radiological evaluations are 
performed repeatedly. Switch between the treatment groups is allowed in case of 
lack of response or toxicity. Postoperatively, patients receive 3-weekly courses of 
CT with a combination of epirubicin and cyclophosphamide (EC). The primary 
endpoint is Radiological Objective Response Rate after completion of the first 12-
week treatment period. Radiological response will be assessed by mammography 
and ultrasound, alternatively magnetic resonance imaging (MRI) of the breast could 
be used if mammography/ultrasound does not allow to perform objective 
measurements of the primary tumor. Clinical measurements using caliper is allowed 
if the tumor is palpable and the tumor size cannot be estimated by radiological 
methods. 
 neoMONARCH study(61) (NCT02441946): assessed the biological effects of 
abemaciclib in combination with anastrozole in the neoadjuvant setting. 
Postmenopausal women with stage I IIIB HR-positive/HER2-negative BC were 
randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus 
anastrozole followed by 14 weeks of the combination. A total of 224 
postmenopausal women with early-stage breast cancer were enrolled and randomly 
assigned to receive a 2-week lead-in of abemaciclib plus anastrozole (n = 74), 
abemaciclib monotherapy (n = 76), or anastrozole monotherapy (n = 74). The 
primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. 
Additional objectives included clinical, radiologic, and pathologic responses, safety, 
as well as gene expression changes related to cell proliferation and immune 
response. In total, 97% of patients completed cycle 1 (2 weeks of abemaciclib, 
anastrozole, or combination) and entered cycle 2, when all patients received 
abemaciclib plus anastrozole treatment for remainder of study treatment (14 weeks). 
Among patients who started cycle 2, 85% of patients completed study treatment (16 
weeks) while 15% of patients discontinued study treatment for the following 

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reasons: AEs (n = 15), patient decision (n = 9), disease progression (n = 5), and 
other (n = 3). In addition, 23% of patients entered the extension period and received 
8 additional weeks of study treatment. After treatment discontinuation, 85% of the 
intent-to-treat (ITT) population underwent definitive surgery. 
Of the 224 ITT patients, baseline tumor Ki67 expression was available for 208 
(93
 5% in 195 (87%) of the tumors. Ki67 expression was assessed at 
baseline and after 2 weeks of treatment in tumors from 75% of patients including 
80% in the combination arm, 69% in the abemaciclib arm, and 76% in the 
anastrozole arm. Ki67 expr
anastrozole alone arm. The geometric mean ratios for abemaciclib plus anastrozole 
versus anastrozole were 0.2 (90% CI, 0.1 0.3; P < 0.001) and 0.3 (90% CI, 0.2 0.4; 
P < 0.001) for abemaciclib versus anastrozole. Abemaciclib, alone or in 
combination with anastrozole, achieved a significant decrease in Ki67 expression 
and led to potent cell-cycle arrest after 2 weeks of treatment compared with 
anastrozole alone. In total, 47% of tumors demonstrated CCCA. More patients in 
the abemaciclib-containing arms vs. anastrozole alone achieved CCCA (58%/68% 
vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 
weeks of combination therapy, 46% of ITT patients achieved a radiologic response, 
with pCR observed in 4%. Subgroup analyses did not demonstrate significant 
association between the abemaciclib-driven change in Ki67 expression at 2 weeks in 
any of the clinical, pathologic, and molecular subgroups. 
Radiologic assessments at EOT, using the same method used at baseline, were 
available for 79% of patients. The radiologic ORR was 46% in the ITT population 
with 5% of patients having a CR and 42% a PR. Of the 190 patients who underwent 
surgery at EOT, 4% of patients had no evidence of invasive disease in the breast and 
axillary lymph nodes. 
In patients with Ki67 analysis available at EOT, the decrease in Ki67 expression 
from baseline to EOT was similar regardless of the initial 2 weeks of therapy and a 
similar rate of CCCA was observed at EOT across all arms. To determine the extent 
to which abemaciclib-containing treatment suppresses tumor cell proliferation in 
high grade tumors, Ki67 expression at baseline, 2 weeks, and EOT as a function of 
tumor grade was examined (n = 138). Pathologic grade 2 and grade 3 tumors 
exhibited higher baseline Ki67 and most tumors, regardless of grade or baseline 
Ki67 expression, showed a reduction in Ki67 with treatment at 2 weeks, with a 
larger reduction observed in the abemaciclib-containing treatment arms compared to 
anastrozole alone. 
PIK3CA mutation status was evaluable for 122 tumors; 36% of tumors harbored a 
PIK3CA-activating mutation. There were more PIK3CA mutant tumors in the 

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combination arm (32%) than in the abemaciclib (19%) and anastrozole (27%) arms. 
The presence of a PIK3CA mutation had no significant effect on Ki67 expression 
change from baseline to 2 weeks, including the rate of CCCA in response to 
abemaciclib alone (P = 0.570) or in combination compared to anastrozole (P = 
0.216). It was also examined whether study treatment had any effect on the presence 
of tumor-infiltrating lymphocytes (TIL) in the tumor stroma. At baseline most of the 
tumors (88%, in combination arm; 92%, in abemaciclib arm; 94%, in anastrozole 
arm) had low TILs (0%
tumors had TILs in the 10% to 40%, and > 40% ranges. Treatment with 
abemaciclib, anastrozole, or abemaciclib plus anastrozole had no effect on the 
percentage of stroma TILs either at 2 weeks or 16 weeks (EOT). Treatment with the 
combination of abemaciclib plus anastrozole resulted in upregulation of the allograft 
rejection, inflammatory response, and IFNg response Hallmark gene sets at 2 weeks 
and EOT. Many other immune pathway gene sets were also enriched, including the 
PD-1 pathway gene set, highlighting a potential increase in the presence of activated 
T cells. Although these changes were consistent across early and late time points for 
the abemaciclib plus anastrozole combination arm, inflammatory immune gene 
changes were not significantly changed for those evaluable tumors treated with 
abemaciclib or anastrozole monotherapy during the 2-week lead-in period. 
The most common all-grade AEs were diarrhea (62%), constipation (44%), and 
nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle 
processes and estrogen signaling; however, combination therapy resulted in 
increased cytokine signaling and adaptive immune response indicative of enhanced 
antigen presentation and activated T-cell phenotypes.  
 
The poor pathological and biomarker responses of NACT achieved in NeoPAL 
study suggest that CDK4/6i might be and alternative, with a better safety profile, to CT in 
early high-risk BC. We hypothesized that some HR-positive/ HER2-negative breast tumors 
derive limited benefit from CT and might be treated with an exclusive endocrine-based 
CDK4/6i approach. In support of this there are results from ACOSGZ1031b study(13). In 
this study, tumors resistant to NAET (defined by Ki67 > 10% after two-week treatment 
with an AI) were also resistant to NACT. These highly proliferating endocrine resistant 
tumors treated with conventional CT had a 5% pCR rate, when a 20% pCR rate was 
expected. In agreement with this, resistant tumors in ACOSOGZ1031b were enriched in an 
E2F4 signature(14). This signature is prognostic of bad outcome and can be downregulated 
in patients by treatment with palbociclib. Interestingly, in BC cell lines resistant to estradiol 
deprivation, abemaciclib and palbociclib, but not paclitaxel nor fulvestrant, were able to 
completely suppress the expression of all genes composing the E2F4 signature(14).   

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In the NeoMONARCH study, abemaciclib, alone or in combination with 
anastrozole as NA in EBC, reduced Ki67 expression after 2 weeks of treatment based on 
geometric mean change and patients with complete cell cycle arrest (Ki67 < 2.7%)(13, 14): 
 78 patients achieved a Ki67 < 2.7%: 67.8% patients treated with abemaciclib + 
anastrozole, 57.7% patients treated with abemaciclib and 14.3% patients treated 
with anastrozole.  
 The ORR by radiologic assessment at the completion of the study treatment (16 
weeks) was of 46.4% and the pCR rate was of 3.7%. 
 These data support continued evaluation of abemaciclib in EBC patients. 
If MONARCH-E mirrors NeoMONARCH results, then MONARCH-E study will 
meet its primary end-point and abemaciclib will obtain the indication in the adjuvant setting 
for a high-risk patient population. Due to MONARCH-E inclusion criteria, abemaciclib is 
being explored mostly in a post-CT setting, so, one question MONARCH-E won´t answer 
is if abemaciclib could avoid the need of CT. This hypothesis can be efficiently tested in a 
neoadjuvant study, which can provide a go-no-go signal for an adjuvant trial and 
meaningful information regarding the target population. 
Current NA studies are optimized regarding the CT duration (4-6 months), but not 
for CDK4/6i/ET duration. The optimal length of CDK4/6i/ET treatment in the neoadjuvant 
setting is unknown. So far, a maximum of 20 weeks has been explored but, as stated above, 
some patients might benefit of longer NAET and some mechanism of action of abemaciclib 
beyond cell cycle arrest, such as induction of senescence, immune cell recruitment and 
apoptosis(62), might be enhanced by  a longer treatment duration. In fact, in the metastatic 
setting abemaciclib/ET achieves, in patients with measurable disease, an impressive 60% 
overall response rate, in the upper range of CT(33).  Interestingly, the response rate 
increase with treatment duration (45% tumor reduction at 6 months vs. 64% at 12 months). 
The fact that NAET achieves low pCR in ER-positive/HER2-negative BC but 
survival outcomes are relatively good, suggest that a biological biomarker might capture 
better the CDK4/6i mechanisms of action. In this regard, it would be worth exploring the 
ability of abemacilcib/ET to induce molecular downstaging detected through a validated 
genomic signature. Exploring the ability of abemacilcib/ET to decrease the risk score of a 
genomic signature with prognostic ability (such as the 21-gene Oncotype DX® Recurrence 
Score (RS)(20), the 70-gene MammaPrint®(21) or others(63)) would highlight the 
potential role of abemaciclib in improving the molecular state of patients who could 
subsequently skip post-surgery adjuvant CT.  
Increasing evidence suggests that HR-positive/HER2-negative EBC is a 
heterogeneous disease(27) , and since the advent of genomic signatures, efforts have been 
made to integrate these signatures into clinical practice in the adjuvant setting for those 
patients with HR-positive/HER2-negative and pathological N0-1 BC.  

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WSG-PlanB (NCT01049425) is a prospective, randomized, multicenter phase III 
trial with CT in HER2-negative EBC. The planned translational analyses included the 
prospective comparison of the prognostic value of histological grade and IHC markers (ER, 
PR, Ki67 index, and IHC4) determined by independent central pathology with that of a 
genomic signature (Oncotype DX RS) in EBC(64). HR-positive/HER2-negative patients 
However, an unfavourable impact of higher Ki67 index on DFS was seen only in the RS > 
25 subgroup of locally confirmed HR-positive patients, whereas no impact of Ki67 index 
25 subgroups. Concordance between RS 
subgroups and the most prognostic value of RS was in the subgroup of intermediate Ki67 
index (from > 10% to < 40%). Hence, using genomic signatures may be particularly useful 
for intermediate/high-risk pN0-1 disease according to clinical and/or IHC markers.  
To sum up, the hypothesis we would like to test is if in intermediate-high risk BC 
patients, defined by TNM and IHC markers, the prolongation of NA abemaciclib + ET is 
non-inferior to standard NACT. 
 
 
 

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2. Objectives 
2.1. 
Primary Objective 
To assess the Residual Cancer Burden (RCB) 0-I rate in both treatment arms. 
2.2.  Primary End-point 
Evaluation of the number of patients with a Residual Cancer Burden (RCB) 0-I index as a 
measure of efficacy. RCB(23) is a continuous variable derived from the primary tumor 
dimensions, cellularity of the tumor bed, and axillary nodal burden. It is estimated from 
routine pathological sections of the primary breast tumor site and the regional lymph nodes 
after the completion of NA therapy. The pathological variables include bidimensional 
diameters of the primary tumor bed, the proportion of primary tumor area containing 
invasive carcinoma, the number of positive lymph nodes, and the diameter of the largest 
nodal metastasis. 
2.3. 
Secondary Objectives 
 Changes in Ki67 index value after 2 weeks of treatment in both treatment arms. 
 RCB 0+I vs. RCB-II vs. RCB-III in both treatment arms (TNM downstaging). 
 Changes in RCB value between both treatment arms. 
 Rate of PEPI score 0 at surgery in both treatment arms. 
 Clinical response measured by magnetic resonance imaging (MRI) according to 
RECIST v1.1 in both treatment arms. 
 Rate of breast conservative surgery (BCS) in both treatment arms. 
 iEFS (invasive Event Free Survival) in both treatment arms. 
 Assessment of safety profile by NCI-CTCAE v5.0 classification. 
 To assess molecular downstaging for high risk genomic groups defined by a 
multigene expression panel. 
2.4.  Secondary End-points 
 Percentage of decrease in the geometric mean of Ki67 index value after 2 weeks of 
treatment in both treatments arms.  
Number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment 
in both treatment arms. 
 RCB is classified in four classes based on the residual disease (RD): 

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o RCB-0 defined as pathological complete response. 
o RCB-I defined as minimal RD. 
o RCB-II defined as moderate RD. 
o RCB-III defined as extensive RD. 
 Variation of the value of RCB based on the RD between the two treatment arms. 
 PEPI(24) (Preoperative Endocrine Prognostic Index) requires pathological stage 
(tumor size and nodal status), level of  Ki67 protein, and Allred ER score measured 
Allred score > 2. 
 Clinical Response Rate (CRR) is defined as the proportion of subjects with 
complete or partial radiographic response. CR and PR definitions are assessed by 
MRI at baseline and prior to breast surgery, with or without regional lymph nodes 
surgery, and categorized according to percent reduction in tumor size. 
 Rate of breast conservative surgery (BCS): defined as the proportion of patients 
who achieved breast-conserving surgery between both treatment arms. 
 Invasive event free survival (iEFS): defined as time from randomization to 
progressive disease or invasive disease recurrence (local, regional, distant, 
or contralateral), or death from any cause. Invasive disease recurrence is defined as: 
o Ipsilateral invasive breast tumor recurrence (including second primary 
invasive breast cancer): an invasive breast cancer involving the same breast 
parenchyma as the original primary lesion.  
o Ipsilateral regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, other regional lymph nodes, chest wall, and/or skin of 
the ipsilateral breast). 
o Distant recurrence (i.e., evidence of breast cancer in any anatomic site 
outside local and/or regional location and that has been either histologically 
confirmed or clinically diagnosed as recurrent invasive breast cancer) 
o Contralateral invasive breast cancer 
o Second primary invasive cancer of non-breast origin. 
 Safety will be assessed by standard clinical and laboratory tests (haematology, 
serum chemistry). AEs grade will be defined by the NCI CTCAE (National Cancer 
Institute Common Terminology Criteria for Adverse Events) version 5.0. AEs terms 
will be coded according to MedDRA dictionary. 

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 Gene expression data provided by a multigene expression panel in sequential tumor 
biopsies. 
2.5.  Exploratory Objectives 
 Correlation of Ki67 protein level change after 2 weeks of treatment with some 
efficacy variables.   
 Genetic changes in sequential tumor samples and tumor evolution during NA 
therapy, and its correlation with some efficacy variables and surrogate endpoints for 
response. 
 To explore T-cell functional activation, immune suppression, neoantigens and 
cytokines production as well as other immune response biomarkers (such as 
CD4/CD8/FOXP3/PDL-1), in order to understand the activity of abemaciclib on the 
tumor microenvironment and the immune response. 
 Circulating tumor DNA (ctDNA) dynamics as a surrogate endpoint for response and 
prognostic implications. 
 Sequential genomic profiling and quantification of ctDNA samples to explore early 
response dynamics, minimal residual disease, tumor tracking, tumor mutational 
burden and clonal diversity along NA therapy and treatment follow up.  
 To investigate if ctDNA dynamics after 2-3 weeks of treatment predicts PEPI score, 
molecular downstaging, and minimal residual disease in ctDNA samples, and its 
correlation with some efficacy variables. 
 To investigate if ctDNA dynamics after 3-4 weeks post-surgery predicts PEPI score 
and molecular downstaging, and its correlation with some efficacy variables. 
 Genetic changes in pre vs. post NA therapy tumor samples to identify potential 
genomic mechanisms of resistance.  
 To describe ctDNA mutation landscape in resistant tumors. 
 Generation and expansion of ex vivo organoid-based models and/or xenographs 
from post-therapy tumors and if possible, from baseline tumors to perform high-
throughput functional screening studies.  
 Identification of indirect biomarkers of tumor biology and treatment activity by 
metabolomic analysis (glutamine pathway).  
 To explore other possible biomarkers of clinical activity in tumor and blood 
samples. 

