Conditions: Triple Negative Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study is an interventional, prospective, multicentric, single-arm, open label, phase Ib clinical trial. This study will be carried out in patients diagnosed of metastatic or locally advanced unresectable triple negative breast cancer with activation of ERK and/or CDK4/6 in which the following will be assesed: the overall response rate, the aggregation of antitumor effect depending on the different kinome profiles and the safety profile to the combination of palbociclib and binimetinib.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Combination, Palbociclib + Binimetinib
Intervention descriptions: intervention 1: Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 100 mg daily, 21 days on / 7 days off, until disease progression. Study treatment will continue until disease progression.

If treatment tolerance is good, after a full cycle patients will be allowed to escalate palbociclib to 125 mg, according to the study investigators' decision. Alternatively, patients with non tolerable grade 2 events will resume at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-on/7-off. Depending on the side-effects, in case of clear relationship with palbociclib is established, palbociclib -instead of binimetinib - will be reduced to 75 mg daily.

Protocol document:
Prot_000.pdf: 
PALBOBIN Clinical Study Protocol 
 
 
 
Phase IB Clinical trial of palbociclib and binimetinib in advanced triple 
negative breast cancer with hyperactivation of ERK and/or CDK4/6 
 
NCT: NCT04494958 
 
 
 
 
 
 
 
 Version 3.0 – 16 June 2021 
 
 


 
 
 
COORDINATING INVESTIGATOR: 
Dr Miguel Quintela Fandino 
CNIO - Breast Cancer Unit 
 
PROTOCOL CODE: PALBOBIN 
 
EudraCT No.: 2020-000930-16 
 
SPONSOR: 
Fundación OncoSur 
 
Previous protocol versions / amendments (number and date): 
- Version 1.0, 14/Jul/2020 
- Version 2.0, 07/Sep/2020 
Current version (number and date): 
- Version 3.0, 16/Jun/2021 
 
Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast 
cancer with hyperactivation of ERK and/or 
CDK4/6 
CONFIDENTIAL: The information and data included in this protocol contain commercial 
secrets and privileged or confidential information that is the property of the Sponsor. No one 
is authorized to make this information public without written permission from the sponsor. 
These limitations apply to all information considered privileged or confidential that is 
facilitated to you in the future. This material may be divulged and used by the team and 
collaborators as needed to conduct the clinical trial. 


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1. PROTOCOL SUMMARY 
1.1. Sponsor 
Fundación OncoSur 
Address: Gran Via Marques del Turia nº 65, 3º-11. 46005 Valencia Office: 
Medical Oncology Service 
Hospital 12 de Octubre 
Avda de Cordoba s.n. 
28041-Madrid 
e-mail: secretaria_tecnica@oncosur.org 
 
Principal Investigator 
Miguel Quintela-Fandino 
Head of the Breast Cancer Unit 
CNIO - Spanish National Cancer Research Center Melchor 
Fernandez Almagro, 3 
Madrid, 28029, Spain 
e-mail:
Phone: 
 
 
1.2. Study Title 
Phase IB Clinical trial of palbociclib and binimetinib in advanced triple negative breast 
cancer with hyperactivation of ERK and/or CDK4/6 
 
 
1.3. Protocol code 
PALBOBIN 
CCI
CCI
CCI
CCI


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1.4. Ethics Committee 
CEIm Hospital 12 de Octubre 
 
 
1.5. Company responsible of the monitoring 
APICES 
 
 
 
 
1.6. Investigational product 
Palbociclib and binimetinib 
 
 
1.7. Phase 
Phase IB 
 
 
1.8. Trial objectives 
Primary objective: 
Primary objective of this study is to determine the 3-months PFS of palbociclib plus 
binimetinib in advanced triple negative breast cancer (TNBC), in patients with activation of 
ERK and/or CDK4/6. 
Secondary objectives: 
- 
To determine response rate of the combination in advanced TNBC, in patients with 
activation of ERK and/or CDK4/6. 
- 
 
- 
To assess the safety of the combination in patients with advanced TNBC. 
Exploratory objective: 
- 
 
CCI
CCI
CCI


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1.9. Study design 
This is an interventional, prospective, multicentric, single-arm, open label, phase IB clinical 
trial. 
The following scheme depicts the basic trial design. 
 
 
 
 
 
Patients diagnosed of metastatic or locally advanced non-curable TNBC that have received 
one or two treatment regimens for advanced disease will be candidates for the trial. A fresh 
tumor sample will be obtained in order to determine the phosphoproteomic profile of the 
tumor, preferably obtained after last treatment or the most recent sample as possible (from 
metastasis or first diagnosis according to sample availability) prior to study inclusion. If the 
patient has not a tumor sample available prior to study inclusion, the patient will not be 
allowed to participate in the study. Activation of the two kinases of interest will be determined 
centrally at CNIO. Only patients with scores above the upper quartile of at least one of them 
will be candidates. It is expected that approximately 40% of patients are positive for CDK4/6 
and/or ERK. 
Patients will then start treatment with continuous oral binimetinib and palbociclib 21 days on 
/ 7days off, until disease progression. Tumor evaluation will be performed every 8 weeks. 
Study treatment will continue until disease progression, unacceptable toxicity, intercurrent 
serious disease, consent withdrawal or investigator´s decision. 
The study will be conducted at 8 Spanish sites and will enroll 25 patients. 
 
 
1.10. Disease 
Advanced triple negative breast cancer. 


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1.11. Study outcome measures 
Primary outcome measure: 
- 
Three-months PFS. 
Secondary outcome measures: 
- 
Overall response rate. 
- 
- 
Number of patients experiencing each AE will be summarized by CTCAE grade 
to evaluate safety profile, according to NCI-CTC v 5 criteria. 
Exploratory outcome measures: 
- 
 
 
 
 
 
1.12. Study population and number of patients 
It is expected to include 25 patients in this trial. 
Patients diagnosed of metastatic or locally advanced non-curable TNBC that have received 
one or two treatment regimens for advanced disease will be included in this study. 
 
 
1.13. Selection criteria 
1.13.1. Inclusion criteria 
1. Women >18 years-old. 
2. Diagnostic of metastatic or locally advanced non-resectable TNBC. 
3. Patient must have received a minimum of one and a maximum of two treatment lines 
for metastatic TNBC. Previous treatments can be of any nature (chemotherapy, 
immunotherapy, antiangiogenics, experimental therapy, etc.). 
Women with known BRCA1/BRCA2 germline mutations must have received a 
platinum based treatment or treatment with a PARP inhibitor. 
CCI
CCI


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4. Patient must have experienced disease progression to the previous treatment line 
according to the RECIST 1.1 or iRECIST criteria. 
5. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study 
inclusion, preferably obtained after last treatment or the most recent sample as 
possible (from metastatic site or first diagnosis according to sample availability). If the 
patient has not a tumor sample available prior to study inclusion, the patient will not 
be allowed to participate in the study. 
6. Ability to understand and signing of the written patient information/informed consent 
form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be 
performed centrally at CNIO. 
7. Ability to understand and signing the written PIS/ICF for study treatment eligibility. 
Signed informed consent form must be available before any study- specific procedure 
for the respective study parts may begin. 
8. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-
quartile according to published definitions [1]. 
9. ECOG performance status of 0-1. 
10. Evaluable disease according to RECIST 1.1 criteria. 
11. Life expectancy >24 weeks. 
12. Adequate bone marrow, liver and renal function as assessed by laboratory 
requirements conducted within 7 days before first study drug administration: 
a. Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte colony-
stimulating factor support within 2 weeks before the first study drug 
administration) 
b. Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks 
before the first study drug administration) 
c. Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the 
first study drug administration) 
d. Total bilirubin ≤ 2  the upper limit of normal (ULN). 


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e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5  ULN (≤ 5 times ULN for patients with liver metastases) 
f. Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the 
modification of diet in renal disease (MDRD) abbreviated formula. 
13. Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior 
treatments (excluding neuropathy which can be ≤ Grade 2, and alopecia). 
14. Patients must be able to take oral medications. 
15. Patients must have adequate cardiac function, defined as: 
a. Left ventricular ejection fraction (LVEF) > 50% as determined by 
echocardiogram or multigated acquisition scan (MUGA). 
b. QTc < 480 msec. 
16. Negative serum pregnancy test in women of childbearing potential (performed within 
7 days before the first treatment). Negative results must be available before the first 
study drug administration. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Pregnancy test will not be performed in postmenopausal women. 
17. Women of reproductive potential must agree to use adequate contraception when 
sexually active. This applies for the time period since the signature of the informed 
consent form and until at least 1 month after the last study drug administration. The 
definition of adequate contraception will be based on the judgment of the investigator 
and on local requirements. Acceptable methods of contraception include, but are not 
limited to, (i) condoms (male or female) 