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2.6.  Exploratory End-points 
 Variation of the Ki67 levels, determined by immunohistochemistry (IHC), between 
pre-treatment and after 2 weeks-treatment biopsies, and its correlation with some 
efficacy variables.  
 Mutational and copy number variation (CNV) data analyzed in pre-treatment and 
surgery tumor samples (large targeted gene panels including TP53 and MYC 
mutations and MYC CNVs) and its correlation with some efficacy variables.  
 Gene expression data provided by a multigene expression panel in sequential tumor 
biopsies and its correlation with some efficacy variables. 
 Monitoring of ctDNA abundance and specific tumoral mutation and genetic changes 
observed in ctDNA samples along treatment and follow up. 
 Mutations and CNV detected in ctDNA collected after recurrence. 
 Values of other proteins, metabolites, RNA or DNA alterations obtained from the 
tissue or blood samples and its correlation with efficacy variables could be used for 
assessment of biomarkers related to activity of abemaciclib and breast tumor 
sensitivity and/or resistance to treatment.   

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3. Investigational Plan 
3.1. 
Study Design 
This is an international, multicenter, open-label, randomized phase II study in the NA 
setting. Approximately 200 pre- and postmenopausal women with HR-positive/HER2-
breast tissue, with indication of NA treatment, will be included.  
Once the screening process (local at site and at the central laboratory) is completed, fully 
eligible patients will be randomized in a 1:1 fashion to the control arm with standard 
chemotherapy based on anthracyclines and taxanes or to the experimental arm with 
Letrozole + Abemaciclib (+ LHRH analogs in premenopausal women). Patients will be 
stratified according to the disease stage (II vs. III), menopausal status (premenopausal vs. 
according to the stipulations below, unless any of the following occur: unacceptable 
toxicity, progressive disease (PD), or withdrawal of informed consent, whatever occurs 
first.  
After the last dose of any of the drugs in the NA combinations, in both treatment arms 
definitive surgery will be performed. For Arm A not earlier than 21 days and not later than 
42 days after the last dose of chemotherapy, and for Arm B within 7 days from the last dose 
of abemaciclib and/or letrozole, unless toxicities are not recovered completely in any 
treatment arm. 
Figure 1. Study Design 
 

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Control Arm (Arm A): 
 Doxorubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 (AC) every 21 days for 
4 cycles followed by 
 weekly paclitaxel 80 mg/m2 for 12 weeks or 3-weekly docetaxel 100 mg/m2 for 4 
cycles. 
Approximately duration of 24 weeks (6 months). 
In Arm A, luteinizing hormone-releasing hormone (LHRH) analogs are not allowed in 
premenopausal women. 
Experimental Arm (Arm B): 
 Letrozole 2.5 mg orally daily + abemaciclib 150 mg orally every 12 hours on a 
continuous dosing schedule, plus LHRH  analogs in premenopausal women, up to 
12 months (±14 days), with study visits each 28 (±3) days from first study dose. 
 
Schedule of study procedures is provided in Protocol Attachment 1. Study Schedule. 
In order to discard metastases, the following tests should be performed before 
randomization: bone scan if bone pain and/or elevated alkaline phosphatase; 
abdominal/pelvic computerized tomography scan (CT) if elevated alkaline phosphatase, 

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abnormal liver function tests, abdominal symptoms or abnormal physical examination; 
chest CT scan if pulmonary symptoms.  
A serum pregnancy test should be done within 7 days of the first dose of study treatment in 
both arms for Child Bearing Potencial (CBP) patients. 
Once the screening process (local at site and at the central laboratory) is completed, fully 
eligible patients will be randomized in a 1:1 manner. Tumor evaluation will be done by 
MRI in baseline and prior to breast surgery, and US will be repeated every 12 week (+/- 1 
week) during the treatment phase to discard PD, as scheduled according to the calendar 
regardless of any dosing delay. 
For Arm B MRI could be done from 11 months of study treatment, to allow enough time to 
plan surgery within 7 days of the last dose of abemaciclib and/or letrozole. 
During treatment phase a serum or urine pregnancy test must be performed in every cycle 
and at the post-treatment visit for CBP patients, including women with tubal ligation. 
After NA treatment in each arm, patients will undergo breast surgery, with or without 
regional lymph nodes surgery, of the primary breast cancer. Adjuvant CT will be allowed 
based on the assessment of the pathological tumor response. 
Those patients who do not complete the NA treatment according to the study protocol 
because of progression of the disease (PD), unacceptable toxicity or informed consent 
withdrawal, will be discontinued from the study treatment 
judgment and only survival follow-up and death dates (if applicable) will be collected.  
Additionally, in those patients who experience recurrence during the follow-up period of 
the study, survival follow-up will also be collected. 
For survival follow-up, only dates on which the patient is alive or not will be collected. 
Patients enrolled on the study will be followed for a period of 10 years. 
For specific details regarding all study procedures, please see Protocol Attachment 1. Study 
Schedule. 
3.2. 
Duration of the study  
It is estimated that the enrollment will be completed approximately in 24 months.  
Following the randomization, patients will receive the treatment for approximately 6 
months in Arm A and 12 months  (±14 days)  in Arm B, unless PD, unacceptable toxicity 
or withdrawal of the informed consent, whatever occurs first. After treatment the patient 
will undergo surgery. After surgery, there will be follow-up of 10 years. 
For safety reasons all patients will have a visit after finishing treatment with the study 
medications.  

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In Arm A patients will have this visit not earlier than 21 days after finishing treatment with 
the study medications and before definitive surgery. In Arm B the visit will be done within 
7 days from the last abemaciclib and/or letrozole dose.  
In some patients, the end of the study treatment (at neoadjuvant setting) may be due to PD 
or toxicity. In case the beginning of the new therapy cannot be delayed as per the 
starting the new anticancer therapy. 
The start date of study is the date of the first site activation. 
The end date of study is the date of the last visit of the last patient (LPLV) including follow 
up. Performing exploratory analyses will be independent of the date of the end of the study. 

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4. Study Population 
4.1. 
Inclusion Criteria 
Patients are eligible to be enrolled in the study only if they meet all of the following 
criteria: 
1. Written informed consent prior to any specific study procedures. 
2. 
 
3. Documentation of histologically confirmed primary invasive adenocarcinoma of the 
breast. Adenocarcinoma with another component of epithelial origin (for example, 
medullary or neuroendocrine) is allowed. 
4. Availability of a primary tumor tissue sample obtained during the diagnostic 
process before treatment for the central Ki67 index and biomarker exploratory 
analyses (following the specifications described in the Sample Management Manual 
of the study). 
5. Documentation of HR positive and HER2 negative BC based on local laboratory 
determination. 
a. HR positive is defined as more than or equal to 10% positive cells by 
immunohistochemistry (IHC) for ER and/or progesterone receptor (PgR). 
b. HER2 negative tumor is determined according to recommendations of 
ASCO/CAP 2018 guidelines.   
6. 
 20%) determined 
at a central laboratory. 
7. Patients should be in the following clinical stages of disease according to the 8th 
edition of the TNM Classification of Breast Cancer, by the UICC (Union for 
International Cancer Control): T1c N1-2 M0 and T2 (> 2cm)  T3, T4a, T4b, N0  
N2, M0 (stages IIA, IIB, IIIA or IIIB). Subpopulation with tumors T2 N0 will 
include high risk patients based on Ki67 index  30% or Ki67 index 
20% 
and <30% if PgR negative and/or histological grade 3.  
8. Patients with diagnosis of suspicious for multifocal or multicentric breast cancer 
will be eligible for the study. At least two tumor lesions should be biopsied. All 
histologically available tumor lesions must comply with the inclusion criteria no. 5.  
a. If all lesions have similar morphological characteristics (i.e. based on local 
lesion will be assessed for central assessment of Ki67 index level. 

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b. If lesions have different morphological characteristics, discordant tumor 
lesions will be centrally evaluated for Ki67 index level. Patients will be 
eligible if at least one tumor lesion complies with criteria 6 and 7.  
 
9. Indication of NA therapy. 
10. At the time of presentation, patients must be candidates for potentially curative 
 
11. Sentinel lymph node biopsy (SLNB) will be preferable after the NA treatment. 
Those patients with SLNB before the NA treatment will be eligible for the study 
only if the SLNB has a negative result (N0). One Step Nucleic Acid Amplification 
(OSNA) method is not allowed.  
12. Pre- and postmenopausal women. 
Postmenopausal status is defined as: 
 Patient underwent bilateral oophorectomy, or 
 
 
 Age < 60 years and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-
stimulating hormone (FSH) and plasma estradiol are in the postmenopausal 
ranges per local normal ranges. 
All women who do not meet the criteria for postmenopausal status are considered       
premenopausal for the purpose of this trial. 
13. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
14. Patients are able to swallow oral medications.  
15. Adequate organ and bone marrow function: 
 
3 (1.5x109/L); 
 
3 (100x109/L); 
 
initial treatment must not begin earlier than the day after the erythrocyte 
transfusion); 
 
ct bilirubin within 
normal limits if Gilbert´s disease); 
 
 

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16. 
-gated 
acquisition scan (MUGA) or echocardiogram (ECHO). 
17. For premenopausal women: agreement to remain abstinent or use single or 
combined non-hormonal contraceptive methods that result in a failure rate of  < 1% 
per year during the treatment period and for at least 3 weeks after the last dose of 
study treatment. Abstinence is only acceptable if it is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Examples of non-hormonal contraceptive methods with a failure rate of  < 1% per 
year include tubal ligation, male sterilization, and certain intrauterine devices.  
Alternatively, two methods (e.g., two barrier methods such as a condom and a 
cervical cap) may be combined to achieve a failure rate of  < 1% per year.  Barrier 
methods must always be supplemented with the use of a spermicide. 
18. Negative serum pregnancy test within 7 days of the first dose of abemaciclib or 
chemotherapy for premenopausal women, and for women who have experienced 
menopause onset < 12 month prior to first dose of therapy. 
19. Patients consent to biological sample provision for biomarker exploratory analyses. 
20. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests and other study procedures. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Previous anti-cancer treatment with therapeutic intent for current breast cancer is 
not allowed. 
2. Patients with inflammatory breast cancer or synchronous bilateral invasive breast 
cancers are not eligible. 
3. Serious and/or uncontrolled preexisting medical condition(s) that in the judgment of 
the investigator, would preclude participation in this study (for example, interstitial 
lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal 
impairment [e.g. estimated creatinine clearance < 30ml/min], history of major 
disease or ulcerative colitis or a preexisting chronic condition resulting in baseline 
Grade 2 or higher diarrhea). 
4. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose- galactose malabsorption. 

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5. Females who are pregnant or lactating. 
6. Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of 
initiating study treatment), fungal infection, or detectable viral infection (such as 
known human immunodeficiency virus positivity or with known active hepatitis B 
or C [for example, hepatitis B surface antigen positive]. Screening is not required 
for enrollment. 
7. Personal history of any of the following conditions: syncope of cardiovascular 
etiology, ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.  
8. Diagnosis of any other malignancy within 5 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the cervix, breast or colorectal. 
9. Prior hematopoietic stem cell or bone marrow transplantation.  
10. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
4.3. 
Discontinuations 
4.3.1. 
Discontinuation of Study Treatment 
The criteria for enrollment must be followed explicitly. If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be discontinued from the 
study treatment, but can be allowed to continue in the study in order to provide the follow-
up data needed for the analysis of the entire population. An exception may be granted if the 
patient, in the opinion of the investigator, is having benefit from the study treatment. In 
these rare cases, the investigator must obtain documented approval from GEICAM to allow 
the patient to continue receiving the study treatment provided by the Sponsor. 
Patients can be discontinued from the study therapy in the following circumstances: 
 
 
 
Unacceptable toxicity as defined in the protocol. 
 
Tumor progression as defined in RECIST v1.1. In this case, the patient will be 
continued only for survival follow-up date. 

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Any clinical adverse event (AE), laboratory abnormality or inter-current illness which, 
in the opinion of the investigator, indicates that continued participation in the study is 
not in the best interest of the patient. 
 
Pregnancy: 
 Instruct to contact the investigator or study staff immediately if they suspect 
they might be pregnant. 
 The investigator must immediately notify GEICAM if a study patient becomes 
pregnant. 
 
Termination of the study by GEICAM. 
 
-cancer therapy, not specified in the 
protocol.  
 
If the patient is non-compliant with study procedures.  
 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g. infectious disease) 
illness. 
All permanent treatment discontinuation should be recorded by the Investigator in the 
eCRF when considered as confirmed. 
4.3.2. 
Discontinuation of Study Sites 
Study Site participation may be discontinued if GEICAM, the investigator or the EC/IRB 
of the study site judges it necessary for any reason.  
4.3.3. 
Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent 
with applicable regulations of Good Clinical Practice (GCP). Stopping the study for 
medical reasons may be required if patients experienced adverse reactions under the study 
treatment or if new information about the safety or effectiveness of the study treatment 
justifies it. 

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5. Treatment 
5.1. 
Treatments Administered 
5.1.1. 
Study Treatment Arm A 
Control Arm (Arm A): 
 Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 21 days for 4 
cycles followed by 
 weekly paclitaxel 80 mg/m2 for 12 weeks or 3-weekly docetaxel 100 mg/m2 for 4 
cycles. 
Approximately duration of 24 weeks (6 months). 
In Arm A, luteinizing hormone-releasing hormone (LHRH) analogs are not allowed in 
premenopausal women. 
If the patient receives weekly paclitaxel 80 mg/m2 for 12 weeks, hematology, biochemistry 
and the hospital visits can be performed every 21 days (each 3 week paclitaxel 
administration corresponds to one cycle). 
The real Body Surface Area (BSA) of the patient determined in the baseline visit will be the 
reference BSA throughout the study. The doses will be recalculated in the event that 
patients experience body weight variations greater than 10% during the treatment period.  
5.1.2. 
Study Treatment Arm B  
Experimental Arm (Arm B): 
 
Letrozole 2.5 mg orally daily + abemaciclib 150 mg orally every 12 hours on a 
continuous dosing schedule, (+ LHRH analogs in premenopausal women), up to 12 
months (±14 days), with study visits each 28 (±3) days from first study dose.  
 
 
5.2. 
Materials and Supplies 
The definition of Investigational Medicinal Product (IMP) is a drug that is being studied or 
used as a reference, even as placebo, in the context of a clinical trial, regardless of its 
authorization. 
All IMPs used in the trial will be named as study treatment along the protocol.  
Abemaciclib will be provided for free to the study sites by the Sponsor with the appropriate 
label for clinical trial use for the purpose of this study.  