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with or without a spermicidal agent; (ii) diaphragm or cervical cap with 
spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. 
Zoledronic acid or denosumab started prior to trial registration is allowed, but in case they are 
required after initiation of trial procedures, adequate justification is required. 
1.13.2. Exclusion criteria 
1.  Participants who have had chemotherapy, radiotherapy, or major surgery within 2 
weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. 
2. Patients that received during the metastatic disease setting any of the study drugs, 
palbociclib or binimetinib. 
3. Participants receiving any other study agents concurrently with the study drugs. 
Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to 
enrollment are allowed. 
4. Participants with symptomatic brain metastases that require chronic steroids. Patients 
with a history of brain metastases are permitted to enroll as long as they have been 
treated, are off of steroids, and have been stable for a minimum of one month on 
imaging. 
5. Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is the 
only location of the disease and it has not progressed. Patients with radiated single 
lesions that has progressed are allowed. 
6. Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug 
interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used 
with caution. 
7. Uncontrolled intercurrent illness including, but not limited to: 
a. ongoing or active infection requiring systemic treatment 
b. symptomatic congestive heart failure 
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d. psychiatric illness/social situations that would limit compliance with study 
requirements 
e. hypertension, defined as systolic blood pressure > 160 mmHg despite medical 
management 
f. myocardial infarction, unstable angina, coronary artery bypass grafting, 
coronary angioplasty, or stenting < 6 months prior to screening 
8. History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or 
Torsades de Pointes. 
9. History of Gilbert's syndrome. 
10. History of neuromuscular disorders that are associated with elevated CK (e.g. 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, 
spinal muscular atrophy). 
11. Previous or concurrent cancer except: 
a. cervical carcinoma in situ 
b. treated basal-cell carcinoma or squamous cell skin cancer 
c. any other cancer curatively treated > 3 years before the first study drug 
administration 
12. Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may 
interfere with the absorption of oral study medication in the opinion of the investigator. 
13. Pregnant women or breast-feeding. 
14. Known HIV-positive individuals on combination antiretroviral therapy. 
15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive 
hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C 
infection requiring treatment. 


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a. Patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible if HBV DNA is negative. 
b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
16. Any condition that in the opinion of the investigator would interfere with evaluation 
of study treatment or interpretation of patient safety or study results, or inability to 
comply with the study and follow-up procedures. 
17. Participation in another clinical study with investigational medicinal products within 
4 weeks before the first study drug administration. 
18. Clinically active infections within 2 weeks before the first study drug administration. 
19. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first study 
drug administration. Patients receiving prophylactic antibiotics (e.g. for prevention of 
a urinary tract infection or to prevent chronic obstructive pulmonary disease 
exacerbation) are eligible. 
20. Known hypersensitivity to any of the study drugs, study drug classes, or excipients 
in the formulation. 
21. Current diagnosis of any retinal disorders including retinal detachment, retinal pigment 
epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or risk 
factors for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or 
hypercoagulability syndrome). 
22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher 
23. Major surgery, open biopsy or significant traumatic injury within 4 weeks before the 
first study drug administration (central line surgery is not considered major surgery). 
24. Renal failure requiring peritoneal dialysis or hemodialysis. 


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25. Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results. 
 
 
1.14. Study calendar 
First patient inclusion: 4Q 2020 
Last patient inclusion: 4Q2021 
Subject participation duration: 6 months + 6 months follow up Study 
duration: 32 months 


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2. TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY .................................................................................................................... 2 
1.1. 
SPONSOR ....................................................................................................................................... 2 
1.2. 
STUDY TITLE ................................................................................................................................... 2 
1.3. 
PROTOCOLCODE ............................................................................................................................. 2 
1.4. 
ETHICS COMMITTEE ......................................................................................................................... 3 
1.5. 
COMPANYRESPONSIBLE OF THEMONITORING .......................................................................................... 3 
1.6. 
INVESTIGATIONAL PRODUCT ............................................................................................................... 3 
1.7. 
PHASE ................................................................................................................................................................................................. 3 
1.8. 
TRIAL OBJECTIVES ........................................................................................................................... 3 
1.9. 
STUDY DESIGN ................................................................................................................................ 4 
1.10. 
DISEASE ........................................................................................................................................ 4 
1.11. 
STUDY OUTCOMEMEASURES ............................................................................................................. 5 
1.12. 
STUDY POPULATION AND NUMBEROF PATIENTS ....................................................................................... 5 
1.13. 
SELECTION CRITERIA ........................................................................................................................ 5 
1.13.1. 
Inclusion criteria ...................................................................................................................... 5 
1.13.2. 
Exclusion criteria ..................................................................................................................... 8 
1.14. 
STUDY CALENDAR ......................................................................................................................... 11 
2. 
TABLE OF CONTENTS ...................................................................................................................... 12 
3. 
ABBREVIATIONS ........................................................................................................................... 15 
4. 
CLINICAL TRIAL CHARACTERISTICS ............................................................................................ 20 
4.1. 
CLINICAL TRIAL IDENTIFICATION ......................................................................................................... 20 
4.2. 
PHASE .............................................................................................................................................................................................. 20 
4.3. 
INVESTIGATIONAL PRODUCT ............................................................................................................. 21 
4.4. 
SPONSOR ..................................................................................................................................... 21 
4.5. 
ETHICS COMMITTEE ........................................................................................................................21 
4.6. 
COMPANYRESPONSIBLE OF THE MONITORING ...................................................................................... 21 
4.7. 
STUDY CALENDAR ......................................................................................................................... 22 
5. 
STUDY RATIONALE AND OBJECTIVES ........................................................................................... 22 
5.1. 
BACKGROUND INFORMATION .......................................................................................................... 22 
5.1.1. 
TRIPLE NEGATIVE BREASTCANCER ...................................................................................................... 22 
5.1.2. 
PALBOCICLIB ............................................................................................................................... 23 
5.1.2.1. 
SAFETY PROFILE OF PALBOCICLIB .................................................................................................... 24 
5.1.2.2. 
CLINICAL EFFICACY OF PALBOCICLIB ................................................................................................ 24 
5.1.3. 
BINIMETINIB ................................................................................................................................ 25 
5.1.3.1. 
TARGET INHIBITION ................................................................................................................... 26 
5.1.3.2. 
TUMOR GROWTH INHIBITION ......................................................................................................... 26 
5.1.3.3. 
CANCER AND THE MAPKINASE PATHWAY....................................................................................... 27 
5.1.3.4. 
RATIONALE FOR THE USEOF BINIMETINIB.......................................................................................... 27 
5.1.3.5. 
SAFETY PROFILE OF BINIMETINIB ..................................................................................................... 28 
5.1.3.5.1. 
BINIMETINIB AS A SINGLE AGENT ................................................................................................ 28 
5.1.3.5.1.1. 
CLINICAL STUDY ARRAY-162-111 ............................................................................................ 29 
5.1.3.5.1.2. 
CLINICAL STUDY CMEK162X1101 ............................................................................................ 30 
5.1.3.5.1.3. 
CLINICAL STUDY CMEK162X2201 ............................................................................................ 31 
5.1.3.5.1.4. 
CLINICAL STUDY CMEK162AUS11 ........................................................................................... 32 
5.1.3.5.1.5. 
CLINICAL STUDY CINC280X2205 .............................................................................................. 32 
5.1.3.5.1.6. 
CLINICAL STUDY ARRAY-162-311 ............................................................................................ 33 
5.1.3.5.2. 
BINIMETINIB IN COMBINATION .................................................................................................... 34 
5.1.3.6. 
GUIDANCE FOR INVESTIGATORS...................................................................................................... 34 


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5.2. 
STUDY RATIONALE ........................................................................................................................ 36 
5.3. 
STUDY OBJECTIVES ........................................................................................................................ 44 
6. 
STUDY DESIGN ................................................................................................................................ 45 
6.1. 
OVERALL DESIGN ........................................................................................................................... 45 
6.2. 
PRIMARY ENDPOINT ........................................................................................................................47 
6.3. 
SECONDARY ENDPOINTS ................................................................................................................. 47 
7. 
PATIENT SELECTION ..................................................................................................................... 47 
7.1. 
INCLUSION CRITERIA ....................................................................................................................... 47 
7.2. 
EXCLUSION CRITERIA .......................................................................................................................50 
7.3. 
RANDOMIZATION PROCEDURES ........................................................................................................ 53 
7.4. 
BLINDING PROCEDURES .................................................................................................................. 53 
8. 
WITHDRAWAL CRITERIA .............................................................................................................. 53 
8.1. 
REASONS FOR WITHDRAWAL ............................................................................................................. 53 
8.2. 
HANDLING OF WITHDRAWALS ........................................................................................................... 54 
8.3. 
RESERVE AND REPLACEMENT SUBJECTS .............................................................................................. 54 
9. 
INVESTIGATIONAL PRODUCT ....................................................................................................... 54 
9.1. 
INVESTIGATIONAL PRODUCT DESCRIPTION ............................................................................................ 54 
9.1.1. 
Binimetinib .............................................................................................................................. 54 
9.1.1.1. 
Description .......................................................................................................................... 54 
9.1.1.2. 
Packaging ............................................................................................................................ 55 
9.1.1.3. 
Shipping, Storage and Disposal .................................................................................................. 55 
9.1.1.4. 
Dosage and administration .........................................................................................................55 
9.1.2. 
Palbociclib .............................................................................................................................. 55 
9.1.2.1. 
Description .......................................................................................................................... 55 
9.1.2.2. 
Packaging ............................................................................................................................ 55 
9.1.2.3. 
Shipping, Storage and Disposal .................................................................................................. 55 
9.1.2.4. 
Dosage and administration .........................................................................................................56 
9.2. 
TREATMENT DURATION ...................................................................................................................56 
9.3. 
CRITERIA FOR DOSE ADJUSTMENTS .......................................................................................................56 
9.3.1. 
Palbociclib .............................................................................................................................. 56 
9.3.2. 
Binimetinib .............................................................................................................................. 58 
9.4. 
ACCOUNTABILITY ........................................................................................................................ 62 
9.5. 
AUXILIARY MEDICINAL PRODUCTS ......................................................................................................63 
9.6. 
CONCOMITANT MEDICATION ............................................................................................................ 63 
9.7. 
PROHIBITED DRUGS ......................................................................................................................... 64 
10. 
STUDY SCHEDULE ...................................................................................................................... 65 
10.1. 
PRE-STUDY VISIT (SCREENING) ........................................................................................................... 67 
10.2. 
STUDY TREATMENT VISITS................................................................................................................. 68 
10.3. 
END OF TREATMENT /EARLY WITHDRAWAL .......................................................................................... 69 
10.4. 
SAFETY FOLLOW-UP VISIT.................................................................................................................. 70 
11. 
ASSESSMENT OF SAFETY / ADVERSE EVENTS ............................................................................ 71 
11.1. 
DEFINITIONS ................................................................................................................................ 71 
11.1.1. 
Adverse event (AE) ................................................................................................................... 71 
11.1.2. 
Serious adverse event (SAE) ....................................................................................................... 71 
11.1.3. 
Additional considerations ........................................................................................................72 
11.2. 
CHARACTERISTICS OF AN ADVERSE EVENT ............................................................................................ 72 
11.2.1. 
Causality assessment .............................................................................................................. 72 
11.2.2. 
Expectedness ........................................................................................................................ 73 
11.2.3. 
Severity ................................................................................................................................ 73 
11.3. 
REPORTING PROCEDURES .................................................................................................................73 


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11.3.1. 
Reporting of adverse events (AEs) ................................................................................................ 73 
11.3.2. 
Reporting of serious adverse events (SAEs) .................................................................................... 74 
11.3.3. 
Reporting of serious adverse events (SAEs) to Health Authorities ........................................................ 74 
11.3.4. 
Follow-up of AEs and SAEs ....................................................................................................... 74 
11.3.5. 
AEs or SAEs that occur after the study ends ................................................................................... 74 
11.3.6. 
Events of special interest .............................................................................................................75 
12. 
STATISTICAL CONSIDERATIONS............................................................................................... 78 
12.1. 
GENERALCONSIDERATIONS ........................................................................................................... 78 
12.2. 
SAMPLE SIZE .................................................................................................................................. 78 
12.3. 
ANALYTICAL POPULATIONS ............................................................................................................ 78 
12.4. 
ANALYSIS OF PRIMARY OBJECTIVE ..................................................................................................... 78 
12.5. 
ANALYSIS OF SECONDARY OBJECTIVES ................................................................................................ 79 
12.5.1. 
Secondary Efficacy evaluations ................................................................................................... 79 
12.5.2. 
Secondary Safety evaluations...................................................................................................... 79 
13. 
DATA HANDLING AND QUALITY ASSURANCE ........................................................................... 79 
13.1. 
MONITORING OF THE TRIAL.................................................................................................................79 
13.2. 
AUDITS ............................................................................................................................................................................................ 79 
13.3. 
REPORTING OFSERIOUS BREACHES ...................................................................................................... 79 
13.4. 
DATA MANAGEMENT .....................................................................................................................80 
13.5. 
ELECTRONIC CASE REPORT FORMS (ECRFS) ......................................................................................... 80 
13.6. 
WEB-BASED ECRF .......................................................................................................................... 81 
13.7. 
ENTERING OF DATA INTO THE ECRF .................................................................................................... 81 
13.8. 
THE QUERY PROCESS .......................................................................................................................81 
13.9. 
SOURCE DOCUMENTS ......................................................................................................................82 
13.10. 
USER ID .................................................................................................................................... 82 
13.11. 
AUDIT TRAIL ............................................................................................................................. 82 
13.12. 
INSPECTION OF RECORDS............................................................................................................... 82 
13.13. 
TRIAL RECORD RETENTION ........................................................................................................... 83 
14. 
ADMINISTRATIVE CONSIDERATIONS ...................................................................................... 83 
14.1. 
LEGAL CONSIDERATIONS ................................................................................................................83 
14.2. 
ETHICS COMMITTEE REVIEW .............................................................................................................. 83 
14.3. 
MODIFICATIONS OF THE PROTOCOL ..................................................................................................... 83 
14.4. 
INFORMEDCONSENT ...................................................................................................................... 84 
14.5. 
CONFIDENTIALITY ........................................................................................................................ 85 
14.6. 
INSURANCE .................................................................................................................................. 85 
14.7. 
PUBLICATIONS ............................................................................................................................. 85 
15. 
SPONSOR’S SIGNATURE PAGE ......................................................................................................87 
16. 
INVESTIGATOR’S SIGNATURE PAGE .......................................................................................... 88 
17. 
REFERENCES .............................................................................................................................. 89 
ANNEX 1. DECLARATION OF HELSINKI ................................................................................................. 92 
ANNEX 2. LIST OF SITES / PRINCIPAL INVESTIGATORS......................................................................... 96 
ANNEX 3. INFORMED CONSENT FORM................................................................................................... 97 
ANNEX 4. NCI-CTC AE CRITERIA ............................................................................................................ 98 


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3. ABBREVIATIONS 
 
Abbreviation 
Full terminology 
AE 
Adverse Event 
AEMPS 
Spanish Agency of Medicines and Medical Devices 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolut Neutrophil Count 
aPTT 
Activate Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine triphosphate 
BC 
Breast cancer 
BCRP 
Breast cancer resistance protein 
BID 
Twice In Day 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CEIm 
Medicinal Research Ethics Committee 
CI 
Confidence Interval 
CK 
Creatine kinase 
CNIO 
Centro Nacional de Investigaciones Oncológicas 
CPK 
Creatine phospokinase 


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Abbreviation 
Full terminology 
CR 
Complete Response 
CRA 
Clinical Research Assistant 
CRC 
Colorectal cancer 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Central serous retinopathy 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DUSP6 
Dual specificity phosphatase 6 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
ECOG-PS 
Eastern Cooperative Oncology Group-Performance Status 
EDC 
Electronic Data Capture 
EGFR 
Epidermal growth factor receptor 
ER 
Oestrogen Receptor 
ERK 
Extracellular Receptor Kinase 
FFPE 
Formalin fixed paraffin embedded 


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Abbreviation 
Full terminology 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma Glutamyl Transpeptidase 
GTP 
Guanosine triphosphatase 
H&E 
Haemotoxylin and eosin 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER2 
Human Epithelial grow factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone receptor 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identity 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 


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Abbreviation 
Full terminology 
LDH 
Lactate Dehydrogenase 
LHRH 
Luteinizing hormone-release hormone 
LLN 
Lower Limit of Normality 
LVEF 
Left Ventricular Ejection Function 
MAP 
Mitogen-activated protein 
MAPK 
Mitogen-activated protein kinase 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
Next-generation sequencing 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OR 
Objective Response 
OS 
Overall Survival 
PARPi 
Poly (adenosine diphosphate-ribose) polymerase inhibitors 
PD 
Progressive disease/Pharmacodynamics 
PDXs 
Patient derived xenografts 


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Abbreviation 
Full terminology 
PET-CT 
Positron Emission Tomography-Computed Tomography 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositide 3-kinase 
PIL 
Patient Information Leaflets 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic(s) 
PKC 
Protein kinase C 
PO 
Oral 
PR 
Partial Response/Progesterone Receptor 
PTMs 
Post-translational modifications 
PTT 
Partial Thromboplastin Time 
PVC 
Polyvinyl Chloride 
QC 
Quality Control 
QTc 
Corrected QT interval 
Rb 
Retinoblastoma 
RBC 
Reed Blood Count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REPD 
Retinal pigment epithelial detachment 
RNA 
Ribonucleic acid 
RP2D 
Recommend Phase 2 Dose 
RPED 
Retinal Pigment Epithelial Detachment 


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Abbreviation 
Full terminology 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
TMF 
Trial Master File 
TNBC 
Triple negative breast cancer 
TSH 
Thyroid stimulating hormone 
TTD 
Time To Deterioration 
ULN 
Upper Limit of Normal 
WDC 
White Blood Count 
 
 
 
4. CLINICAL TRIAL CHARACTERISTICS 
4.1. Clinical trial identification 
Code: 
PALBOBIN 
Title: 
Phase IB Clinical trial of palbociclib and binimetinib in advanced triple negative breast 
cancer with hyperactivation of ERK and/or CDK4/6 
 
 
4.2. Phase 
Pase IB 


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4.3. Investigational product 
Palbociclib plus binimetinib 
 
 
4.4. Sponsor 
Fundación OncoSur 
Address: Gran Via Marques del Turia nº 65, 3º-11. 46005 Valencia Office: 
Medical Oncology Service 
Hospital 12 de Octubre 
Avda de Cordoba s.n. 
28041-Madrid 
e-mail: secretaria_tecnica@oncosur.org 
 