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Letrozole, doxorubicin, cyclophosphamide and paclitaxel or docetaxel are marketed 
products and will be procured according to local practice and regulation.  
5.2.1.  
Storage, preparation and administration 
Investigators and site staff are reminded to continuously monitor temperatures and ensure 
that thermometers are working correctly as required for proper storage of study treatment.  
Abemaciclib should be stored at controlled room temperature in their original container, as 
specified on the drug labels and in the summary of product characteristics (SmPC). 
For abemaciclib provided by the Sponsor, any temperature excursions must be reported 
immediately to GEICAM and documented. Once a deviation is identified, the study 
treatment MUST be quarantined and not used until GEICAM provides documentation of 
permission to use the study treatment product.  
Abemaciclib should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements. Returned study treatment provided by the Sponsor 
should be stored separately from study treatment that needs to be dispensed. 
Storage area temperature conditions must be monitored and recorded daily. A daily 
temperature log will also be kept at the study site. 
Refer to the current SmPC for details regarding the storage and handling of letrozole, 
doxorubicin, cyclophosphamide and paclitaxel or docetaxel. Any issue or deviation that 
affect the storage conditions or handling of letrozole, doxorubicin, cyclophosphamide and 
paclitaxel or docetaxel must be reported to the Sponsor for its information. 
5.2.1.1. 
Abemaciclib 
Abemaciclib will be supplied as bottles with 60 film-coated tablets containing 50mg of 
abemaciclib.  
Initially dose will be 150mg twice a day = 6 tabs/day or 3 bottles/cycle (28 days cycle). 
Abemaciclib should be taken twice a day continuously for 12 months (±14 days) or until 
unacceptable toxicity occurs.The dose can be taken with or without food. It should not be 
taken with grapefruits or grapefruit juice. 
Patients should take the doses at approximately the same time every day, preferable in the 
morning and evening. 
The tablet should be swallowed whole, with a glass of water (patients should not chew, 
crush, or spit tablets before swallowing). 
If a patient vomits or misses a dose of abemaciclib, the patient should be instructed to take 
the next dose as its scheduled time; an additional dose should not be taken. 

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The patient number should be recorded on the label in the spaces provided by site personnel 
at the time of assignment to patient. Site personnel must ensure that patients clearly 
understand the guidelines for self-medication. Patients should be given a sufficient supply 
to last until their next study visit. Unused drug and/or empty bottles should be returned to 
the site at the next study visit. Returned unused medication MUST NOT be re-dispensed to 
patient. 
At each visit patient will be dispensed the number of bottles necessary to complete the 
cycle, according the dose prescribed. In the event of dose modification, request should be 
made of the patient to return all previously dispensed medication to the clinic and new 
bottles will be dispensed. 
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 5.4.1. 
5.2.1.2. 
Letrozole 
Letrozole should be taken orally and can be taken with or without food. 
A missed dose should be taken as soon as the patient remembers. However, if it is almost 
time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the 
patient should go back to her regular dosage schedule. Doses should not be doubled 
because with daily doses over the 2.5mg recommended dose, over-proportionality in 
systemic exposure was observed. 
Please, refer to the current SmPC for further details. 
5.2.1.3.  Doxorubicin, Cyclophosphamide and Paclitaxel or Docetaxel 
Investigators should consult the locally approved prescribing information for storage and 
administration instructions. 
5.2.2. 
 Accountability 
It is the responsibility of the investigator to ensure that a current record of abemaciclib 
disposition is maintained at each study site where study treatment provided by the Sponsor 
are inventoried and disposed.  
A drug dispensing log, including records of drug received from the Sponsor will be 
provided by GEICAM if the staff at the investigational site does not have an established 
system that meets these requirements, and will be kept at the study site. Records or logs 
must comply with applicable regulations and guidelines.  
On a per-patient basis, records must be maintained documenting dates and quantities (ie, 
pill counts) of provided study treatment dispensed and returned at each study visit. Any 

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study treatment provided by the Sponsor accidentally or deliberately destroyed must be 
documented.  
Abemaciclib provided by the Sponsor will be preferably destroyed at each participating 
site. The site must obtain written authorization from the Sponsor before it is destroyed, and 
this destruction must be documented on the appropriate form. 
It is also the responsibility of the investigator to ensure that current records of letrozole, 
doxorubicin, cyclophosphamide and paclitaxel or docetaxel dispensations are available to 
assure traceability. 
5.3. 
Method of Assigning a Patient to a Treatment 
Patients will be screened by one of the investigators prior to study entry. An explanation of 
the study and discussion of the expected side effects and presentation of the informed 
consent document will take place. Eligible and consented patients will be screened and then 
enrolled into the study.  
All patients screened in the study, will be included in a Patient Screening Log maintained at 
each site and at the GEICAM central office. 
No patients can be enrolled and receive study treatment until the patient has been screened 
in the study. All eligibility criteria must be met at the time of enrollment (not necessary in 
screening failure patient). There will be no exceptions. Any question should be addressed 
with GEICAM prior to enrollment. An eligibility checklist must be completed and signed 
by the Principal Investigator or Sub-Investigator before enrolling each patient to confirm all 
inclusion/exclusion criteria and stratifications factors. This eligibility checklist should be 
filed with the study documentation. Once the eligibility checklist is completed, the study 
personnel at the site will enroll the patient through the eCRF and the system will send the 
unique randomization number of the patient and the assigned arm to the site. This 
randomization number should be used on all documentation and correspondence with the 
GEICAM central office. Only after the confirmation of enrollment by the system, the 
patient can receive the study treatments. All patients enrolled in the study will be registered 
in a Patient Enrollment and Identification Log that will be only maintened at the site. 
Study treatment(s), must be administered within 5 days from enrollment.  
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Treatment 
All dose modifications should be based on the worst preceding toxicity.  
Every effort should be made to administer study treatment at the planned dose and 
schedule. However, in the event of significant treatment-related toxicity, administration of 

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study treatment may need to be adjusted as described in the following sections. Depending 
on the nature of the toxicity observed, dose adjustments may be required for one or more 
study treatment in the combination.  
All dose modifications/adjustments must be clearly documented in the patient's source 
notes and the appropriate section of the eCRF.  
Control Arm (Arm A): 
If a treatment-related toxicity has not been recovered as the study protocol states after 1 
complete cycle period of dose interruption or delay, permanent discontinuation of study 
treatment may be considered. Treatment resumption for patients recovering from 
treatment-related toxicity after > 1 cycle of treatment interruption or cycle delay, but 
should be discussed with GEICAM. 
In the event that the start of a new cycle is delayed due to treatment-related toxicity, 
procedures required on day 1 of the given cycle will be performed when medication is 
resumed. New cycle day 1 procedures (ie. physical examination, ECOG performance 
status, blood chemistry, hematology) that were performed prior to knowing the need to 
delay the start of the cycle do not need to be repeated (1) if not required to determine 
whether study drug may be resumed and (2) if performed within 7 days prior to study drug 
resumption. 
Experimental Arm (Arm B): 
If a treatment-related toxicity has not been recovered as the study protocol states after 1 
month of dose interruption, permanent discontinuation of study treatment may be 
considered. Treatment resumption for patients recovering from treatment-related toxicity 
after > 1 month of treatment interruption, but deemed to be deriving obvious clinical 
 
Each study visit and procedure (ie. physical examination, ECOG performance status, blood 
chemistry, hematology) will be performed as scheduled according to the calendar 
regardless of any dosing omission and/or interruption, every 28 (± 3) days from the start of 
treatment.  
 
5.4.1.  
Abemaciclib 
In the event of significant treatment-related toxicity, abemaciclib dosing may be interrupted 
or delayed and/or reduced. Patients are to be instructed to notify investigators at the first 
occurrence of any adverse sign or symptom. 

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5.4.1.1. 
Dose Adjustements 
Management of some adverse reactions may require dose interruption and/or dose 
reduction. Dose level reductions should be made in 50mg decrements. For example, if the 
starting dose of abemaciclib for a study is 150mg every 12 hours, dose reduction 1 would 
be 100mg every 12 hours, dose reduction 2 would be 50mg every12 hours. Please see 
Table 2. 
Table 2. Dose adjustment recommendations for adverse reactions 
 
Abemaciclib dose combination therapy 
Recommended dose 
150mg twice daily 
First dose adjustment 
100mg twice daily 
Second dose adjustment 
50mg twice daily 
 
Once a dose has been reduced for a given patient, all subsequent doses should be 
administered at that dose level, unless further dose reduction is required. Dose re-escalation 
is not allowed. 
5.4.1.2 Guidelines for Diarrhea Management 
At enrollment, patients should receive instructions on the prompt management of diarrhea. 
In the event of diarrhea, supportive care measures should be initiated as early as possible. 
These include the following: 
 At the first sign of loose stools, the patient should initiate antidiarrheal therapy (e.g. 
loperamide) and notify the investigator for further instructions and appropriate 
follow-up. 
 Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear 
liquids per day). 
 Site personnel should assess response within 24 hours. Guidance for Grade 2 
diarrhea is to wait for 24h to see if diarrhea goes down to grade 1 or gets solved. 
 
Refer to Table 3 for additional information for diarrhea management and dose 
modification. 
 
Table 3: Dose Modification and Management- Diarrhea 
 
At the first sign of loose stools, start treatment with antidiarrheal agents, such as 
loperamide. 

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CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 
No dose modification is required. 
Grade 2  
If 
 
Grade 1, suspend dose until resolution. 
Dose reduction is not required 
Grade 2 that persistsa, or recursb after 
resuming the same dose despite 
maximal supportive measures  
 Grade 1 
Resume at next lower dose 
Grade 3 or 4 or requires 
hospitalization 
a Determination of persistent events will be at the discretion of the investigator. 
b Please note that recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured 
from the stop date of the preceding event). 
 
5.4.1.3 General Guidance for Increases in Serum Creatinine and Assessment of Renal 
Insufficiency 
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
transporters without affecting glomerular function (as measured by iohexol clearance). In 
clinical studies, increases in serum creatinine occurred within the first month of 
abemaciclib dosing, remained elevated but stable through the treatment period, were 
reversible upon treatment discontinuation, and were not accompanied by changes in 
markers of renal function, such as blood urea nitrogen (BUN), cystatin C, or calculated 
glomerular filtration rate based on cystatin C.  
 
5.4.1.4 General Guidance for Interstitial Lung Disease (ILD)/Pneumonitis Events 
Interstitial lung disease (ILD) / pneumonitis has been identified as an adverse drug reaction 
(ADR) for abemaciclib. The majority of events observed in clinical trials were Grade 1 or 
Grade 2 with serious cases and fatal events reported. Additional information is available in 
the Investigator Brochure (IB). 
Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis and 
ask your patients to report any new or worsening pulmonary symptoms such as dyspnoea, 
cough and fever; these symptoms should be investigated and treated as per local clinical 
practice and/or guidelines (including corticosteroids as appropriate). If ILD/pneumonitis is 
suspected, investigations may include imaging such as high resolution computer 
tomography (HRCT), broncheoalveolar lavage (BAL), and biopsy as clinically indicated.  
For patients who develop radiological changes suggestive of pneumonitis and have few or 
no symptoms (Grade 1), abemaciclib should be continued without dose modification. For 

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persistent or recurrent Grade 2 ILD/pneumonitis events, abemaciclib should be suspended 
 
Grade 3 ILD/pneumonitis events, permanently discontinue abemaciclib (see also Table 8: 
refer to dose adjustment table for non-hematological toxicities). 
5.4.1.5 General Guidance for Hepatic Monitoring 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation are 
considered as ADR with the use of abemaciclib, and should be monitored according to 
Table 4 and Table 5, respectively.  
 
Table 4: Dose Modification and Management 
 Increased ALT (GPT/SGPT) / AST 
(GOT/SGOT) 
 
Monitor ALT and/or AST prior to the start of abemaciclib therapy, every 2 weeks for the 
first 2 months, monthly for the next 10 months, and as clinically indicated. 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 (> ULN-3.0 x ULN) 
Grade 2 (> 3.0-5.0 x ULN) 
No dose modification is required 
Persistent Grade 2 that does not 
resolve with maximal supportive 
measures within 7 days to baseline or 
Grade 1, or Recurrenta Grade 2  or 
Grade 3 (> 5.0-20.0 x ULN)  
Suspend dose until toxicity resolves to baseline 
or Grade 1 
Resume at next lower dose 
 
with total bilirubin > 2 x ULN, in the 
absence of cholestasis
Discontinue abemaciclib 
Grade 4 (> 20.0 x ULN) 
Discontinue abemaciclib 
a Please note that recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured 
from the stop date of the preceding event). 
 
To ensure patient safety the investigator should collect specific recommended clinical 
information and follow-up laboratory tests as shown below in Table 5.  
Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. If a study patient experiences elevated ALT and/or AST 
5×ULN and elevated TBL 2×ULN, or ALT and/or AST 8×ULN, liver tests, including ALT, 
AST, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatine 

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phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the abnormality 
and to determine if it is increasing or decreasing.  If the abnormality persists or worsens, 
clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests below.  
 
Table 5: Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality 
 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-
HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
    HBV DNA c 
Anti-actin antibody b 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA c 
    EBV DNA c 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNA c 

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    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA c 
    HSV (Type 1 and 2) DNA c 
Microbiology  
Liver kidney microsomal type 1 (LKM-1) 
antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Not required if anti-smooth muscle antibody (ASMA) is tested. 
c Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
 
5.4.1.6 General Guidance for Hematology Toxicity and Dose Modification 
Hematologic toxicities including neutropenia, leukopenia, anemia, and thrombocytopenia 
have been observed in patients treated with abemaciclib, and causality has been established. 
Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib. 
Patients should be monitored closely for signs of infection, anemia, and bleeding. The 
following instructions on Table 6 must be followed: 
 
 Table 6: Dose Modification and Management 
 Hematologic Toxicities 
Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 weeks for 
the first 2 months, monthly for the next 10 months, and as clinically indicated. 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required 
Grade 3 
Suspend dose until 
 
Dose reduction is not required 
Recurrentb Grade 3 or Grade 4 
 
Resume at next lower dose 
Patient requires administration 
of a blood cell growth factor 
Suspend abemaciclib dose for at least 48 hours after the 
last dose of blood cell growth factor and until toxicity 
 2 
Resume abemaciclib at next lower dose unless the dose 
was already reduced for the toxicity that led to the use of 

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the growth factor  
b Please note that recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured 
from the stop date of the preceding event). 
 
5.4.1.7 General Guidance for Venous Thromboembolic Events (VTE) 
VTE has been identified as an adverse drug reaction (ADR) for abemaciclib in combination 
with ET. However, in studies with single-agent abemaciclib use in the metastatic BC or 
other tumor types, including non-small cell lung cancer (NSCLC), no increased rates of 
VTEs were observed as compared to the incidence of VTEs for these particular patient 
populations who were treated with other anticancer agents. At this time, the mechanism 
underlying the association between abemaciclib and the occurrence of VTEs is not known. 
Venous thromboembolic events have been reported with other CDK4 and 6 inhibitors, and 
ET is known to be associated with the occurrence of VTEs. Monitor patients for signs and 
symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) and treat as 
medically appropriate. 
 
Table 7: Dose Modification and Management 
 Venous Thromboembolic Events 
CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
Suspend dose and treat as clinically indicated. Abemaciclib may be 
resumed when the patient is clinically stable. 
Grade 3 or 4 
Suspend dose and treat as clinically indicated. Abemaciclib may be 
resumed when the patient is clinically stable. 
5.4.1.7 General Guidance for Non-hematologic Toxicities (excluding diarrhea, 
increased ALT/AST and Venous Thromboembolic Events) Monitoring 
 Non-hematologic toxicities excluding diarrhea and increased  ALT/AST: 
 Grade 1 or 2: no dose modification is required. 
 Persistent or recurrent Grade 2 toxicity that does not resolve with maximal 
supportive measures within 7 days to baseline or Grade 1: suspend dose until 
toxicity resolves to baseline or Grade 1. Resume at next lower dose. 
 Grade 3 or 4: suspend dose until toxicity resolves to baseline or Grade 1. Resume at 
next lower dose. Permanently discontinue abemaciclib in case of Grade 3 or 4 
ILD/pneumonitis. 
 