Principal Investigator 
Miguel Quintela-Fandino 
Head of the Breast Cancer Unit 
CNIO - Spanish National Cancer Research Center Melchor 
Fernandez Almagro, 3 
Madrid, 28029, Spain 
 
 
 
4.5. Ethics Committee 
CEIm Hospital de 12 de Octubre 
 
 
4.6. Company Responsible of the Monitoring 
APICES 
CCI
CCI


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4.7. Study calendar 
First patient inclusion: 4Q 2020 
Last patient inclusion: 4Q2021 
Subject participation duration: 6 months + 6 months follow up Study 
duration: 32 months 
 
 
 
5. STUDY RATIONALE AND OBJECTIVES 
5.1. Background information 
5.1.1. Triple negative breast cancer 
Breast cancer is the most common invasive cancer in women worldwide, with more than one 
million cases diagnosed in 2012 and it is also the most common cancer in women in Europe 
and Spain, with more than 494.000 and 27.700 new cases diagnosed in 2012 respectively 
[2,3]. It is estimated than 1 in 8 women in the European Union will develop breast cancer 
before the age of 85 [4]. 
Triple-negative breast cancer (TNBC) is a notoriously aggressive disease, as indicated by 
poor survival rates relative to other forms of BC [5,6], defined as lacking expression of 
oestrogen receptor (ER) and/or progesterone receptor (PR) as well as amplification of human 
epidermal growth factor receptor 2 (HER2), respectively [7]. Although TNBC only 
constitutes approximately 15–20% of breast cancer cases, it is disproportionately responsible 
for breast cancer-associated deaths and carries a dismal prognosis, compared with hormone 
receptor-positive (HR+) breast cancers [8-10]. More than one-third of patients with TNBC 
will present distant metastases, either recurrent or de novo metastatic disease [5]. 
Adjuvant chemotherapy is the current standard treatment for TNBC, but modest response 
rates underscores a need for more effective treatments. For patients with HR+ breast cancer, 
endocrine therapy targeting ER is available in the form of aromatase inhibitors and selective 
oestrogen receptor modulators (e.g. tamoxifen) 
CCI


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and other antagonists [7], but no effective targeted therapy which exploits the molecular 
properties of tumour cells exists for TNBC patients. 
Aggressive chemotherapy, radiotherapy and surgery remain the mainstay treatments [11]. 
Furthermore, patients who develop resistance to treatment, or who do not respond to 
treatment whatsoever, follow an aggressive clinical course characterised by metastasis and 
a higher 5-year mortality [12]. 
TNBC is a molecularly heterogeneous disease characterized by genomic instability along 
with high expression of cell-cycle genes [13] and clearly necessitates a more tailored 
approach to treatment. For chemotherapy-resistant TNBC patients, the development of 
targeted therapies which synergise with current treatment options to overcome resistance is 
therefore paramount. The complex biology of TNBC suggests that combination treatments 
will be required to achieve effective and durable disease control. 
 
 
5.1.2. Palbociclib 
Palbociclib is an orally active pyridopyrimidine, highly selective, reversible inhibitor of 
cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple 
signaling pathways which lead to cellular proliferation. 
Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking 
progression of the cell from G1 into S phase of the cell cycle. Palbociclib preclinical data 
indicate that it may be expected to have direct effect on growth arrest as well as potential 
secondary cytoreductive activity. Treatment of cultured tumor cells with palbociclib causes 
growth arrest that is accompanied by the inhibition of specific retinoblastoma (Rb) 
phosphorylation by CDK4 or CDK6 on residues serine -780 and 
-795 of Rb. Consequently the phosphorylation status of these sites serves as specific 
biomarkers of CDK4/6 inhibition by palbociclib. 
Testing of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed 
high activity against luminal breast cancers, particularly ER-positive breast cancers. 
Palbociclib is indicated for the treatment of hormone receptor (HR)-positive, human 
epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast 
cancer: 
- 
in combination with an aromatase inhibitor; 
- 
in combination with fulvestrant in women who have received prior endocrine 
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5.1.2.1. 
Safety profile of palbociclib 
The overall safety profile of palbociclib is based on pooled data from 872 patients who 
received palbociclib in combination with endocrine therapy (N=527 in combination with 
letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-
positive, HER2-negative advanced or metastatic breast cancer. 
The most common (≥20%) adverse reactions of any grade reported in patients receiving 
palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, 
nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common 
(≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, infections, 
anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase 
(ALT) increased. 
5.1.2.2. 
Clinical efficacy of palbociclib 
The efficacy of palbociclib in combination with fulvestrant versus fulvestrant plus placebo 
was evaluated in an international, randomised, double-blind, parallel-group, multicentre 
study conducted in women with HR-positive, HER2-negative locally advanced breast cancer 
not amenable to resection or radiation therapy with curative intent or metastatic breast cancer, 
regardless of their menopausal status, whose disease progressed after prior endocrine therapy 
in the (neo)adjuvant or metastatic setting. 
A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 
months from completion of adjuvant endocrine therapy or on or within 1 month from prior 
endocrine therapy for advanced disease, were randomised 2:1 to palbociclib plus fulvestrant 
or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal 
therapy, menopausal status at study entry (pre/peri- versus postmenopausal), and presence 
of visceral metastases. Pre/perimenopausal women received the LHRH agonist goserelin. 
Patients with advanced/metastatic, symptomatic, visceral spread, that were at risk of life- 
threatening complications in the short term (including patients with massive uncontrolled 
effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver 
involvement), were not eligible for enrolment into the study. 
Patients continued to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, 
whichever occurred first. 
Patients were well matched for baseline demographics and prognostic characteristics 
between the palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. All 
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in each treatment arm had received a previous chemotherapy regimen for their primary 
diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases, and 
60% had received more than 1 prior hormonal regimen for their primary diagnosis. 
The primary endpoint of the study was investigator-assessed PFS evaluated according to 
RECIST 1.1. Supportive PFS analyses were based on an Independent Central Radiology 
Review. Secondary endpoints included OR, CBR, OS, safety, and time-to-deterioration 
(TTD) in pain endpoint. 
The study met its primary endpoint of prolonging investigator-assessed PFS [11.2 (9.5, 12.9) 
vs 4.6 (3.5, 5.6) months; Hazard ratio of 0.497 (95% CI: 0.398, 0.620), 
p<0.000001], demonstrating a statistically significant prolongation in PFS and a clinically 
meaningful treatment effect. 
A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm 
was observed in all individual patient subgroups defined by stratification factors and baseline 
characteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 
0.75]) and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with 
visceral site of metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of 
metastatic disease (HR of 0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless 
of lines of prior therapy in the metastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 
0.93]), 
1 (HR of 0.46 [95% CI: 0.32, 0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or ≥3 lines 
(HR of 0.59 [95% CI: 0.28, 1.22]). 
 
 
5.1.3. Binimetinib 
Binimetinib (also known as MEK162, ARRY-438162 or ONO-7703) is an orally 
bioavailable, selective and potent mitogen-activated protein (MAP) kinase, kinase (MEK)1 
and MEK2 inhibitor. 
As a MEK inhibitor, this compound has the potential to benefit patients with advanced 
cancers by inhibiting the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) 
pathway. 
Binimetinib is currently being investigated as a single agent and in combination with a variety 
of additional compounds, including inhibitors of serine/threonine-protein kinase B-Raf 
(BRAF), phosphatidylinositide 3-kinase (PI3K), epidermal growth factor receptor (EGFR), 
cyclin-dependent kinase 4/6 (CDK4/6), chemotherapy and immune checkpoint inhibitors. 
Binimetinib in combination with encorafenib is indicated for the treatment of adult patients 
with unresectable or metastatic melanoma with a BRAF V600 mutation. 


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5.1.3.1. 
Target Inhibition 
Binimetinib is an adenosine triphosphate (ATP)-uncompetitive inhibitor of MEK1 and 
MEK2. In cell-free systems, binimetinib inhibits MEK1 and MEK2. In vitro, binimetinib 
potently inhibits MEK-dependent phosphorylation of extracellular regulated signal kinase 
(ERK) in human BRAF-mutant melanoma cell lines, as well as NRAS-mutant melanoma 
lines. 
In vivo, binimetinib has been evaluated for its ability to inhibit tumor growth and 
phosphorylation of ERK, the primary biomarker of MEK inhibitory activity, in xenograft 
models in nude mice. In vivo, binimetinib treatment results in dose- and time-dependent 
inhibition of phosphorylation of ERK in the HT-29 human colorectal cancer (CRC) 
xenograft. Similarly, levels of both phosphorylated ERK (pERK) and dual specificity 
phosphatase 6 (DUSP6) messenger ribonucleic acid (mRNA) (a target gene of pERK) are 
reduced in the A375 BRAF-mutant melanoma xenograft model. Lastly, in ex vivo 
experiments, binimetinib reduces pERK levels in ex vivo stimulated human whole blood 
cells. 
5.1.3.2. 
Tumor Growth Inhibition 
In vitro, binimetinib potently inhibits the proliferation of human cancer cell lines. 
Binimetinib is particularly active in cells harboring activating mutations in the BRAF, NRAS 
and KRAS genes, although activity is also observed in cell lines that lack such mutations. 
Synergistic interactions with the BRAF inhibitor encorafenib and PI3K inhibitors buparlisib 
and alpelisib have been observed in subsets of melanoma, CRC, pancreatic and lung-derived 
cancer cell lines. Lastly, binimetinib displays synergistic effects when combined with the 
protein kinase C (PKC) inhibitor sotrastaurin in cell line models of uveal melanoma. 
In vivo, single-agent binimetinib inhibits the growth of tumors in numerous xenograft models, 
including those derived from NSCLC and CRC, pancreatic and melanoma cancers. 
Binimetinib is also active in primary human explant models derived from several cancer 
types (CRC, ampullary, pancreatic and cholangiocarcinoma). Combining binimetinib with a 
variety of standard chemotherapy agents such as cisplatin, gemcitabine, taxanes or 5-
fluorouracil/oxaliplatin resulted in enhanced antitumor activity in numerous in vivo tumor 
models. Similarly, combinations of binimetinib with a variety of targeted agents have shown 
activity in vivo in multiple tumor models. In cutaneous melanoma, binimetinib combination 
effects are observed with the BRAF inhibitor encorafenib and the CDK4/6 inhibitor 
ribociclib. Similarly, in models of uveal melanoma, binimetinib combined effectively with 
the PKC inhibitor sotrastaurin. In subsets of xenograft models of CRC, NSCLC and 
pancreatic cancer, antitumor effects have been observed when binimetinib was combined 
with a variety of PI3K inhibitors (buparlisib, alpelisib). Moreover, in BRAF- mutant CRC, 
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inhibitor cetuximab. Lastly, binimetinib also demonstrated anti-angiogenic activity in 
Matrigel plug assays in mice. 
5.1.3.3. 
Cancer and the MAP Kinase Pathway 
Growth factor-mediated proliferative signals are transmitted from the extracellular 
environment to the nucleus through several pathways, including the RAS/RAF/MEK/ERK 
mitogen-activated protein kinase (MAPK) pathway [14]. This pathway comprises an 
evolutionarily conserved signaling cascade initiated by the RAS family of small guanosine 
triphosphatases (GTPases), which activate the RAF kinases. Activated RAF kinases 
phosphorylate and thereby activate MEK1 and MEK2, which in turn phosphorylate and 
activate the extracellular regulated signal kinase (ERK)1 and ERK2 kinases. Subsequent 
phosphorylation of a variety of downstream effector proteins, including transcription factors, 
by activated ERK serve to regulate key cellular activities including proliferation, 
differentiation, migration, survival and angiogenesis. Aberrant signaling through this pathway 
has been shown to lead to unconstrained cell growth and cell transformation [15,16] and is a 
characteristic feature of many cancers. 
Inappropriate activation of the RAS/RAF/MEK/ERK pathway can occur through a variety 
of mechanisms, including activating mutations in RAS and B-Raf proto- oncogene, 
serine/threonine-protein kinase (BRAF) [17,18], activated growth factor signaling [19,20] 
and stress response signals [21,22]. Preclinical studies indicate that the presence of mutations 
that activate RAS/RAF/MEK/ERK pathway signaling, are predictive for response to MEK 
inhibitors [23]. Collectively, these data suggest that targeting MEK may inhibit cancer 
signaling mediated by a wide variety of signals, making MEK an attractive target for the 
treatment of cancer and its associated symptoms. 
 
 
5.1.3.4. 
Rationale for the use of binimetinib 
Use of binimetinib in the clinic is based on: 
- 
(a) potent target inhibition in human cancer cell lines and xenograft models; 
- 
(b) inhibition of tumor growth in human cancer cell lines and xenograft models, both as 
a single agent and in combination with targeted and standard chemotherapy agents; 
and 
- 
(c) hypersensitivity of BRAF-mutant, NRAS-mutant and KRAS-mutant human cancer 
cell lines to binimetinib. 
Binimetinib has demonstrated potent activity against MEK1/2 both in vitro and in vivo. In 
cellular assays, binimetinib has been shown to markedly inhibit the phosphorylation of ERK 
in human cancer cell lines and in human whole blood. In the BRAF-mutant HT-29 human 
colon carcinoma tumor and BRAF-mutant A375 


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human melanoma xenograft models, binimetinib significantly inhibited the phosphorylation 
of ERK following oral (PO) doses. 
Binimetinib has displayed antiproliferative activity in cell line models of cancer in vitro and 
in vivo. For instance, binimetinib inhibited the proliferation of both Malme- 3M melanoma 
and HT-29 colorectal cancer (CRC) cells in vitro. Further studies in large sets of human 
cancer cell lines have confirmed the antiproliferative activity of binimetinib, particularly in 
models harboring activated alleles of the BRAF, NRAS, and to a lesser extent, KRAS genes. 
In vivo, binimetinib has demonstrated significant dose-dependent inhibition of tumor growth 
in a wide array of xenograft models in mice. In addition, robust combination activity between 
binimetinib and both standard chemotherapy agents (cisplatin, gemcitabine, 5-fluorouracil 
[5- FU]/oxaliplatin, taxanes) and targeted agents, such as RAF inhibitors (encorafenib), 
phosphatidylinositide 3-kinase (PI3K) inhibitors (alpelisib, buparlisib, BEZ2335), cyclin-
dependent kinase 4/6 (CDK4/6) inhibitors (ribociclib), protein kinase C (PKC) inhibitors 
(sotrastaurin) and epidermal growth factor receptor (EGFR) inhibitors (erlotinib, 
cetuximab), has been observed. Also, combining binimetinib with an immunomodulating 
anti-programmed death-1 (PD1) antibody (RPM1-14) in the syngeneic CT26 CRC allograft 
tumor model, resulted in enhanced tumor growth inhibition relative to treatment with either 
drug as a single agent. 
5.1.3.5. 
Safety profile of binimetinib 
As of 20 January 2018, a total of 2816 healthy subjects and patients have received at least 1 
dose of binimetinib, either as a single agent or in combination with other targeted agents, 
standard chemotherapy agents or immunomodulating agents. These patients constitute the 
binimetinib safety population, which includes 229 healthy subjects, 17 subjects with hepatic 
dysfunction, 6 subjects with renal dysfunction, 164 patients with rheumatoid arthritis and 
2400 patients with advanced cancer. 
5.1.3.5.1. Binimetinib as a Single Agent 
Binimetinib has been administered as a single agent to 943 patients with cancer across 7 
studies. 
1. Clinical Study ARRAY-162-111 (N = 93; completed): Phase 1, dose- escalation 
study in patients with advanced solid tumors followed by expansion cohorts in 
patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant 
metastatic CRC. 
2. Clinical Study CMEK162X1101 (N = 21; ongoing): Phase 1, dose-escalation study 
in Japanese patients with advanced solid tumors with an expansion phase in patients 
with RAS or BRAF mutation. 


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3. Clinical Study CMEK162X2201 (N = 183; ongoing): Phase 2 study in patients with 
locally advanced and unresectable or metastatic malignant cutaneous melanoma, 
with BRAF V600 or NRAS mutations. 
4. Clinical Study CMEK162AUS11 (N = 110; completed): Phase 2 study in patients 
with select solid tumors or hematological malignancies that have been pre-identified 
to have activation of the RAS/RAF/MEK/ERK pathway. 
5. Clinical Study CINC280X2205 (N = 22; ongoing): Phase 2 study in Chinese patients 
with advanced KRAS/BRAF/NRAS-mutant NSCLC. 
6. Clinical Study CMEK162A2301 (N = 269; ongoing): Phase 3, 2-arm, randomized 
study in patients with advanced unresectable or metastatic NRAS Q61 mutation-
positive melanoma. 
7. Clinical Study ARRAY-162-311 (N = 245; ongoing): Phase 3, 2-arm, randomized 
study in patients with recurrent or persistent low-grade serous carcinomas of the 
ovary, fallopian tube or primary peritoneum. 
 