Table 8: Dose Modification and Management 
 Nonhematologic Toxicities Excluding 
Diarrhea, ALT/AST Increased, and Venous Thromboembolic Events 

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CTCAE Grade 
Abemaciclib Dose Modifications 
Grade 1 or 2 
No dose modification is required 
Persistent or recurrenta Grade 2 toxicity 
that does not resolve with maximal 
supportive measures within 7 days to 
baseline or Grade 1 
Suspend dose until toxicity resolves to baseline 
or Grade 1 
Resume at next lower dose 
Grade 3 or 4 b 
a Please note that recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured 
from the stop date of the preceding event). 
b  Permanently discontinue abemaciclib in case of Grade 3 or 4 ILD/pneumonitis. 
 
Patients discontinuing abemaciclib treatment permanently due to treatment related 
toxicity will continued with letrozole in the active treatment phase of the study. 
5.4.2. 
Letrozole 
The most frequently reported adverse reactions in clinical studies with letrozole were hot 
flushes, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.  
Important additional adverse reactions that may occur with letrozole are: skeletal events 
such as osteoporosis and/or bone fractures and cardiovascular events (including 
cerebrovascular and thromboembolic events). 
No dose adjustment is required. Treatment interruption for letrozole-related toxicities will 
be performed as per the investigator´s best medical judgment. 
In the event of a toxicity requiring dosing delay of abemaciclib, the administration of 
letrozole +/- LHRH analogs should be continued as pre-planned schedule. 
Patients discontinuing letrozole permanently due to treatment related toxicity will 
continue with abemaciclib in the active treatment phase of the study. 
5.4.3.  Doxorubicin, Cyclophosphamide and Paclitaxel or Docetaxel 
criteria for all dose modifications/adjustments. 
5.5. 
Medication Errors and Overdose 
Medication errors may result in this study from the administration or consumption of the 
wrong drug, by the wrong patient, at the wrong time or at the wrong dosage strength. Such 
medication errors occurring to a study participant are to be captured on the adverse event 

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(AE) page of the eCRFs and on the SAE form when appropriate. In the event of medication 
dosing error, GEICAM should be notified immediately.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
 Medication errors involving patient exposure to the product; 
 Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) eCRF page (refer to Management, Timing and 
Assessment of Adverse Events section for further details). 
5.6. 
General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medication (over-the-counter or other 
products) during the study without prior consultation with the investigator. Any 
medications including herbal supplements, vitamins, or treatment taken by the patient from 
28 days prior to the start of study treatment and up to 30 days following the last dose of 
study treatment and the reason for their administration must be recorded on the eCRF.  
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded. Anesthetics used for 
rec
necessary to list the specific anesthetics. Palliative and supportive care for cancer-related 
symptoms will be offered to all patients in this study. 
5.6.1. 
Prohibited Medications 
The following treatments are prohibited throughout the duration of the active treatment 
phase: 
 Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy other than the ones stated in the protocol, will be 
permitted during the active treatm
 
 Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (eg, 
raloxifene) are prohibited during the active treatment phase. 

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 Any concurrent radiotherapy: is prohibited throughout the duration of the active 
treatment phase of the study. Patients requiring this procedure will be discontinued 
from the active treatment phase and will enter the follow-up phase. This 
radiotherapy will be considered an alternative cancer therapy and will result in 
censoring the patient. 
 Bisphosphonates and receptor activator of nuclear factor kappa B ligand 
(RANKL), used as anti-tumor treatment.  
 In Arm A, luteinizing hormone-releasing hormone (LHRH) analogs are not 
allowed regardless of the menopausal status. 
 
5.6.2. 
Medications Not Recommended 
The following treatments are not recommended throughout the duration of the active 
treatment phase. Alternative therapies should be considered whenever possible. If usage of 
the following treatments is deemed necessary, consultation and agreement with GEICAM is 
required prior to treatment initiation.  
 CYP3A inhibitors/inducers: abemaciclib is predominantly cleared by oxidative 
metabolism via CYP3A4. Clinical drug interaction studies with a CYP3A inhibitor 
and CYP3A inducer significantly altered the PK of abemaciclib and its circulating 
major metabolites. Concomitant use of CYP3A inducers may reduce the activity of 
abemaciclib. Abemaciclib can be co-administered with drugs which are substrates 
of CYP enzymes. 
CYP3A inducers. At a minimum, it is recommended to avoid concomitant use of 
CYP3A inducers and consider alternative agents. 
CYP3A inhibitors. Concomitant use of strong and moderate CYP3A inhibitors may 
increase the likelihood of AEs related to abemaciclib. At a minimum, it is 
recommended to avoid concomitant use of strong CYP3A inhibitors (for example, 
voriconazole) and use caution with coadministered moderate (for example, 
ciprofloxacin) or weak (for example, ranitidine) CYP3A inhibitors.  
Please, refer to Protocol Attachment 5. The information in this attachment is 
provided for guidance to investigators and does not preclude the use of these 
medications if clinically indicated. 
 Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids. Steroids given for physiological replacement, as anti-emetics or 
inhaled as well as short course of oral/topical steroids given for allergic reactions or 
asthma flares are allowed. 

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 The use of herbal medicine is not recommended during the active treatment phase. 
 Erythropoietin should be avoided, taking into considerations the recommendations 
from ASCO/ASH Clinical Practice Guideline(65).  
5.6.3. 
Permitted Medications 
The following treatments are permitted throughout the duration of the active treatment 
phase:  
 Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care 
(eg, analgesics, antidiarrheals, antidepressants) may also be used at the 
 discretion. All medications should be recorded.  
 Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte 
macrophage 
colony 
stimulating 
factor 
[GM-CSF]): 
Primary 
prophylactic use of granulocyte-colony stimulating factors is not permitted but they 
may be used to treat treatment-emergent neutropenia as indicated by the current 
American Society of Clinical Oncology (ASCO) guideline. If neutropenic 
complications are observed in a cycle in which primary prophylaxis with CSFs was 
not received, secondary prophylaxis may be given at the discretion of the 
investigator, but only if dose reduction or delay are not considered to be a 
reasonable alternative. 
 Bone-sparing agents (e.g., bisphosphonates, denosumab for the treatment of 
osteoporosis/osteopenia) are allowed in the study provided patients are on stable 
doses for at least 4 weeks prior to randomization. 
 Influenza and/or COVID-19 vaccines should be preferably administered at the 
time of the cycle with the lowest myelosuppression. 
 Caution is advised on theoretical grounds for any surgical procedures during the 
study:  
o For minor surgeries and procedures (for example, ambulatory), 
investigators should treat as clinically indicated and closely monitor any 
signs of infection or healing complications.   
o For major surgeries, the recommendation is to suspend dosing of 
abemaciclib for at least 7 days before and may be resumed as clinically 
indicated. 
Consider monitoring neutrophils and platelets before surgery and before 
resuming abemaciclib. 
The scars should be aseptic and healing process be reasonable before 
resuming abemaciclib. 

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8 days must be discussed with GEICAM.   
 
5.6.4. 
General Guidance for Women of Child Bearing Potential and/or Use of 
Contraceptive Methods 
Based on findings in animals, abemaciclib can cause fetal harm when administered to a 
pregnant woman. In animal studies, abemaciclib was teratogenic and caused decreased fetal 
weight at maternal exposures that were similar to human clinical exposure based on the 
area under the plasma concentration versus time curve (AUC) at the recommended human 
dose. Therefore, teratogenicity is considered an important potential risk for abemaciclib. 
There are no available human data informing the drug-associated risk. Pregnant women 
should be advised of the potential risk to a fetus. Additionally, there are no available human 
data informing the drug-associated risk. A nursing woman should be advised to discontinue 
breastfeeding during treatment with abemaciclib.    
 A female of childbearing potential, must have a negative serum pregnancy test 
within 7 days of the first dose of abemaciclib or CT and agree to use a highly 
effective contraception method during the treatment period and for 3 weeks 
following the last dose of abemaciclib or CT.  
 Contraceptive methods may include an intrauterine device [IUD] or barrier method. 
If condoms are used as a barrier method, a spermicidal agent should be added as a 
double barrier protection. 
 Cases of pregnancy that occur during maternal exposures to abemaciclib or CT 
should be reported. If a patient is determined to be pregnant following abemaciclib 
initiation, she must discontinue treatment immediately. Data on fetal outcome and 
breast-feeding are to be collected for regulatory reporting and drug safety 
evaluation. 
5.7. 
Treatment Compliance 
Patients will be required to return all bottles/blisters of abemaciclib and letrozole as well as 
the completed patient diary at each visit. Drug accountability will be performed prior to 
dispensing drug supply. The number of remaining tablets of abemaciclib, and letrozole will 
be documented and recorded.  
The patient number should be recorded on the bottle/blister label at time of assignment to a 
patient. Site personnel must ensure that patients clearly understand the directions for self-
medication. Patients should be given a sufficient supply to last until their next study visit. 
Unused drug and/or empty bottles/blister should be returned to the site at the next visit. 
Patients included in the control arm B will be given a patient diary and will be asked to 
return the completed diary at each study visit in order to assess compliance.  

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To be considered compliant, each study patient must have received at least 80% of the 
planned number of doses of primary therapy based on the number of days of actual dose 
administration. Dose adjustments must follow instructions provided in the dose adjustment 
guidelines section. 
Doxorubicin, cyclophosphamide and paclitaxel or docetaxel will be administered at the 
hospital and will be supervised by the investigator or his designee.  
 
 

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6. Efficacy and Safety Evaluations, Sample Collection and 
Testing (Standard Laboratory Testing) and Appropriateness 
of Assessments 
Study procedures and their timing (including tolerance limits for timing) are summarized in 
the Study Schedule, Protocol Attachment 1. 
6.1. 
Efficacy Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
6.1.1. 
Primary Efficacy Assessments 
The primary efficacy variable is Residual Cancer Burden (RCB) 0-I rate. 
RCB is a continuous variable derived from the primary tumor dimensions, cellularity of the 
tumor bed, and axillary nodal burden. It is estimated from routine pathological sections of 
the primary breast tumor site and the regional lymph nodes after the completion of NA 
therapy. The pathological variables include bidimensional diameters of the primary tumor 
bed, the proportion of primary tumor area containing invasive carcinoma, the number of 
positive lymph nodes, and the diameter of the largest nodal metastasis. 
6.1.2. 
Secondary Efficacy Assessments 
Secondary efficacy assessments are: 
 Percentage of decrease in the geometric mean of Ki67 index value after 2 weeks of 
treatment in both treatments arms.  
Number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment 
in both treatment arms. 
 RCB(23) is classified in four classes based on the residual disease (RD): 
o RCB-0 defined as pathological complete response. 
o RCB-I defined as minimal RD. 
o RCB-II defined as moderate RD. 
o RCB-III defined as extensive RD. 
 Variation of the value of RCB based on the RD between the two treatment arms. 
 PEPI(24)  (Preoperative Endocrine Prognostic Index) requires pathological stage 
(tumor size and nodal status), level of  Ki67 protein, and Allred ER score measured 

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on the surgical specimen. PEPI score 0 includes p
Allred score > 2. 
found to have a low risk of recurrence (P024 recurrence(44, 66) and IMPACT(45, 67, 68)  
studies). In addition, recent results from ACOSOG Z1031 trial showed that recurrence risk 
over 5 years for patients with PEPI = 0 disease was 3.6% (versus 14.4% for patients with 
PEPI > 0). 
Preoperative Endocrine Prognostic Index (PEPI)* 
Pathology, biomarker status 
Recurrence-Free 
Survival 
Breast Cancer-
Specific Survival 
HR 
Points 
HR 
Points 
Pathological tumor size 
T1/2 
- 
0 
- 
0 
T3/4 
2.8 
3 
4.4 
3 
Nodal status 
Negative 
- 
0 
- 
0 
Positive 
3.2 
3 
3.9 
3 
Ki67 level 
 
 
 
 
0% - 2.7% (0-1**) 
- 
0 
- 
0 
> 2.7% - 7.3% (1-2**) 
1.3 
1 
1.4 
1 
> 7.3% - 19.7% (2-3**)  
1.7 
1 
2.0 
2 
> 19.7% - 53.1% (3-4**) 
2.2 
2 
2.7 
3 
> 53.1% (> 4) 
2.9 
3 
3.8 
3 
ER status, Allred score 
 
 
 
 
0-2 
2.8 
3 
7.0 
3 
3-8 
- 
0 
- 
0 
* The total PEPI score assigned to each patient is the sum of the risk points derived from the pT 
stage, pN stage, Ki67 level, and ER status of the surgical specimen. The total risk point score for 
each patient is the sum of all the risk points accumulated from the four factors in the model. 
*The natural logarithm interval corresponding to the percent Ki67 values on the original percentage 
scale. 
 
 Clinical Response Rate (CRR) is defined as the proportion of subjects with 
complete or partial radiographic response. CR and PR definitions are assessed by 
MRI at baseline and prior to breast surgery, with or without regional lymph nodes 
surgery, and categorized according to percent reduction in tumor size. 

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 Breast-conserving surgery (BCS) rate: defined as the proportion of patients who 
achieved breast conserving surgery between both treatment arms. 
 Invasive event free survival (iEFS): defined as time from randomization to 
progressive disease or invasive disease recurrence (local, regional, distant, 
or contralateral), or death from any cause. Invasive disease recurrence is defined as: 
o Ipsilateral invasive breast tumor recurrence (including second primary 
invasive breast cancer): an invasive breast cancer involving the same breast 
parenchyma as the original primary lesion.  
o Ipsilateral regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, other regional lymph nodes, chest wall, and/or skin of 
the ipsilateral breast). 
o Distant recurrence (i.e., evidence of breast cancer in any anatomic site 
outside local and/or regional location and that has been either histologically 
confirmed or clinically diagnosed as recurrent invasive breast cancer). 
o Contralateral invasive breast cancer. 
o Second primary invasive cancer of non-breast origin. 
 Safety will be assessed by standard clinical and laboratory tests (haematology, 
serum chemistry). AEs grade will be defined by the NCI CTCAE (National Cancer 
Institute Common Terminology Criteria for Adverse Events) version 5.0. AEs terms 
will be coded according to MedDRA dictionary. 
 Gene expression data provided by a multigene expression panel in sequential tumor 
biopsies. 
6.2. 
Safety Assessments  
Investigators are responsible for monitoring the safety of patients who have been enrolled 
in this study and for alerting GEICAM of any event that seems unusual. 
The investigator is responsible for appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health-care 
option, adverse events that are serious or that caused the patient to discontinue before 
completing the study. The patient should be followed until the event is resolved or 
explained. Frequency of follow-up evaluation is left to the discretion of the investigator. 
During the course of the study, all patients enrolled in the trial must be evaluated according 
to the schedule outlined in the flow charts and described below. The results of the 
evaluation will be recorded in the eCRF pages until the patients are not followed anymore. 
Serious Adverse Event Reporting:  

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adverse events to regulatory authorities, IRBs, Ethics Committees or other third 
parties.  In addition to the obligations set forth below, Investigator and Institution 
agree to provide Lilly with a copy of all information Investigator and/or Institution 
submit to regulators related to any adverse events for the Study Drug that occur 
during the Study that Investigator and/or Institution have not otherwise provided 
Lilly; 
 
to notify Lilly, sub-investigators, and the IRB of any problems involving risk to 
Study patients and report new safety information to IRBs in accordance with 
applicable requirements; 
 
to notify Lilly within fifteen (15) business days of Investigator and/or Institution 
nt 
participating in the Study and receiving Study Drug. For purposes of this 
 (1) death; (2) in-patient hospitalization or prolonged 
hospitalization; (3) life-threatening; (4) persistent or significant disability or 
incapacity; (5) congenital anomaly or birth defect; or (6) other serious events that 
may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other five listed outcomes. Serious adverse events should be 
reported to Lilly using a CIOMS Form or other form acceptable to 
Lilly. Investigator and Institution further agree to make available promptly to Lilly 
such records as may be necessary and pertinent for Lilly to further investigate an 
adverse event in the Study that is possibly associated with the Study Drug. 
 
6.2.1. 
Timing of Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
Vital signs assessments will include blood pressure, pulse and body temperature. Baseline 
standard FEVI is mandatory; and after treatment with antracyclines (only for Arm A), on 
the other visits it will be only performed if clinically indicated. 
The following safety laboratory assessments will be performed by the local laboratories, at 
the times specified in the Study Schedule: 
 Hematology*: hemoglobin, WBC, absolute neutrophils, lymphocytes, platelet 
count. 
Blood Chemistry*: fasting glucose, alkaline phosphatase, ALT, AST, total bilirubin, 
serum creatinine, sodium, potassium, total calcium, urea (or BUN). 

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If the patient receives weekly paclitaxel 80 mg/m2 for 12 weeks, hematology and blood 
chemistry can be performed every 21 days (each 3 week paclitaxel administration 
corresponds to one cycle). 
* In arm B the haematology and blood chemistry will be performed every two weeks for 
the first two visits and from visit 3 onwards, every four weeks (± 3 days). 
 
All AEs (and their relatedness to the study treatment) occurring during the study will be 
documented in the eCRF. AEs will be graded according to NCI-CTCAE version 5.0. 
6.2.2. 
Definitions 
The safety definitions are described in the Table 9. 
Table 9: Safety definitions  
Concept 
Definition 
Adverse Event (AE) 
Any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical 
investigation 
subject 
administered 
an 
investigational 
(medicinal) product and that does not necessarily have a 
causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended 
sign, symptom or disease temporally associated with the use 
of investigational product, whether or not considered related 
to the investigational product.  
Laboratory and vital signs abnormalities should be reported 
as AE only in case they lead to an action on study treatment 
or if they are serious.  
Any temporary increase in the severity of a symptom or 
previous sickness that happens after the baseline of the study 
is considered also as an AE. 
Adverse Reaction (AR) 
All untoward and unintended responses to a medicinal 
product related to any dose administered.  
All expected ARs are listed in the Investigator's Brochure 
(IB) in case of not authorized investigational product or 
Summary of Product Characteristics [SmPC] in case of an 
authorized investigational product. If the nature or the 
severity of an adverse reaction is not consistent with the 

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applicable product information, the AR is defined as 
unexpected. The basis for the decision is the current version 
of the corresponding reference document that has been 
submitted and approved by the competent authority and the 
ethics committees. 
Accountability criteria 
The Sponsor will classify the adverse event, based in their 
causation relation with the investigational product, following 
the Karch y Lasagna (1977) algorithm, as: 
o Related (final, probable and possible): there is 
reasonable temporal sequence between the study 
treatment administration and the appearance of the 
adverse event. This event matches with the adverse 
reaction described for the investigational product, 
improves with the omission and reappears after its re-
causes. 
o Not related (conditional or improbable or not 
related): there is no reasonable temporal sequence 
between the investigational product administration 
and the appearance of the adverse event. This event 
does not matches with the adverse reaction described 
for the study treatment and can be explained by other 
causes. 
For expedited reporting purposes it is considered as related 
the categories: final, probable and possible from Karch y 
Lasagna (1977) algorithm and as not related the category 
conditional or improbable of that algorithm.  
The determination of the possible relation with the study 
treatment is responsibility of the principal investigator of the 
site or the person designated by him.  
Serious Adverse Event 
(SAE) and Serious 
Adverse Reaction 
(SAR) 
Any  adverse event or adverse reaction that, at any dose: 
o is fatal (results in death), 
o initial or prolonged inpatient hospitalization, 
o a life-threatening experience (that is, immediate risk 
of dying, defined as an event in which the patient was 
at risk of death at the time of the event; it does not 

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refer to an event which hypothetically might have 
caused death if it were more severe), 
o persistent or significant disability/incapacity, 
o congenital anomaly/birth defect or 
o an important medical event, defined as a medical 
event that may not be immediately life-threatening or 
result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may 
jeopardize the patient or may require intervention 
(eg. medical, surgical) to prevent one of the other 
serious outcomes listed above.  
(minor/mild/severe). 
The following events will be considered as Special situations 
events and they have to be documented as a SAE and 
notified to the Pharmacovigilance Department of GEICAM 
immediately: overdose, misuse and abuse inadvertent or 
accidental exposure to investigational product, medication 
error, suspected transmission of an infectious agent via IP 
and cancer (except for breast cancer).   
 
 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
Any serious adverse reaction whose nature, intensity or 
consequences do not correspond with the reference 
information for the investigational product (example, 
Investigator Brochure [IB] in case of not authorized 
investigational 
product 
or 
Summary 
of 
Product 
Characteristics 
[SmPC] 
in 
case 
of 
an 
authorized 
investigational product).  
The unexpected nature of an adverse reaction is based in the 
fact of not being observed previously and not in what could 
be advanced based on the pharmacological properties of the 
study treatment.  
6.2.3 
Management, Timing and Assessment of Adverse Events 
AE Classification  
Adverse events should be classified following version 5.0 of 
the Common Terminology Criteria for Adverse Events 

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(CTCAE) of the National Cancer Institute (NCI).  A copy 
can 
be 
downloaded 
in 
the 
NCI 
web 
site: 
http://evs.nci.nih.gov/ftp1/CTCAE. The investigators team 
must have access to the CTCAE-NCI version 5.0.  
The AE not included in the CTCAE will be classified as 
described on Protocol Attachment 3. 
The causal relation between the investigational product and 
the AE will be assessed by the investigator using the Karch y 
Lasagna (1977) algorithm. 
Procedure to notify an 
AE to GEICAM 
The site must notify to GEICAM, through eCRF, the 
following events: 
o All adverse events that occur after signed Informed 
Consent Form.  
o Preexisting conditions that get worse during the 
study.  
o The evaluation of the possible relationship of each 
adverse event to the study treatment or protocol 
procedure.  
o The 
circumstances 
and 
data 
that 
causes 
the suspension of the treatment of a patient due to an 
adverse event. 
o The events related with progression/recurrence will 
not be recorded as adverse events, unless the 
investigator believes they could  have been caused by 
the study treatment.   
o The events leading to the clinical outcome of death 
from disease progression will not be recorded as 
adverse events, unless the investigator believes they 
could  have been caused by the study treatment.  
Timing and assessment 
of AE/SAE (see 
Protocol Attachment 4) 
The site staff will report on the eCRF the information of the 
AE/SAE in the following  periods: 
 Baseline (after the patient signs the ICD and 
before study treatment administration): study site 
personnel will note the occurrence and nature of each 

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patient´s 
medical 
condition(s) 
and 
preexisting 
conditions in the appropriate section of the eCRF. If a 
patient 
never 
receives 
study 
treatment 
but 
experiences an AE/SAE after the ICD is signed, 
ONLY events the investigator believes may have 
been caused by a protocol procedure will be reported 
to GEICAM via eCRF and SAE form (if applicable). 
 During treatment with the study treatment: during 
the study treatment administration, site personnel will 
record any change in the condition(s) and the 
occurrence and nature of any AE/SAE. A CTCAE 
grade rating will be assigned before each cycle for 
any AE experienced during the previous cycle.  
 30-day (±7 days) post-treatment follow-up period: 
for safety reasons all patients will have a visit after 
finishing treatment with the study medications.  
In Arm A patients will have this visit 30 (±7) days 
after finishing treatment with the study medications. 
In Arm B the visit will be done within 7 days from 
the last abemaciclib and/or letrozole dose.  
Patients should be closely followed for study 
treatment AE/SAE in order to detect delayed toxicity. 
If study treatment-related toxicity is present beyond 
30 days post-treatment, patients must be followed 
until it resolves or improved to baseline, the 
relationship 
is 
reassessed 
as 
unrelated, 
the 
investigator confirms that no further improvement 
can be expected, another therapy is initiated, or death. 
 Long-Term Follow-up Period (after the 30-day 
(±7 days) post-discontinuation/post-treatment): 
ongoing SAEs, and new SAEs thought to be related 
to study treatment or protocol procedures should be 
documented on the eCRF and immediately reported 
to GEICAM via the designated transmission method. 
If the study has been closed the notification to 
GEICAM 
will 
be 
done 
via 
the 
designated 
transmission method.  

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 SAES related with study treatment should be 
collected and analyzed until they are solved or until 
the toxicity is considered irreversible. 
Reporting of Study 
Specific AE/ Adverse 
Events of Special 
Interest (AESIs) 
Adverse Events of Special Interest (AESIs) for abemaciclib 
are: diarrhea, neutropenia, liver enzyme increased, venous 
thromboembolism (VTE) and infections. AESIs must be 
reported in eCRF.  
If an AESI meets seriousness criteria, it must be reported as 
a SAE according to the procedure described in section 6.2.4. 
6.2.4. 
Management, Timing and Assessment of SAEs/pregnancies 
Timing of  SAEs (see 
Protocol Attachment 4) 
All the SAEs (either spontaneously or during the trial visits) 
will be collected since the patient signs the Informed 
Consent Document (ICD) see Attachment 4. 
All the SAEs must be documented in the medical record of 
the patient and in the eCRF. A follow up of all the SAEs 
should be done until they are solved or until the toxicity is 
considered irreversible.  
Pregnancies 
If a patient becomes pregnant while enrolled on a GEICAM 
study, it must be reported in the Pregnancy Form and sent to 
the GEICAM pharmacovigilance department within 24 
hours of becoming aware of it. 
SAEs which do not need 
to be notified to the 
Pharmacovigilance 
Department of 
GEICAM  
The following events are not considered SAEs: 
o A visit to the emergency room or other hospital 
department lasting less than 24 hours that does not 
result in admission (unle
-threatening event). 
o Elective surgery planned before signing consent. 
o Hospitalization which is due solely to a planned 
study visit and without prolongation. 
o Routine health assessment requiring admission for 
baseline/trending of health status (eg. routine 
colonoscopy). 
o Medical/surgical admission for purpose other than 
remedying ill health state that was planned before 

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study entry. Appropriate documentation is required 
in these cases. 
o Admission encountered for another life circumstance 
that carries no bearing on health status and requires 
no medical/surgical intervention (eg. lack of housing, 
economic inadequacy, caregiver respite, family 
circumstances, administrative). 
o Progression of the malignancy during study 
(including signs and symptoms of progression), 
unless the outcome is fatal and death occurred before 
the end of treatment. Thereafter death due to disease 
progression.  has not to be reported as SAE. They 
will be reported in the eCRF and in the patient 
record. 
o Hospitalization due to signs and symptoms of 
disease progression. 
o An overnight stay in the hospital that is only due to 
transportation, 
organization 
or 
accommodation 
problems and without medical background.  
The rest of SAEs must be notified as described as follows. 
Procedure to notify a  
SAE to the  
Pharmacovigilance 
Department of 
GEICAM 
The SAE reporting to GEICAM is required to comply with 
applicable laws, regulations and standards regarding 
the study, to collect and report AEs to Regulatory 
Authorities, IRBs, Ethics Committees or other third parties.   
The SAEs must be notified to the Pharmacovigilance 
Department of GEICAM. A member of the investigator 
team must complete and sign the GEICAM SAE notification 
form which will be sent by fax/mail, immediately and 
always during the 24 hours following knowledge of the 
SAE. 
Pharmacovigilance Department of GEICAM  
Fax: 
  
  
GEICAM will review the received form and, if necessary, 
will ask more information to the investigator. 

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When additional information is obtained about the SAEs, or 
this is solved or is improbable it will change, a follow-up 
report must be also completed and sent by fax/mail, 
immediately and always during the following the 24 hours 
to the Pharmacovigilance Department of GEICAM. 
If GEICAM suspects that the SAE could be a SUSAR, the 
investigator should give the follow up information 
requested. 
All SAEs/AESIs from the time the patient have the first dose 
of the study treatment through 30 days following the last 
administration of study reatment must be reported according 
to the procedure described below. All SAE regardless of 
timing must be reported, if considered related to study 
treatment. 
Likewise, progression of a patient's underlying condition 
leading to one of the above should also not be reported as a 
SAE. 
GEICAM will report all SAEs and AESIs immediately to 
the Chief Investigators.  
All SAEs and AESIs will be followed-up by the investigator 
until satisfactory resolution. 
Annually all SARs will be reported at the DSUR to the 
competent authorities and the leading ethics committee, 
including all SUSARs.  
Withdrawal from further treatment shall be at the discretion 
of the investigator. 
 
Overdose 
 
A non-relevant overdose (accidental or intentional) with the 
study drug is an event suspected by the investigator or 
spontaneously notified by the patient and defined as: 
 The intake up to 8 tablets of abemaciclib in the same 
day. 
 The intake of 180 tablets in a 28-day cycle. 
It is to be reported to GEICAM in the eCRF. 

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A relevant overdose (accidental or intentional) with the 
study treatment is an event suspected by the investigator or 
spontaneously notified by the patient and defined as: the 
administration of a quantity of a medical product which is 
above the maximum recommended dose according to the 
product information. 
It has to be reported within one working day as a SAE on a 
SAE form.  
Death on Study 
Any death occurring during the active treatment part of the 
study and within 30 days following the last treatment must 
be reported to GEICAM as the Sponsor within 24 hours, 
regardless of the relation to study treatment, and has to be 
reported on the death report form section of the eCRF.  
The cause of death should be documented (cancer-related, 
treatment-related, cancer- and treatment-unrelated). Autopsy 
reports should be collected whenever possible and sent to 
the GEICAM.  
Deaths that occur due to tumor progression do not have to 
be reported as a SAE unless they occurred before end of 
treatment.  
Deaths after the end of study which are considered to be 
related to study treatment have to be reported as SAEs.  
To the extent feasible sufficient information including 
relevant laboratory values, ECG, scan, biopsy or autopsy 
results must be provided by the investigator in the SAE 
narrative (even if investigator determines the SAE is not 
related) so as to permit an independent causality assessment 
by a Competent Authority. 
6.2.5. 
Management, Timing and Assessment of SUSARs 
Expedited Notification 
of  SUSAR to the 
Competent Authorities 
and EC/IRB 
The Pharmacovigilance Department of GEICAM or its 
designee is responsible to notify to each of the competent 
authorities and EC/IRBs of the participating countries, all 
the SUSARs collected in the study, following the procedures 
shown in the current legislation.   