The most frequently reported adverse events (AEs) with single-agent binimetinib 45 mg BID 
treatment (all grades) have been blood creatine kinase (CK) increased, diarrhea, dermatitis 
acneiform, edema peripheral, rash, nausea and fatigue. The majority of these AEs have been 
Grade 1/2, with the exception of blood CK increased, which was reported as Grade 3/4 for 
21% of patients with metastatic melanoma in the “binimetinib 45 mg population” (N = 427) 
which includes pooled data from 2 clinical studies (CMEK162A2301 [Phase 3], 
CMEK162X2201 [Phase 2]), and for 29% of patients with low-grade serous carcinomas of 
the ovary, fallopian tube or primary peritoneum in the binimetinib arm of the randomized 
period of Clinical Study ARRAY-162-311 (Phase 3; N = 227). 
5.1.3.5.1.1. Clinical Study ARRAY-162-111 
Clinical Study ARRAY-162-111 is a completed Phase 1, open-label, dose-escalation study of 
oral binimetinib in patients with advanced solid tumors followed by expansion cohorts in 
patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant metastatic 
CRC. 
A total of 93 patients were enrolled and received at least 1 dose of binimetinib (4 patients at 
30 mg BID, 44 patients at 45 mg BID, 41 patients at 60 mg BID and 4 patients at 80 mg 
BID), including 19 patients in the dose-escalation phase and 74 patients in the dose-
expansion phase. 
Four dose levels were evaluated (30 mg BID, 45 mg BID, 60 mg BID and 80 mg BID) 
following a 3+3 dose-escalation design. Enrollment of cohorts containing 4 patients each, 3 
of whom in each cohort were evaluable for dose-escalation decisions, proceeded at doses of 
30 mg BID and 45 mg BID without observation of DLTs. Seven patients were enrolled at 60 
mg BID, 6 of whom were evaluable, and 


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no DLTs were observed. Enrollment proceeded to 80 mg BID; 4 patients were enrolled, 3 of 
whom were evaluable. Two patients receiving 80 mg BID experienced DLTs, thus the 80 mg 
BID dose was declared nontolerable and 60 mg BID was declared the MTD. Additional 
DLTs observed in the expansion cohorts included Grade 3 pneumonia and Grade 3 blood 
CK increased (one patient each at the 45 mg BID dose level) and Grade 3 mucosal 
inflammation and Grade 3 generalized edema (one patient each at the 60 mg BID dose level). 
Following determination of the MTD in the dose-escalation phase, 74 patients were enrolled 
in the expansion phase, including 28 patients in the biliary cancer cohort, 31 patients in 
KRAS-mutant CRC cohort and 15 patients in the BRAF-mutant CRC cohort. After initiation 
of the expansion phase, a higher-than-expected frequency of ocular AEs affected the ability 
to treat patients continuously at the MTD, thus a reduced dose of 45 mg BID was 
implemented for the remainder of newly enrolled patients in the expansion phase cohorts. 
All 93 patients reported at least 1 AE, the most common (≥ 20% of patients) of which were 
rash (59%), nausea (56%), vomiting (52%), diarrhea (51%), edema peripheral 
(46%), fatigue (43%), anemia (26%) and abdominal pain (22%). 
Fifty-two patients (56%) experienced at least 1 Grade 3/4 AE. Grade 3 AEs reported for > 1 
patient were anemia (10 patients [11%]); abdominal pain and dehydration (4 patients [4%] 
each); AST increased, blood alkaline phosphatase increased, blood CK increased, dyspnea, 
ECG QT prolonged, fatigue, hypokalemia, hyponatremia, small intestinal obstruction and 
syncope (3 patients [3%] each); and constipation, dermatitis acneiform, GI hemorrhage, 
hyperbilirubinemia, hypertension, international normalized ratio (INR) increased, 
lymphopenia, melena, pain in extremity, pneumonia, rash, and renal failure acute (2 patients 
[2%] each). The Grade 4 AE reported for > 1 patient was anemia (3 patients [3%]). 
Twenty-eight patients (30%) reported at least 1 SAE on study or within 30 days of the last 
dose of binimetinib. Serious AEs reported in > 1 patient were anemia (4 patients [4%]); and 
bacteremia, dehydration, GI hemorrhage, small intestinal obstruction, pneumonia and ulcer 
hemorrhage (2 patients [2%] each). All other SAEs occurred in 1 patient (1%) each. 
5.1.3.5.1.2. Clinical Study CMEK162X1101 
Clinical Study CMEK162X1101 is an ongoing Phase 1, open-label, dose-escalation study of 
binimetinib as a single agent in Japanese patients with advanced solid tumors with an 
expansion cohort in patients with RAS or BRAF mutation. 
Enrollment is complete, with 21 patients enrolled and treated with at least 1 dose of 
binimetinib (6 patients at 30 mg BID and 15 patients at 45 mg BID), including 14 patients 
in the dose-escalation phase and 7 patients in the dose-expansion phase. 


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Fourteen patients with advanced solid tumors received binimetinib in the dose- escalation 
phase and 11 were eligible for the dose-determining set. Two dose levels were evaluated (30 
mg BID and 45 mg BID) and dose escalation was guided by an adaptive Bayesian Logistic 
Regression Model and implemented with the Escalation with Overdose Control principle. 45 
mg BID was declared the MTD. 
Following determination of the MTD in the dose-escalation phase, 7 patients were enrolled 
in the expansion phase and received binimetinib at the MTD (45 mg BID). No DLTs were 
reported in the expansion portion of the study. 
All 21 patients (100%) reported at least 1 AE, the most common (≥ 20.0% of patients) of 
which were blood CK increased (81.0%); AST increased (71.4%); retinal detachment 
(61.9%); diarrhea and lipase increased (57.1% each); ALT increased (52.4%); pyrexia, blood 
ALP increased, hypoalbuminemia, and dermatitis acneiform (47.6% each); amylase increased 
and dry skin (42.9% each); stomatitis, paronychia and rash (38.1% each); fatigue, edema 
peripheral and decreased appetite (33.3% each); cheilitis, GGT increased and hemoglobin 
decreased (28.6% each); and lymphopenia, constipation, blood creatinine increased, 
epistaxis and pruritus (23.8% each). 
Seventeen patients (81.0%) experienced at least 1 Grade 3/4 AE; those reported for > 1 
patient were blood CK increased (7 patients [33.3%]); lipase increased and lymphopenia (4 
patients [19.0%] each); and ALT increased, AST increased, cancer pain, fatigue, GGT 
increased and pneumonia (2 patients [9.5%] each). All other Grade 3/4 AEs occurred in 1 
patient (4.8%) each. 
Ten patients (47.6%) reported at least 1 SAE on study or within 28 days of the last dose of 
binimetinib. Serious AEs reported in > 1 patient was pneumonia (2 patients [9.5%]). All other 
SAEs occurred in 1 patient (4.8%) each. 
5.1.3.5.1.3. Clinical Study CMEK162X2201 
Clinical Study CMEK162X2201 is an ongoing Phase 2, open-label study of single- agent 
binimetinib in adult patients with locally advanced and unresectable or metastatic malignant 
cutaneous melanoma with BRAF V600 or NRAS mutation. 
Enrollment is complete, with 183 patients enrolled and treated with at least 1 dose of 
binimetinib (158 patients at 45 mg BID [41 BRAF mutant and 117 NRAS mutant] and 25 
patients at 60 mg BID [all BRAF mutant]). This section describes the data for the 25 patients 
treated with binimetinib 60 mg BID [all BRAF mutant]) as of the data cutoff date for the 
primary analysis (07 January 2014). 
As of the data cutoff date for the primary analysis (07 January 2014) 25 patients were treated 
with binimetinib 60 mg BID. All 25 patients (100%) reported at least 1 AE, the most common 
(≥ 20.0% of patients) of which were blood CK increased and edema peripheral (56.0% 
each); diarrhea (52.0%); fatigue and nausea (48.0% 


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each); retinopathy (40.0%); vomiting (36.0%); dermatitis acneiform (32.0%); arthralgia 
(24.0%); and dry skin, hypertension and rash (20.0% each). 
Eighteen patients (72.0%) in the 60 mg BID cohort experienced at least 1 Grade 3/4 AE; those 
reported for > 1 patient were blood CK increased (6 patients [24.0%]); nausea and vomiting 
(3 patients [12.0%] each); and AST increased, blood ALP increased, blood lactate 
dehydrogenase increased, gastritis and syncope (2 patients [8.0%] each). All other Grade 3/4 
AEs occurred in 1 patient (4.0%) each. 
Nine patients (36.0%) in the 60 mg BID cohort reported at least 1 SAE on study or within 
30 days of the last dose of binimetinib. Serious AEs reported in > 1 patient was gastritis (2 
patients [8.0%]). All other SAEs occurred in 1 patient (4.0%) each. 
5.1.3.5.1.4. Clinical Study CMEK162AUS11 
Clinical Study CMEK162AUS11 is a completed Phase 2, open-label study to determine the 
efficacy and safety of treatment with single-agent binimetinib in patients with select solid 
tumors or hematological malignancies that have been pre- identified (prior to study consent) 
to have activation of the RAS/RAF/MEK/ERK pathway and whose disease has progressed 
on or after standard treatment. 
A total of 110 patients were enrolled and treated with at least 1 dose of binimetinib (45 mg 
BID). As of the data cutoff date for the final analysis (08 October 2015), all patients (100%) 
reported at least 1 AE, the most common (≥ 20.0% of patients) of which were fatigue 
(50.0%), diarrhea (47.3%), nausea (44.5%), rash (43.6%), edema peripheral (40.9%), 
vomiting (38.2%), blood CK increased (34.5%), dyspnea (30.9%), anemia (26.4%), 
constipation and decreased appetite (22.7% each) and AST increased (20.0%). 
Eighty-one patients (73.6%) experienced at least 1 Grade 3/4 AE; those reported for ≥ 5.0% 
of patients were blood CK increased (17 patients [15.5%]), dyspnea (15 patients [13.6%]), 
anemia (11 patients [10.0%]), fatigue (10 patients [9.1%]) and abdominal pain and lipase 
increased (6 patients [5.5%] each). 
Fifty patients (45.5%) experienced at least 1 SAE on study or within 30 days of the last dose 
of binimetinib. Serious AEs reported in > 1 patient were dyspnea (12 patients [10.9%]); 
abdominal pain, dehydration and small intestinal obstruction (4 patients [3.6%] each); 
hypoxia, pneumonia and urinary tract infection (3 patients [2.7%] each); and cellulitis, 
edema peripheral, hemoptysis, pleural effusion, pulmonary embolism, pyrexia, sepsis and 
vomiting (2 patients [1.8%] each). All other SAEs occurred in 1 patient (0.9%) each. 
5.1.3.5.1.5. Clinical Study CINC280X2205 
Clinical Study CINC280X2205 is an ongoing Phase 2, open-label, multiple-arm study of 
binimetinib, AUY922, alpelisib (BYL719), INC280 or LDK378 as single 