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Timing of notification  
The deadline for reporting a SUSAR shall be 15 calendar 
days from when GEICAM or its designee becomes aware of 
it. When suspected SUSAR caused the death of the patient 
or endangered her life, GEICAM or its designee will send 
the information within 7 calendar days from the date on 
which it becomes aware. 
Expedited reporting of 
other relevant safety 
information 
GEICAM or its designee will also notify, expeditiously, all 
the information that could modify the balance benefit/risk of 
the investigational product, or determine changes in its 
administration pattern or in the study performance, such as: 
o A qualitative change or an increase in the percentage 
of occurrence of the SAR expected, which are 
considered clinically significant. 
o The SUSAR occurring after completion of the study 
and are reported by the investigator to the Sponsor.  
o New events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of 
patients, such as: 
 SAE that could be related with the study 
procedure and could modify the conduct of 
the trial. 
 A significant risk to patients such as lack of 
efficacy in a drug used to treat a life-
threatening illness. 
 A major safety finding from a newly 
completed 
animal 
study 
(such 
as 
carcinogenicity). 
 A temporary halt of a trial for safety reasons 
if the trial is conducted with the same 
investigational medicinal products in another 
country and if this information is known by 
GEICAM. 
This relevant information shall be notified as soon as 
possible and no later than 15 days after GEICAM or its 
designee becomes aware of it. Additional information will 
also be notified as quickly as possible.  
Development Safety 
The DSUR that include the SAEs and SUSARs collected 

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Update Report (DSUR) 
during the study will be sent by GEICAM or its designee to 
the Competent Authorities and EC/IRB at the time 
established by the current legislation. 
Notification to  
investigators 
GEICAM or its designee will communicate to the 
investigators any safety information that may affect the 
safety of trial patients, as soon as possible.  
Information on SUSAR occurred during the study will be 
sent to investigators every 6 months, in aggregate, in a list 
along with a brief analysis of the data provided.  
They will be informed also, throughout the entire study, of 
any safety aspect that impacts the performance on the 
clinical trial or in the product development, including the 
interruption or modification in the development program of 
the protocol safety-related.  
6.3. 
Other Assessments  
6.3.1. 
Biomarker Assessments 
Detailed instructions for the collection, handling and shipment of samples are outlined in 
the Sample Management Manual (SMM) that will be available to the investigator and will 
be distributed at the time of site activation.  
The following samples will be collected and analyzed for molecular characterization (for 
example, analysis of pathways activation, gene expression profiling, evaluation of immune 
response, etc): 
1. Tumor Tissue: 
1.1. For Ki67 screening: pre-treatment formalin-fixed paraffin embedded (FFPE) 
core tumor biopsy (fine needle aspiration will not be allowed). 
In case of patients with 2 or more tumor lesions: if all histologically available 
lesions have similar morphological characteristics (i.e. based on local grade, 
central laboratory for Ki67 assessment. If tumor lesions have different 
morphological characteristics, all discordant tumor lesions will be centrally 
evaluated for Ki67.  
For eligibility into the study, tissue of breast tumor samples collected prior to 
exposure to any systemic therapy from potential patients must be sent to the 

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designated central laboratory, where Ki67 status will be evaluated (as described 
in Section 4.1, Inclusion Criteria) using a Ki-67 IHC assay.  
The use of Ki-67 IHC assay to identify patients for eligibility into the study is 
supported by a risk assessment by Sponsor. Clinicians will consider each 
-67 IHCassay result, to 
decide on study eligibility. No treatment decision shall be made solely on the 
basis of the Ki-67 IHC assay result. However, in order to be eligible to be 
enrolled, a patient must have a Ki-67 IHC assay diagnostic-positive status with 
Ki-
 
Ki-67 kit is a standardized IHC assay that detects expression of Ki67 
in FFPE BC tissue specimens using a Ki-67 antibody that is CE-marked for 
detection of Ki67 antigen in normal and neoplastic cells. The investigational 
Ki-67 IHC kit is manufactured by Agilent Technologies, Inc. This IHC assay is 
a validated assay (the kit protocol and components are locked, manufactured in 
a GMP facility and analytically validated) and comply with regional regulatory 
requirements for investigational devices. For the purposes of this study, the kits 
 
1.2. For secondary and exploratory biomaker analysis: 
1.2.1. Pre-treatment sample:  
According to the Sample Management Manual, FFPE tumor tissue will 
be provided from clinical sites to perform the analysis of a multigene 
expression platform (OncotypeDx®), in order to explore the 
downstaging of risk category [based on the Recurrence Score (RS)]. 
Additionally, one FFPE core biopsy will be required for biomarker 
analysis if there is not enough tumor tissue available after screening. 
In selected sites, an additional core needle fresh tumor biopsy must be 
collected for generation of organoid-based models and/or xenographs.  
1.2.2. After 2 weeks of treatment (between day 14 and day 21, preferably 
as close to day 14 as possible): FFPE core needle biopsy will be 
required (fine needle aspiration will not be allowed). The lesions had 
to be centrally evaluated at baseline. 
 
1.2.3. Tumor surgery specimen: FFPE tumor block. The lesions had to be 
centrally evaluated at baseline. 

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Additionally, in selected sites, fresh tumor tissue post-treatment will be 
collected for generation of organoid-based models and/or xenographs 
(fine needle aspiration will not be allowed).  
To comply with secondary end points of the study, we will evaluate Ki67 at 2 
weeks to evaluate potential decrease of Ki67 after treatment, and Ki67 level at 
surgery for assessment of endpoints as PEPI score. Additionally, downstaging of 
risk category based on multigene expression platforms will be assessed (a multigene 
expression platform used for risk classification, could be OncotypeDx®, based on 
the RS; GEICAM could provide the investigators with the RS results from pre-
treatment samples of patients once the breast surgery has been performed, so this 
information could be considered by the investigators to plan the adjuvant treatment 
for these patients). No patient management decisions are made based on the Ki67 
results related to these secondary endpoints. 
Other tumor tissue biomarkers, including DNA, RNA and protein analytes could be 
analyzed to investigate possible associations with resistance/sensitivity to treatment. 
Biomarkers that will be analyzed will be selected based on their known relevance to 
mechanisms involved in breast cancer development and therapy related pathways.  
Examples of such biomarkers could be TP53 and MYC mutations, MYC copy 
number variations (CNVs) or tissue expression of CD4/CD8/FOXP3/PDL-1. The 
relationship between centrally assessed biomarkers and the outcome or the 
resistance/sensitivity to treatment will be reported in an exploratory fashion. The 
prognostic or predictive relevance of intrinsic subtypes, genomic profiles and/or 
molecular patterns could be evaluated using genomic, transcriptomic, proteomic and 
metabolomic 
analysis. 
Highthrough-put 
techniques, 
for 
example, 
whole 
genome/exome next-generation sequencing (NGS) and whole transcriptome RNA 
sequencing (RNA-Seq) could be performed on pre-treatment and surgery tumors to 
explore the genetic changes in tumors after NA therapy. 
The generation and expansion of ex vivo organoid-based models and/or xenographs 
from post-therapy tumors and from baseline tumors will be pursued to carry on 
high-throughput functional screening studies.  
2. Blood Biospecimens:  
2.1 Plasma and whole blood samples for ctDNA exploratory biomarker analysis 
will be collected at the following timepoints:  
 Treatment phase: at baseline (within 7 days prior to initiate study 
treatment), at 2-3 weeks (wk), at 12 wk (+/- 1 wk), and at EOT for any 
reason (collected within the following 2 wk, prior to surgery) and at 4 
weeks post-surgery (+/- 2 wk, collected before starting adjuvant CT). 

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 Follow-up phase: every 6 months (+/-28 days), during the first five 
years, every year (+/-28 days) during the following 5-years and after 
recurrence, whatever occurs first. 
2.2. Plasma and/or whole blood samples for other biomarker analysis (e.g. 
metabolic and immune response analysis): pre-treatment (within 7 days prior to 
initiate study treatment), 2-3 wk, 12-wk (+/- 1 wk), 6 months (+/- 2 wk) for both arms 
(EOT for arm A, if it occurs before 6 months), and EOT for arm B before surgery. A 
local serology report performed at any time along the study, but preferably at baseline 
visit, should be sent to the central laboratory. This serology must include at least 
HIV, hepatitis B and hepatitis C and, only if available, also hepatitis A, Human 
Papillomavirus (HPV) and Pox virus. 
Plasma and/or whole blood samples will be retained for potential biomarker analyses 
related to treatment response and treatment metabolism. Biomarker exploratory 
analysis would include at least characterization of mutational genetic profiles and 
monitoring residual disease and tumor burden in ctDNA samples along the study, as 
well as proteomics, metabolomics and immune response related analyses. Genomic, 
epigenetic, proteomic and metabolomic variation may help to explain some of the 
variability in response seen with some drugs among different individuals. Comparing 
the DNA, RNA, protein, and metabolite patterns of patients who respond well and 
those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment. Collecting samples for 
biomarker analyses and retaining them makes it possible to seek explanations for 
differences in, for example, exposure, efficacy, tolerability, or safety not anticipated 
prior to the beginning of the study.  
All biomarkers will be correlated with efficacy endpoints or surrogate endpoints, as 
feasible. The relationship between centrally assessed biomarkers and the outcome or the 
resistance/sensitivity to treatment will be reported in an exploratory fashion. Additional 
exploratory analysis might be performed and described in a previous Statistical Analysis 
Plan. 

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7. Data Quality Assurance 
To ensure accurate, complete and reliable data, GEICAM will do the following: 
 Provide instructional material to the study sites, as appropriate. 
 Sponsor a start-up training session to instruct the investigators and study 
coordinators. This session will give instructions on the protocol, the completion of 
the eCRFs, and study procedures. 
 Make periodic visits to the study site to review study progress, investigator and 
patient compliance with the clinical trial protocol requirements and any emergent 
problems. 
 Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax. 
 Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection. 
 Conduct a quality review of the database.  
 Verify the quality of the data. 
To ensure the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and 
patient medical records in the patient files as original source documents for the study. If 
requested, the investigator will provide GEICAM, applicable regulatory agencies, and 
applicable ethical review boards with direct access to original source documents. 
7.1. 
Data Management and Registries file 
Data for this study will be recorded in an eCRF with web access, designed, created and 
maintained by GEICAM using Oracle Clinical®. Data will be transcribed by the site staff 
from the source documents onto the eCRF. The eCRF will never be considered as source data 
for this trial. 
This eCRF meets the 21 CFR part 11, ensuring the validation of the system, the traceability 
and the audit trail, the retention, protection, reproducibility and recovery of trial data, control 
of access to information and electronic signature, among others. 
Visit data should be entered into the eCRFs within 5 business days. Each eCRF should be 
completed by the investigator or delegate as stated in the Site Delegation List.  
Electronic queries will be raised if data is unclear or missing. GEICAM will perform a data 
review and additional requests can be sent through the eCRF, which the investigator is 

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obliged to respond to by modifying or clarifying the data questioned. The requests with 
their responses will be managed through the eCRF. 
If a correction is made, the corrected information will be entered into the eCRF, 
overwriting the initial information. An audit trail allows you to identify the modification.  

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8. Sample Size and Statistical Methods 
8.1. 
Determination of Sample Size 
8.1.1. 
Sample Size determination  
A Bayesian design has been used to define the most appropriate sample size: 
The major advantage of this Bayesian approach is it allow us to evaluate how similar 
response rates between both treatment arms are, without using a very large non-inferiority 
study. 
Comparability of RCB0/1 will be declared if the following Bayesian criterion is achieved in 
the primary RCB0/1 analysis:  
Posterior P(true RCB0/1Chemo  true RCB0/1Abema+AI < 5%) > 80% 
Full detail regarding the Bayesian model for ORR (including prior specifications) will be 
provided in the statistical analysis plan (SAP).  
Simulations were conducted to evaluate probability of declaring comparability based on 
various scenarios of underlying true RCB0/1 values.  Different underlying true RCB0/1 
values for abemaciclib plus an AI were considered in the scenarios. 
Three scenarios were explored (n=150, n=200, and n=250) and it is considered that the 2nd 
scenario with a sample size of 200 patients is the best option. Simulation results are shown 
in the table below. 
 
 
 8.2. Statistical and Analytical Plans 
8.2.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of GEICAM. The interpretation 
of study results will be the responsibility of the principal investigator of the study.   

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Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be dated and 
maintained by GEICAM. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition and/or its analysis 
will also be reflected in a protocol amendment. 
All analysis will be performed using the SAS Enterprise Guide 7.1 version. 
8.2.1.1. 
Patient Populations 
Intent to treat population (ITT): the ITT population will include all patients who are 
enrolled according to the initial treatment assignment. The ITT population will be the 
primary population for the efficacy analysis. It will be performed a sensitivity analysis 
using the Per-protocol population. 
Per-protocol population: a subset of the ITT population that received at least one dose of 
study treatment and completed the study without any major protocol deviations according 
to the protocol deviation manual.  
Safety population: will include all patients enrolled in the study who received at least one 
dose of study treatment, according to the actual treatment received. This population is for 
the safety analysis.  
Biomarker population: a subset of the safety population with available samples and 
clinical data for biomarker analyses. 
 8.2.2. 
Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
 summary of patients screened and by site 
 total number of patients screened 
 total number of patients enrolled 
 total number of patients treated 
 summary of reasons for patients enrolled, but not treated. 
A detailed summary of reasons for patient discontinuation from study treatment will be 
provided. 
A summary of all identified important protocol violations will be provided. 
8.2.3. 
Patient Characteristics 
Patient characteristics will include a summary of the following:  

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 patient demographics 
 baseline disease characteristics 
 preexisting conditions/secondary conditions 
 prior therapy 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be 
used to summarize the patient sample and to estimate parameters of interest. Ninety-five 
percent confidence intervals will be provided for estimates of interest where possible.  
8.2.4. 
Concomitant Therapy  
A summary of concomitant therapies will be generated in the safety population.  
8.2.5. 
Treatment Compliance  
Treatment information will be collected at each dose administration. The estimate of 
percent compliance will be given by: 
    Percent Compliance =       Actual dose administered per week 
    x   100 
 
 
 
 
     Dose expected to be administered per week 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. 
To be considered compliant patients should have received at least 80% of the planned 
number of doses.  Exploratory analysis of the impact of compliance on selected efficacy 
endpoints may be performed if deemed necessary. More information can be found in SAP. 
8.2.6. 
Efficacy Analyses 
All efficacy definitions are described in section 6.1. 
All efficacy analysis will be based on the ITT population. Additional efficacy analyses will 
be performed on the PP population.  
8.2.6.1. 
Analyses of Primary Endpoint 
The primary endpoint is Residual Cancer Burden (RCB) 0-I rate in both treatment arms.  
Residual Cancer Burden (RCB): The information about the result of RCB will be provided 
by the local laboratory. If the patient has no information about the RCB the patient will be 
considered as non-responders in the RCB rate analysis.  
RCB rate on each treatment arm will be estimated by dividing the number of patients with 
RCB 0-I by the ITT patients with measurable disease by treatment arm 
 
RCB Rate =                               Number of RCB 0-I                       

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     ITT population with measurable disease 
Comparability between the two treatment arms will be assessed using the following 
Bayesian criterion: 
Posterior P(true RCB0/1Chemo  true RCB0/1Abema+AI < 5%) > 80% 
Posterior medians and Bayesian credible intervals will be reported for the RCB0/1 rate for 
each arm. In addition, arms will be compared using a Cochran-Mantel-Haenszel (CMH) 
test using the stratification factors. The accompanying 2-sided 95% confidence intervals 
(CIs) in each arm and the difference between arms will be computed. 
Additionally a similar analysis will be also performed in the PP population as a sensivity 
analysis. 
8.2.6.2. 
Analysis of Secondary Endpoints 
The secondary efficacy endpoints are: 
Changes in Ki67 index value after 2 weeks of treatment in both treatment arms: it will 
be evaluated the Percentage of decrease in the geometric mean of Ki67 index value after 2 
weeks of treatment in both treatments arms. Values after 2 weeks of treatment will be 
expressed as geometric mean proportion of the baseline and transformed into percentage 
changes. An ANOVA analyses will be conducted at a two-sided 5% significance level for a 
within-treatments and between-treatment comparison. This analysis will be conducted in 
the ITT population. 
Also to measure the changes in Ki67 after 2 weeks of treatment it will be assessed the 
number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment in both 
treatment arms in the ITT population. 
Additionally a similar analysis will be also performed in the PP population as a sensivity 
analysis. 
 
Residual Cancer Burden (RCB): RCB is classified in four classes based on the residual 
disease. It will be assess the differences between RCB 0+I vs. RCB-II vs. RCB-III in both 
treatment arms, also the distribution of RCB on each arm will be estimated. For this 
analysis it will be used the ITT population. 
Kruskal-Wallis test will be used to examine differences between treatment arms. 
Additionally a similar analysis will be also performed in the PP population as a sensivity 
analysis. 