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agents in Chinese patients with advanced (stage IIIB or stage IV) non-small cell lung cancer 
(NSCLC) who have received ≤ 2 prior lines of antineoplastic therapy. Each treatment arm is 
independent from one another. Approximately 20 to 25 patients are planned to be enrolled to 
each treatment arm according to their molecular alterations, with KRAS-, NRAS- or BRAF-
mutant patients enrolled to receive binimetinib. 
As of the data cutoff date (18 January 2018), a total of 22 patients have been enrolled and 
treated with binimetinib 45 mg BID. All 22 patients (100%) reported at least 1 AE, the most 
common (≥ 30.0% of patients) of which were anemia, blood CK increased and rash (72.7% 
each), AST increased (68.2%), diarrhea (63.6%), hypoalbuminaemia (59.1%), edema 
peripheral and pyrexia (50.0% each), vomiting (40.9%), hyponatremia and mouth ulceration 
(36.4% each) and asthenia, dyspnea and hypocalcemia (31.8% each). 
Twenty patients (90.9%) experienced at least 1 Grade 3/4 AE; those reported for > 1 patient 
were blood CK increased (8 patients [36.4%]), anemia (5 patients [22.7%]), hypokalemia 
dyspnea, pleural effusion (3 patients [13.6%]), and ECG QT prolonged, hypoalbuminemia, 
hypertension and pneumonia (2 patients [9.1%] each). 
Eighteen patients (81.8%) experienced at least 1 SAE on study or within 30 days of the last 
dose of binimetinib. Serious AEs reported in > 1 patient were blood CK increased and 
dyspnea (4 patients [18.2%] each), pleural effusion and pyrexia (3 patients [13.6%] each) 
and lung infection and pneumonia (2 patients [9.1%] each). 
5.1.3.5.1.6. Clinical Study ARRAY-162-311 
Clinical Study ARRAY-162-311 (MILO study) is an ongoing Phase 3, 2-arm, multinational, 
randomized, open-label study to evaluate binimetinib (45 mg BID) vs. physician’s choice of 
selected chemotherapies (liposomal doxorubicin, paclitaxel or topotecan) in patients with 
low-grade serous carcinomas of the ovary, fallopian tube or primary peritoneum who had 
recurrent or persistent disease after at least 1 prior platinum-based chemotherapy treatment 
and no more than 3 prior lines of chemotherapy. A total of 360 patients, were to be 
randomized 2:1 to receive binimetinib or physician’s choice chemotherapy. The primary 
objective was to determine whether treatment with binimetinib prolongs PFS as compared 
to physician’s choice chemotherapy. The study enrollment was discontinued after the 
planned interim analysis showed that the hazard ratio for PFS crossed the predefined futility 
boundary. 
Enrollment is complete, with a total of 341 patients (228 binimetinib and 113 physician’s 
choice) randomized to treatment and a total of 333 patients (227 patients binimetinib arm and 
106 patients physician’s choice arm) who received at least 1 dose of binimetinib or 
physician’s choice in the randomized period. 


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All 227 binimetinib-treated patients (100%) reported at least 1 AE, the most common (≥ 30% 
of patients) of which were diarrhea (71%), nausea (59%), vomiting (56%), blood CK 
increased (53%), fatigue and edema peripheral (52% each), dermatitis acneiform (49%), 
abdominal pain (35%) and dry skin (33%). In the crossover period, all 18 binimetinib-treated 
patients (100%) reported at least 1 AE, and the most frequently reported AEs were similar 
to those reported in the randomized period. 
Two hundred patients (88%) in the binimetinib arm experienced at least 1 ≥ Grade 3 AE in 
the randomized period. Of these AEs ≥ Grade 3, the events reported for ≥ 10% of patients in 
the binimetinib arm were blood CK increased (66 patients [29%]), hypertension (27 patients 
[12%]), vomiting (24 patients [11%]), anemia (23 patients 
[10%]) and diarrhea (22 patients [10%]). In the crossover period, 14 binimetinib- treated 
patients (78%) experienced at least 1 ≥ Grade 3 AE. 
One hundred twenty-one patients (53%) in the binimetinib arm reported at least 1 SAE on 
study or within 30 days of the last dose of binimetinib in the randomized period. Serious AEs 
reported in ≥ 2% of patients in the binimetinib arm were vomiting (16 patients [7%]); 
intestinal obstruction (14 patients [6%]); small intestinal 
obstruction (11 patients [5%]); diarrhea (10 patients [4%]); anemia (9 patients [4%]); sepsis 
and urinary tract infection (8 patients [4%] each); abdominal pain, ascites, nausea and 
subileus (7 patients [3%] each); pulmonary embolism (6 patients [3%]); and pleural effusion 
and renal failure acute (5 patients [2%] each). In the crossover period, 15 binimetinib-treated 
patients (83%) reported at least 1 SAE on study or within 30 days of the last dose of 
binimetinib. 
5.1.3.5.2. Binimetinib in combination 
Binimetinib has been administered in combination with other targeted agents, standard 
chemotherapy agents or immunomodulating agents to 1457 patients across 16 clinical studies. 
The most frequently reported AEs with the combination of binimetinib 45 mg BID + encorafenib 
450 mg once daily (QD) treatment (all grades) in patients with BRAF V600- mutant metastatic 
melanoma who were previously naïve to BRAF/MEK inhibitors have been nausea, diarrhea, 
fatigue, vomiting, arthralgia, blood CK increased, constipation and headache. The majority of 
these AEs have been Grade 1/2. This data is derived from pooled data from 3 clinical studies of 
the combination of binimetinib + encorafenib. 
See the updated version of binimetinib investigator brochure for more information. 
5.1.3.6. 
Guidance for Investigators 
Binimetinib is an investigational drug for which limited safety data are available. It should 
be used with appropriate caution typical for an investigational drug. 


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Binimetinib has demonstrated an acceptable and manageable safety profile in nonclinical 
toxicology studies and clinical studies. As with any investigational drug, unexpected AEs 
may occur. 
Available clinical data for binimetinib indicate a predictable safety profile consistent with 
those reported for other allosteric MEK1/2 inhibitors including the characteristic class effects 
of ocular toxicities, elevations of CK that are mostly asymptomatic, liver function test 
abnormalities (elevation of aspartate aminotransferase [AST], alanine aminotransferase 
[ALT] and total bilirubin), left ventricular dysfunction, skin toxicities including rash and 
acneiform dermatitis, hypertension, thromboembolic events, diarrhea, edema and 
hemorrhage. The majority of these toxicities are generally reversible and manageable by 
appropriate supportive medical care and/or dose modifications or discontinuation. 
Supportive therapy for the management of binimetinib-associated toxicities should be based 
on Investigator experience. 
Binimetinib may cause fetal harm (teratogenicity) when administered to a pregnant woman. 
Binimetinib must not be used in pregnant women or nursing women, and the use of highly-
effective contraception is recommended for male and female subjects participating in clinical 
studies. Additionally, women of childbearing potential must be advised to use highly 
effective contraception. 
Ocular toxicities can occur with binimetinib administration. Patients should be assessed for 
symptoms of new or worsening visual impairment. Patients with a history or current 
evidence of retinal vein occlusion (RVO) or risk factors for RVO (e.g., uncontrolled 
glaucoma or history of hyperviscosity or hypercoagulability syndrome) should be excluded 
from studies with binimetinib. 
New onset hypertension, or worsening of pre-existing hypertension, can occur with the use 
of binimetinib. Patients should be monitored for hypertension and treated as needed with 
standard anti-hypertensive therapy. 
Left ventricular dysfunction, defined as symptomatic or asymptomatic decreases in ejection 
fraction, can occur with binimetinib. Before binimetinib administration, patients should have 
a baseline left ventricular ejection fraction (LVEF) evaluation and periodically on study as 
per protocol. 
Venous thromboembolism can occur with the use of binimetinib. Binimetinib should be used 
with caution in patients who are at risk for, or who have a history of venous 
thromboembolism. 
Rash events are among the most frequently observed AEs reported with MEK inhibitors 
when used as a single agent. Patients receiving binimetinib should be monitored for skin 
toxicities and for secondary infections. 
Overall, the risk for binimetinib to be a cause of or be affected by significant drug- drug 
interactions is predicted to be low. However, given the predominant role of 


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UGT1A1 in the metabolism of binimetinib, special consideration should be taken for co-
administration of drugs that are UGT1A1 inhibitors or inducers, and administration of 
binimetinib to patients with low UGT1A1 activity. In addition, binimetinib has been shown 
to be a substrate for P-gp and BCRP in vitro. The impact of P-gp/BCRP inhibitors on the PK 
of binimetinib in vivo is unknown; therefore, it is recommended that P-gp and BCRP 
inhibitors are dosed with caution. 
 