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Residual Cancer Burden (RCB) value: RCB value will be obtained from the residual 
disease. It will be evaluate the differences of mean between both treatment arms. For this 
analysis it will be used the ITT population. 
The T-test or Wilcoxon test will be used to examine differences between treatment arms. 
Additionally a similar analysis will be also performed in the PP population as a sensivity 
analysis. 
 
Rate of PEPI score 0 at breast surgery: Rate of PEPI score of 0 at baseline will be 
estimated by dividing the number of patients with PEPI score of 0 at surgery by the ITT 
patients in both arms. 
  
Rate of PEPI score 0 at surgery=  
Number of patients with PEPI score 0 at surgery             
       
 
 
ITT patients 
This rate will be reported, including a 95% confidence interval. 
CRR rate comparison between the two treatment arms will be assessed using CMH test 
with the same stratification factors. Additionally a similar analysis will be also performed 
in the PP population as a sensivity analysis. 
  
Clinical Response Rate (CRR): A patient will be considered to have achieved a CRR if 
the patient has a sustained complete response (CR) or partial response (PR) assessed by 
MRI. Otherwise, the patient will be considered as non-responders in the CRR rate analysis. 
Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no follow-up assessments) will be considered as non-responders in the CRR 
rate analysis.  
CRR rate on each treatment arm will be estimated by dividing the number of patients with 
objective response (CR or PR) by the ITT patients with measurable disease by treatment 
arm 
 
Objective Response Rate =                 Number of CRs + PRs                       
  
 
 
 
    ITT population with measurable disease  
 
The CRR rate will be reported, including a 95% confidence interval. 
In addition, the best clinical response for each patient will be summarized by treatment 
arm. CRR rate comparison between the two treatment arms will be assessed using CMH 
test with the same stratification factors.   

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Additionally a similar analysis will be also performed in the PP population as a sensivity 
analysis. 
 
Rate of breast conservative surgery (BCS): Defined as the proportion of patients who 
achieved breast-conserving surgery between both treatment arms. 
BCS rate on each treatment arm will be estimated by dividing the number of patients with 
conservative surgery by the ITT population.  
BCS Rate =                 Number of patients with conservative surgery                       
     ITT patients 
The BCS rate will be reported, including a 95% confidence interval. 
BCS rate comparison between the two treatment arms will be assessed using CMH test.    
  
Invasive Event Free Survival (iEFS): iEFS data will be censored on the date of the last 
tumor assessment on study for patients who do not have progression or invasive recurrence 
(local, regional, distant, or contralateral), and who have not died due to any cause while on 
study.   
iEFS will be analyzed in the ITT population. A stratified and non-stratified log-rank test 
(two-sided) will be used to compare iEFS time between treatment arms at the final analysis. 
iEFS for the two arms will be assessed using Kaplan-Meier methods and displayed 
graphically where appropriate. The median event times and 95% CIs will be estimated. Cox 
regression models will be used to estimate the treatment hazard ratio and its 95% 
confidence interval. Additionally a similar analysis will be also performed in the PP 
population as a sensivity analysis. 
    
8.2.7. 
Safety Analyses 
The toxicity and tolerability of study treatments will be evaluated in the safety population. 
Safety analyses will include summaries of the incidence of adverse events by maximum 
CTCAE grade v5.0that occur during the study treatment period or within 30 days of the last 
dose of study treatment, regardless of causality and according to the relationship to study 
treatment as assessed by the investigator. Additionally, the following safety-related 
outcomes will be summarized: 
 study treatment discontinuations due to adverse events, 
 deaths, 
 SAEs, 

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 hospitalizations and transfusions.  
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
Adverse events will also be analyzed in this timeframe. Serious adverse events not related 
with study treatment will be collected and analyzed from enrollment till 30 days after each 
patient´s last dose.   
Adverse events data and serious adverse events will be presented in frequency tables by 
grade. Hematological and clinical biochemistry toxicities will be assessed from laboratory 
test parameters. The safety analysis will be performed in the safety population.  
8.2.8. 
Other Analyses 
8.2.8.2. 
Biomarker Analyses 
The biomarker analysis of the present study will be exploratory and primarily make use of 
descriptive statistical methods. For continuous variables, descriptive statistics including the 
mean, standard deviation, median, minimum, and maximum values, will be provided (by 
treatment arm, if applicable). Categorical variables will be summarized by numbers and 
proportions, and provided by treatment arm. In all possible cases, the 95% confidence 
intervals will be calculated. If appropriate, a chi-squared test will be used to test group 
differences for categorical variables. 
If applicable, parametric test (analysis of variance or t test) or non-parametric testing, such 
-sum test or Kruskal Wallis test for continuous variables, and the 
-test or Fisher exact test for categorical variables will be used to test group 
differences. All test performed will be two-
-error rate 
without correction for multiplicity. 
Rate of RCB 0-I, PR, CR and/or CRR and other efficacy endpoints or surrogate endpoints 
will be reported, including a 95% confidence interval. Comparison of these endpoints 
between the two treatment arms will be assessed using CMH test or Kruskal-Wallis 
test.  The Kaplan-Meier limit-product method could be used to estimate other efficacy 
endpoints (ej. iEFS). The comparison of those endpoints between groups would be 
performed using the Log-Rank test. The Kaplan-Meier survival curves will be presented 
graphically. Median (EFS, iEFS, etc.) with the 95% confidence interval will be reported. 
Cox regression models will be used to estimate unadjusted and adjusted hazard ratio and its 
95% confidence interval. The Wald test will be used to establish the prognostic importance 
of each variable. Univariate and multivariate analyses could be carry out to explore the 
influence of the selected variables in rate of RCB 0-I, CRR, iEFS, etc. If it is appropriate, 
additional statistical analyses will be performed to investigate any possible relationship of 

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biomarker levels with outcome and/or chemotherapy or abemaciclib plus endocrine therapy 
anti-tumor efficacy. Any additional sensitivity analyses will be outlined in specific SAPs. 
8.2.9. 
Subgroup Analyses  
Exploratory subgroup analysis may be performed if deemed appropriate. 
8.2.12. Criteria for End of Study 
This study will be considered complete following the data cut-off date and datalock for the 
final analysis. The data cut-off date for the final analysis will occur after all enrolled 
patients have been followed for at least 10 years or withdraw of the informed consent, 
whatever occurs first.   
If further data are collected that are not included as part of the final locked database, the 
postlock data will eventually be combined with the locked database and stored in a data 
library separate from the locked database.   
The end date of study is the date of the last visit of the last patient including follow up. 
Performing exploratory analysis will be independent of the date of the end of the study. 

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9. Informed Consent, Confidentiality, Responsibility Insurance 
and Regulatory Considerations 
9.1. 
Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and 
benefits of participating in the study, including answering any questions the patient may 
have throughout the study and sharing any new information that may be relevant to the 
patient's willingness to continue his or her participation in the trial in a timely manner. 
The informed consent document will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is screened into the study, and 
to document that the patient is satisfied with his or her understanding of the risks and 
benefits of participating in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each patient 
or legal representative. This includes obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior 
to the administration of study treatment.   
As used in this protocol, the term "informed consent" includes all consent and assent given 
by patients or their legal representatives. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information, given a copy of the 
revised form and give their consent to continue in the study.  
9.2. 
Respect of Confidentiality 
The investigator will be responsible for preserving the suitable information about each patient 
(for example, name, address, telephone number, social security number and study 
identification) so that the competent authorities can have access to said information if 
necessary. These records must be confidentially preserved for the time indicated by the 
legislation. 
The investigators and GEICAM and its designee will maintain the confidentiality of all 
patients participating in the study, according to Good Clinical Practice, GCP and local 
legislation. 
This clinical trial will be held in accordance and in compliance with local current 
legislation. Any treatment of personal data that is held within the clinical trial, for Sponsor, 
Principal Investigator, Site, and / or any other participant in the clinical trial, especially as 
far as informed consent, shall conform to the provisions of General Data Protection 

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Regulation (EU) 2016/679 with regard to the processing of personal data and on the free 
movement of such data, and repealing Directive 95/46/EC and any other applicable 
normative.  
9.3. 
Insurance and Compensation for Injury 
The Sponsor shall ensure that the trial subjects are compensated for any damage suffered as 
a result of the trial. 
The trial Sponsor has hired an insurance policy covering the damage, as well as any 
liability that might be incurred by the Sponsor, principal investigator and members of the 
investigator team, including contracted clinical investigators, and the hospital or site where 
the clinical trial is conducted, according to applicable legislation. 
9.4. 
Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki and that are consistent with good clinical practices and the 
applicable laws and regulations. Each investigator will conduct the study according to 
applicable local or regional regulatory requirements and align his or her conduct in 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities. 
9.4.1. 
Investigator Information 
Physicians with a specialty in medical oncology will participate as investigators in this 
clinical trial. 
If investigators are added after the study has been approved by GEICAM, an EC/IRB, or a 
regulatory agency, these additions will not be considered changes to the protocol. 
9.4.2. 
Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page 
and send a copy of the signed page to GEICAM. 

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10. Practical Considerations 
This trial will be managed using a risk-based approach. Critical processes/ data 
identification and risk identification, evaluation, control, communication and review will be 
performed according to GEICAM SOPs and will be incorporated to the Risk Management 
Plan of the study.   
10.1.  Monitoring, Audit and Inspections 
Onsite and/or remote monitoring visits to the study site will be made periodically during 
the study and according to the Monitoring Plan Document to ensure that all aspects of the 
protocol are followed. During the visits to the site, the monitor must review the original 
records of the patients, the records of medication stocks and document preservation 
according to the Monitoring Plan Document. The monitor must evaluate the study 
procedures and discuss the possible problems with the investigator. During the course of 
the study, audit visits can be carried out in the participating sites. The investigator will 
allow direct access to the source documents/data for the tasks of monitoring, audit, 
reviewed by the EC/IRB and the inspection by the Competent Authorities. 
10.2 Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate 
an immediate hazard to study subjects. Should other unexpected circumstances arise that 
will require deviation from protocol-specified procedures, the investigator should consult 
with GEICAM or designee (and IRB or IEC, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from 
the inclusion or exclusion criteria. 
10.3.  Preservation of Study Documentation 
The copies of all the relevant information will be preserved by the investigator for a period 
of at least 25 years after the end of the study, according to current legislation. 
10.4.  Protocol Modification 
Once it has been authorized by the EC/IRB and the competent authority any protocol 
modification must be documented by writing, in the form of an amendment. 
The amendments must be duly identified, by its chronological order number, dated and 
signed by GEICAM and the Chief investigator. 
The protocol amendments considered as substantial must be notified to the EC/IRBs 
involved in the trial and to the competent authority. The authorization of the involved 
EC/IRBs and/or the competent authority will be necessary before their application. 

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After reading the protocol amendment, each principal investigator will sign the protocol 
amendment signature page and send a copy of the signed page to GEICAM. 
Any change in the study plan requires a protocol amendment. An Investigator must not 
make any changes to the study without EC/IRB and Sponsor approval except when 
necessary to eliminate apparent immediate hazards to the patients. A protocol change 
intended to eliminate an apparent immediate hazard to patients may be implemented 
immediately, but the change must then be documented in an amendment. All protocol 
amendments must be reviewed and approved, by the Sponsor.  
10.5.  Use of the Information and Publication 
All the information concerning the study treatment provided by GEICAM in relation to this 
study, and not previously published, is considered to be confidential information with 
property right of GEICAM. This information comprises the basic information about the 
product, the clinical protocol, the work forms where appropriate, the e-CRFs, the assessment 
methods, the technical methodology and the basic scientific data. This confidential 
information will be the property of GEICAM, it must not be disclosed to third parties without 
the prior written consent of GEICAM and it must not be used other than for the purposes of 
the study. 
The information developed during the practice of this clinical study is also considered to be 
confidential. This information can be disclosed to the extent considered necessary by 
GEICAM.  
To allow the use of the information derived from this study and to ensure the compliance 
with the current rules, the investigator is obliged to provide GEICAM with all the results of 
examinations and all the data developed in this study. Except in that required by law, the 
information obtained during the study can only be provided to the doctors and to the 
competent authorities by GEICAM. 
GEICAM commits to comply with current legislation relating to studies, which establishes 
the obligation to publish the results, both positive and negative, in conferences and 
journals, with reference to the EC/IRB that approved the study, and its funding source. The 
list of authors will be developed in accordance with the GEICAM SOPs (standard operating 
procedures). The different disclosures will be decided by the Chief Investigators. By 
signing this protocol, the Chief Investigators and Principal Investigators accept the terms of 
the 
publications policy and commit to respect them.  
10.5.1 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and 
to comply with applicable laws, regulations and guidance, GEICAM will, at a minimum 
register interventional clinical trials sponsored by GEICAM anywhere in the world, on 

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ClinicalTrials.gov or other publicly accessible websites (European Union Clinical Trials 
Register and national clinical trials public website (if applicable)), as required by GEICAM 
policy and local health authorities.  
10.5.2 
Clinical Trial Results Disclosure 
GEICAM will post the results of clinical trials on ClinicalTrials.gov or other publicly 
accessible websites, as required by GEICAM Policy/Standard and applicable local laws 
and/or regulations. 
10.6.  Ethics Committees and/or IRBs 
GEICAM or its designee or the Investigator will supply relevant documents for submission 
the 
, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, will be 
he 
protocol and subject informed consent must be obtained and submitted to GEICAM or 
designee before commencement of the study (ie, before shipment of the Sponsor-supplied 
study treatment or study specific screening activity). GEICAM or its designee will notify 
the site once GEICAM or its designee has confirmed the adequacy of site regulatory 
documentation and, when applicable, GEICAM or its designee has received permission 
from competent authority to begin the trial. Until the site receives notification, no protocol 
activities, including screening, may occur. 
As per applicable regulatory requirements, GEICAM or its designee or the Investigator will 
submit the required reports of the progress of the study to the EC/IRB and will communicate 
the possible SAE, the life-threatening adverse events and deaths. At the end of the study, 
GEICAM or its designee or the Investigator must inform the EC/IRB of trial closure. Al these 
notifications will be performed according to the applicable regulatory requirements. 
 
 
 
 
 

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Hurvitz S, editor Biological effects of abemaciclib in a phase 2 neoadjuvant study for 
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Ellis MJ, Tao Y, Luo J, A'Hern R, Evans DB, Bhatnagar AS, et al. Outcome prediction for 
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Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression 
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Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits 
of human breast tumours. Nature. 2000;406(6797):747-52. 

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EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 125 of 137  
 
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Maisonneuve P, Disalvatore D, Rotmensz N, Curigliano G, Colleoni M, Dellapasqua S, et al. 
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Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-
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EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
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43. 
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological 
complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. 
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tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. 
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Cuzick J SI, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. 
Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year 
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O'Brien N, Conklin D, Beckmann R, Luo T, Chau K, Thomas J, et al. Preclinical Activity of 
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Mol Cancer Ther. 2018;17(5):897-907. 
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Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: 
Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017;35(32):3638-46. 
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Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D, et al. MONARCH 1, A Phase II 
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HR(+)/HER2(-) Metastatic Breast Cancer. Clin Cancer Res. 2017;23(17):5218-24. 
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Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A, et al. NeoPalAna: Neoadjuvant 
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Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2017;23(15):4055-65. 
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Curigliano G, Gomez Pardo P, Meric-Bernstam F, Conte P, Lolkema MP, Beck JT, et al. 
Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. Breast. 
2016;28:191-8. 
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Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle. 
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Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and 
cancer. Biochim Biophys Acta. 2002;1602(1):73-87. 
58. 
Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev 
Cancer. 2001;1(3):222-31. 

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59. 
Kim ES KK, Goldman JW, Lopez PG, Jalal SI, Mahadevan D, Gutierrez M, Pulla MP, Schaefer 
ES, Shaheen MF, Johnston EL, Cai N, John WJ, Paz-Ares L. A Phase Ib study of abemaciclib in 
combination with multiple single agents in stage IV NSCLC.  American Society of Clinical Oncology 
(ASCO); Chicago. J Clin Oncol2015. 
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Tolaney SM BM, Beck JT, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, 
Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra C, Kalinsky K, Puhalla S, 
Rexer BN, Burris HA, Goetz MP, editor A Phase 1b study of abemaciclib with therapies for 
metastatic breast cancer. American Society of Clinical Oncology (ASCO); 2015; Chicago. 
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Hurvitz SA, Martin M, Press MF, Chan D, Fernandez-Abad M, Petru E, et al. Potent Cell-
Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in 
neoMONARCH, Phase II Neoadjuvant Study in HR(+)/HER2(-) Breast Cancer. Clin Cancer Res. 
2020;26(3):566-80. 
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Goel S, DeCristo MJ, McAllister SS, Zhao JJ. CDK4/6 Inhibition in Cancer: Beyond Cell Cycle 
Arrest. Trends Cell Biol. 2018;28(11):911-25. 
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Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, et al. Use of Biomarkers to Guide 
Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: 
American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 
2017;35(24):2838-47. 
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Nitz U, Gluz O, Christgen M, Kates RE, Clemens M, Malter W, et al. Reducing 
chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer 
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(WSG) PlanB trial. Breast Cancer Res Treat. 2017;165(3):573-83. 
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Bohlius J, Bohlke K, Castelli R, Djulbegovic B, Lustberg MB, Martino M, et al. Management 
of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice 
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Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, et al. Letrozole is more 
effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, 
estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin 
Oncol. 2001;19(18):3808-16. 
67. 
Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, 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):5108-16. 
68. 
Dowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, et al. Biomarker 
changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal 
status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 
2005;23(11):2477-92. 
 

 
GEICAM/2019-01 (CARABELA)                                                                EudraCT number: 2019-002123-15 
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 128 of 137  
 
Protocol Attachment 1. Study Schedule 
Study Schedule of Events and Timelines. 
GEICAM/2019-01 (CARABELA) 
During Study Treatment. 
All visits/treatment ± 3 days of scheduled 
treatment day. 
Post-
treatment 
visit (from 
the last 
study 
treatment 
dose)t,u 
Post-surgery 
 
Visit 
Baseline 
 
Cycle/Visit 1 
Cycle/Visit 2 
Subsequent 
Cycles/Visits 
Post-
surgery 
visit  30 
days (± 7 
days) 
from 
surgery 
Follow-up Period 
every 3 months 
after Post-surgery 
visit, during the 
first 2 years, every 
6 months during 
the following 3 
years, and once a 
year to complete 
the 10 years FU. 
(±14 days for the 3-
monthly period, ± 
28 days for the rest 
of the visits) 
Day of cycle 
 
 
1 
1 
1 
 
 
 
Procedure/Laboratory/  
Diagnostic Test 
Within 28 days
(+ 10 days) 
RANDOMIZATION 
 
 
 
 
 
 
ICD for Entry (before any 
study specific tests)a 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical and surgical history 
and demographicsb 
X 
 
 
 
 
 
 
Physical examinationc 
X 
X 
X 
X 
X 
X 
 

 
GEICAM/2019-01 (CARABELA)                                                                EudraCT number: 2019-002123-15 
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 129 of 137  
 
ECOG PS 
X 
X 
X 
X 
X 
X 
 
Hematologyd 
X 
X 
Day 1f & 14 (± 
1 day) (only 
Arm B) 
X 
Day 1 & 14 (± 
1 day)(only 
Arm B) 
X 
X 
X 
 
Blood Chemistrye 
X 
X 
Day 1f & 14 (± 
1 day) (only 
Arm B) 
X 
Day 1 & 14 (± 
1 day) 
(only Arm B) 
X 
X 
X 
 
Pregnancy testg 
X 
X 
X 
X 
X 
 
 
Standard 12-lead ECG 
X 
If clinically indicated 
 
 
MUGA or ECHO 
X 
 
 
Xh 
 
 
 
Concomitant medications 
X 
X 
 
AEs and SAESi  
X 
X 
AC followed by 
Docetaxel/Paclitaxel (Arm A) 
 
Xj 
X 
X 
 
 
 
Abemaciclib+Letrozol (Arm 
B) 
 
Xk 
X 
X 
 
 
 
Tumor Assessment 
Xl 
Every 12 week (± 1 week) during the treatment 
phase 
Prior to 
surgery 
 
 
Date of death  
 
 
 
 
 
 
Xm 
Biological samples 
 
 
 
FFPE tumor tissue for central 
determination of Ki67n 
X 
 
 
 
 
 
 

GEICAM/2019-01 (CARABELA)                                                               EudraCT number: 2019-002123-15 
Protocol Version 2.0 of 29-Jun-2021
Confidential                                                                    Page 130 of 137  
FFPE tumor tissue for 
biomarker analysiso
X 
X 
pre-dose and after 
2 weeks of 
treatment  
(between day 14 
and day 21)
X 
(post-
treatment 
biopsy or 
surgery)
Tumor tissue for organoids or 
xenographs generationp
X 
pre-dose
X 
(post-
treatment 
biopsy or 
sugery)
Blood (plasma and whole 
blood) samples for ctDNA 
exploratory biomarker studiesq
X 
pre-dose and after 
2-3 wk
X 
after 12 wk 
EOT (prior 
to surgery)
X 
X 
every 6 m during the 
first five years, 
every 12 m during 
the following 5-
years and at disease 
recurrence, whatever 
occurs first. 
Blood (plasma and/or whole 
blood) samples for other 
biomarker analysis (e.g. 
metabolomics and immune 
response related studies)r 
X 
pre-dose and after 
2-3 wk 
(local serology 
report)s
X 
after 12 wk and 
6 m both arms 
(EOT for Arm A)
EOT (prior 
to surgery)

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 131 of 137  
 
Study Schedule of Events and Timelines. Protocol GEICAM/2019-01 (CARABELA) 
a 
Signed, written informed consent (approved by the EC/IRB) obtained prior to any study specific 
procedure. 
considered as a specific study procedure itself, and may be 
obtained greater than 28 days prior to the randomization. 
b Includes local laboratory ER/PgR/HER2 expression levels and methods used to assess them, previous 
treatments. Sex, Race and date of birth.  
c 
Physical examination includes measurements of height (BL only), weight, body surface area, blood 
pressure, pulse rate and body temperature. For Arm A ONLY: the real Body Surface Area (BSA) of the 
patient determined in the baseline visit will be the reference BSA throughout the study, except in the event 
that patients experience body weight variations greater than 10%; in those cases the BSA will be 
recalculated and the CT drugs dose will be adjusted accordingly. For Arm B: the real Body Surface Area 
(BSA) only will be mandatory at baseline visit. 
d 
Hemoglobin, WBC, absolute neutrophils, lymphocytes and platelet count. In the experimental arm 
(Arm B), the hematology and blood chemistry will be performed every two weeks for the first two 
visits(lab test day 14 ± 1 day) and from visit 3 onward, every four weeks (±3 days). In the control arm 
(Arm A), the hematology and blood chemistry will be performed every three weeks (±3 days). If the 
patient receives weekly paclitaxel 80 mg/m2 for 12 weeks, hematology can be performed every 21 days. 
e 
Fasting glucose, alkaline phosphatase, ALT, AST, total bilirubin, serum creatinine, sodium, potassium, 
total calcium and urea (or BUN). In the control arm (Arm A), the hematology and blood chemistry will be 
performed every three weeks (±3 days). If the patient receives weekly paclitaxel 80 mg/m2 for 12 weeks, 
blood chemistry can be performed every 21 days. 
f 
Not on cycle 1, if the assessments were performed within the 7 days previous day 1 of treatment. The 
initiation of the treatment will be within 5 days after enrollment.   
g 
Negative serum pregnancy test within 7 days of the first dose of abemaciclib (Arm B) or chemotherapy 
(Arm A) for premenopausal women, and for women who have experienced menopause onset < 12 month 
prior to first dose of therapy (CBP women). 
During treatment phase a serum or orine pregnancy test must be performed in every cycle and at the 
post-treatment visit, for CBP women, including women with tubal ligation. 
h 
ECHO or MUGA will be performed at Screening, and for Arm A after the treatment with 
anthracyclines, and if clinically indicated in any treatment arm. It is strongly recommended to use the 
same method of measurement for the same patient throughout the duration of the study. 
i 
After informed consent form signature, but prior to initiation of study treatment, only SAEs caused by a 
protocol-mandated intervention will be collected. Adverse events to be monitored continuously during the 
treatment period. All AEs occurring during the study and until the treatment discontinuation visit 30 days 
after the last study medication to be recorded with grading according to NCI-CTCAE, thereafter all study 
treatment-related SAEs should continue to be collected. 
j 
Doxorubicin (60mg/m2) and Cyclophosphamide (600mg/m2) (AC) iv will be given every 21 days for 4 
cycles followed by weekly Paclitaxel (80mg/m2) for 12 weeks or three-week Docetaxel (100mg/m2) x 4 
cycles. If the patient receives weekly paclitaxel 80 mg/m2 for 12 weeks, study visits and procedures 
 
k 
Letrozole 2.5mg plus Abemaciclib 150mg q12 hours will be taken orally, daily, and continuously for 12 
months (±14 days) , the study visits will be performed each 28 (±3) days from first study dose. 
Premenopausal women must be given LHRH (luteinizing hormone-releasing hormone) analogs. 
l 
In order to discard metastasis the following tests should be performed before randomization: bone scan if 
bone pain and/or elevated alkaline phosphatase; abdominal/pelvic computerized tomography scan (CT) if 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 132 of 137  
 
elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms or abnormal physical 
examination; chest CT if pulmonary symptoms. Baseline MRI and other diagnostic tests can be 
performed within 28 days (+ 10 days) prior to randomization. 
Tumor evaluation will be done by MRI in baseline and prior to breast surgery, and US will be repeated 
every 12 week (+/- 1 week) during the treatment phase to discard PD, additional imaging techniques could 
 For Arm B MRI could be done from 11 months of study 
treatment, to allow enough time to plan surgery within 7 days of the last dose of abemaciclib and/or 
letrozole. 
m The patients will be followed for survival until death, loss to follow-up, withdrawal of consent or study 
termination by GEICAM. After progression, the tumor assessment will be performed according to the 
standard medical practice. The date of survival and death (if applicable) will be collected in the eCRF.  
n A FFPE tumor tissue block for central determination of Ki67 will be collected and sent to the 
sponsor-designated central laboratories prior to study initiation. Fine needle aspiration will not be allowed. 
In case of patients with 2 tumor lesions: if both lesions have similar morphological characteristics (i.e. 
laboratory for Ki67 assessment. If tumor lesions have different morphological characteristics, both tumor 
lesions will be centrally evaluated for Ki67.  
o FFPE tumor tissue for biomarker analysis must be collected at baseline (according to the Sample 
Management Manual, FFPE tumor tissue will be provided from clinical sites to assess a multigene 
expression platform - OncotypeDx®-; additionally, a core biopsy must be sent to the pathology central lab 
of the study if there is not enough tumor tissue available after screening), after 2 weeks of treatment 
(between day 14 and day 21, preferably as close to day 14 as possible) and at EOT (post-treatment core 
biopsy or surgery block). Fine needle aspiration will not be allowed.  
p Tumor tissue for generation of organoid-based models and/or xenographs will be collected in 
selected sites at baseline and at EOT (post-treatment core biopsy or surgery) . Fine needle aspiration will 
not be allowed. 
q Plasma and whole blood for ctDNA analysis: at baseline (within 7 days prior to initiate study 
treatment), at 2-3 weeks (wk), at 12 wk (+/- 1 wk), at EOT for any reason (collected within the following 
2 wk, prior to surgery), at 4 weeks post-surgery (+/- 2 wk, collected before starting adjuvant CT), every 6 
months (+/- 28 days) during the first five years of follow up, every 12 months (+/- 28 days) during the 
following 5-years and after recurrence, whatever occurs first. 
EOT means the date of last dose, not the safety visit. 
r 
Plasma and whole blood for other biomarker analysis (e.g. metabolomic and immune response related 
analysis): pre-treatment (within 7 days prior to initiate study treatment), 2-3 wk, 12-wk (+/- 1 wk), 6 
months (+/- 2 wk) in both arms (EOT prior to surgery for Arm A), and EOT prior to surgery for arm B. 
s 
A local serology report (local serology report) performed at any time along the study, but preferably at 
baseline visit, should be sent to the central laboratory. This serology must include at least HIV, hepatitis B 
and hepatitis C and, only if available, also hepatitis A, Human Papillomavirus (HPV) and Pox virus. 
t 
For safety reasons all patients will have a visit after finishing treatment with the study medications.  
In Arm A patients will have this visit not earlier than 21 days after finishing treatment with the study 
medications and before definitive surgery. In Arm B the visit will be done within 7 days from the last 
abemaciclib and/or letrozole dose 
In some patients, the end of the study treatment (at neoadjuvant setting) may be due to PD or toxicity. In 
visit may be performed in advance and always before starting the new anticancer therapy. 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 133 of 137  
 
u After the last dose of any of the drugs in the NA combinations, in both treatment arms definitive surgery 
will be performed. For Arm A not earlier than 21 days and not later than 42 days after the last dose of 
chemotherapy, and for Arm B within 7 days from the last dose of abemaciclib and/or letrozole, unless 
toxicities are not recovered completely in any treatment arm. 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 134 of 137  
 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status 
ECOG Performance Status 
Grade 
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 all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
 
5 
Dead 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-65. 
 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
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Protocol Attachment 3. Adverse event (AE) non defined in CTCAE 
CTC Grade 
Equivalent to:
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity. 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no treatment 
or medical intervention is indicated although this could improve the 
overall well-being or symptoms of the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in treatment or medical intervention 
is indicated in order to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the survival of the 
patient at direct risk. 
Grade 4 
Life-
threatening / 
disabling 
An immediate threat to life or leading to a permanent mental or 
physical conditions that prevents work or performing daily activities; 
treatment or medical intervention is required in order to maintain 
survival.  
Grade 5 
Death 
AE resulting in death. 
 
 
 
 
 
 
 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 136 of 137  
 
Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide 
Time 
After ICD 
Before Study 
Treatment 
During Therapy 
30-Day (±7 days)  
Post-treatment  
Follow-up Period 
Long-Term  
Follow-up Period 
Events to 
Collect  
AE/SAEs 
New/Ongoing AE/SAEs 
New/Ongoing SAEs 
 
 
Related to 
Procedures 
Regardless of Relatedness to 
Study Treatment or Procedures 
Related to Study 
Treatment or Procedures 
Abbreviations:  AE = adverse event, ICD = informed consent document, SAE = serious adverse event. 
 
 
 

GEICAM/2019-01 (CARABELA)
EudraCT number: 2019-002123-15
 
Protocol Version 2.0 of 29-Jun-2021 
 
Confidential                                                                    Page 137 of 137  
 
Protocol Attachment 5. List of inducers and strong inhibitors of 
CYP3A
The information in this list is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated. 
Strong inducers 
 Carbamazepine 
 Dexamethasone 
 Phenobarbital/phenobarbitone 
 Phenytoin 
 Rifapentine 
 Rifampin 
 Rifabutin 
 
 
Moderate inducers 
 Bosentan 
 Lenisurad 
 Modafinil 
 Primidone 
 Telotristat ethyl 
Strong inhibitors 
 Aprepitant 
 Ciprofloxacin 
 Clarithromycin 
 Conivaptan 
 Diltiazem 
 Erythromycin 
 Fluconazole 
 Itraconazole 
 Ketoconazole 
 Nefazodone 
 Posaconazole 
 Troleandomycin 
 Verapamil