 
5.2. Study rationale 
Triple negative breast cancer phosphoproteomic taxonomy 
Triple-negative breast cancer (TNBC) is an immunohistochemically-defined breast cancer 
subtype negative for ER, PR and HER-2 expression, with a dismal prognosis [24]. 
Approximately 80% overlap with the basal-like expression cluster [25-27]. Although several 
gene-centric approaches have been explored to classify TNBC [25,26, 28-33], no clear 
signatures have yet been reported that can be used for precision medicine treatment of 
individual patients. The extreme heterogeneity of this disease is illustrated by the fact of 
subgrouping the disease by paring the classifiers down to 29 of the most frequently mutated 
genes resulted in sets of mutations that are unique to individual patients [32]. Patient 
classification tools should not only accurately predict a patient’s clinical course but also 
provide therapeutic solutions. These results are difficult to achieve because of the nature of 
high-throughput studies. For instance, the fine-tuning of gene-expression patterns is 
technically and conceptually challenging. NGS studies have defined cancer subtypes by 
point mutations, which are actionable targets in several malignancies, but not in breast cancer 
[34]. Highly penetrant oncogenes are rarely found in breast cancers, except for HER-2 
amplification, which suggests that the "TNBC phenotype" is the result of coexisting, 
moderately penetrant, genetic changes. 
TNBC can be simplistically reduced to 2 clinical subtypes: tumours of those patients who 
relapse within 3 years after treatment for locoregional disease, and tumours of the patients 
who, with few exceptions, rarely relapse [24]. To understand further the TNBCs classified by 
the 2 patterns of relapse, we chose a less commonly used investigative approach (in-depth 
high-throughput phosphoproteomics), based on the following reasons: 
- 
1) proteins are the "effector" molecules of tumour cells [35-38]; and 
- 
2) the functional status of proteins is modulated through post-translational 
modifications (PTMs), of which phosphorylation is the most ubiquitous in 
cellular signaling events [35-38]. 
The investigation of tumour behaviour assessing gene-centric layers ignores he "upper-level" 
(proteome) regulatory events [39,40]; thus, interrogating the proteome, 


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and, in particular its PTMs, might provide a more accurate and functional assessment of 
tumour behaviour. We hypothesized that all the existing (genomic, transcriptomic, etc.) 
aberrations across different patients might coalesce into a discrete number of 
phosphorylation-driven patterns of activation of the proteome that would account for the 2 
main clinical subtypes of TNBC. These patterns would be driven by some of the ~500 
kinases encoded by the human genome, and the kinases might be targetable by any of the 
available >200 clinical-grade inhibitors. 
In this study, we aimed for 4 objectives: 
- 
1) to define the phosphoprofiles that could differentiate the relapsed cases from 
the other cases, 
- 
2) to identify the hyperactive kinases driving these profiles, 
- 
3) to translate this information into an application that could be usable in a 
routine clinical environment, and 
- 
4) to investigate the usefulness of driver kinases as therapeutic targets. 
 
 
Summary of our results 
We profiled a training set of 34 TNBC cases [half of them with early relapse and half of them 
long-term (>12 years) relapse free; all of them paired by classic prognostic factors] and 10 
TNBC cell lines. The cell lines were also classified by their ability to kill or not by distant 
metastatic spread nude mice (3 of them were classified as aggressive - MDA-MB-231, 
HS578T and MDA-MB-157 - whereas the other 7 were unable to kill the animals). We 
identified 15160 non-redundant phosphorylation sites. Of those, 702 showed significant 
regulation between the patients with and without relapse (159 were up-regulated in the 
patients with early relapse). Roughly 40% of these peptides were previously unknown, but 
the most important application is that we piggybacked this cluster of up-regulated 
phosphopeptides to their driving kinases. By using an in-house built bioinformatic algorithm 
(herein, KSEAS), we were able to pinpoint which kinases showed hyperactivation, and this 
activation was what caused the specific phosphoprofile of the aggressive cases. Twelve 
kinases were enriched in the phosphoprofile of the aggressive cases, and several of them 
overlapped with the kinases driving the profiles of the aggressive cell lines. 


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Figure 1: workflow summary. Tumor samples and cell lines lysates were analyzed by mass 
spectrometry after phospho-enrichment. A matrix of 1.5 million spectra was analyzed and ~700 
phosphosites were significantly regulated and splitting the relapsed cases versus the others. Driving 
kinases of this profile were predicted by an in house developed in silico algorithm. The hyperactivity 
of kinases accounting for the aggressive profiles was finally assayed in TMAs of an independent 
validation set by using conventional immunohistochemistry, turning these data into an easy 
application. 
 
 
 
We then performed a "mass-spectrometry-to-immunohistochemistry translation" step, in 
order to apply this information into the daily routine clinical practice. Six of the 12 kinases 
preserved independent prognostic factor (adjusted by conventional prognostic factors) in an 
independent validation set of N=173 early TNBC cases treated with surgery followed by 
adjuvant chemotherapy and >11 years follow-up. Finally, we used the six kinases to perform 
a "phosphosignature" and a taxonomy that could easily classify TNBC cases. The taxonomy 
showed two main patterns, one of them with 0/6 kinases activated that was associated to 
>93% long-term relapse-free. The second main pattern (1 or more out of six kinases with 
hyper- activity) gathered virtually all the relapsing cases. This second pattern could be further 
split into several sub-patterns characterized by activation of various kinases. Having 1 or 
more of the six kinases hyperactivated increased the risk of relapse by greater than 9-fold, 
adjusted by conventional prognostic factors. Such high risk justifies pharmacological 
interventions in this group beyond standard chemotherapy, whereas the remaining cases can 
be considered virtually cured. These six kinases were: KIT, PRKCE, P70S6K, PNKP, CDK6 
and ERK. 


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Figure 2: Kaplan-Meier curve from patients having one of more hyperactivated kinases. By 
applying our phosphosignature, we were able to detect a group of patients (0/6 kinases of the 
phosphosignature hyperactivated) that was virtually long-term cured. The patients with one or more 
hyperactive kinases had a greater than 900% higher risk of relapse. Of note, as it can be observed 
in the curve, most of the relapses occurred during the 5 years after loco-regional treatment. This 
independent validation set was constituted by N=173 patients. 
 
 
 
Another question of key importance is whether a kinase-based classification is more 
parsimonious than a genomic classification (based on the status of mutated or wild- type 
genes). Considering that our taxonomy considers 6 kinasees, and only 2 status per kinase are 
possible, a maximum of different patterns would be found among a random patient series. 
However, we found that our 173 patients fitted to just 31 unique different patterns; 4-6 
patients were found per pattern, and several patterns 
(33) were not found in any patient. The most frequent patterns involved CDK6 and/or ERK 
(co)activation. Interestingly, when the mutational status of the top 20-mutated genes across 
the series was overlaid to the kinase classification, we found that diverse mutational patterns 
"collapsed" into single kinase patterns; in other words, kinase-activation patterns are a more 
over-arching classification of TNBC, functionally speaking, than any classification type that 
can be achieving by combining sets of mutated genes. 


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Figure 3: convergence of diverse mutational patterns into discrete kinase patterns. This figure 
shows the status of the 6 kinases of the signature (colored if hyperactivated, empty if not) and the top 
20-mutated genes (colored if mutated, empty if wild-type) among 65 patients of the validation set (red- 
colored squares: relapsed patients; yellow-colored squares: non-relapsed in >12 years). It can be 
observed how each pattern defined by a unique combination of hyperactivated kinases agglutinates 
several different mutational patterns. 
 
 
 
Regarding the therapeutic potential, we tested all the two-by-two combinations of agents 
targeting the six mentioned kinases in the TNBC cell lines (15 different regimens). Across 
the 10 cell lines, the combinations were synergistic in 99.4% of the cases. The findings were 
validated in vivo. 


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Figure 4: Therapeutic role of the 6 kinases in the signature. We gathered compounds with activity 
against each of the six kinases and tested in vitro their synergism against the 10 TNBC cell lines in 
the panel. The left panel shows the results in MDA-MB-231, where all the combinations yielded 
synergy. There are clinical-grade available drugs against some of these targets, specifically CDK6, 
KIT and ERK. The right chart shows the tumor growth inhibition from MDA-MB231 tumor xenografts 
allowed to grow to 500mm3 and then exposed to different agents alone or in combination. As it can 
be observed, ERK inhibition plus CDK6 inhibition induces tumor regression, something that is not 
commonly observed in TNBC in absence of chemotherapy. 


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Figure 5: Therapeutic combination selection based on hyperactive kinases: a different model 
(MDA-MB-157, aggressive TNBC) was xenografted and different doublets were administered to the 
animals. As it can be observed, in this model with hyperactivation of KIT and CDK6, the combination 
of palbociclib and sunitinib was the most effective. Doublets where one of the agents targets one non- 
activated kinase are usually non-effective. 
 
 
 
Up to 6 different xenografts from TNBC cell lines and 4 patient derived xenografts (PDXs) 
were studied. The activity of the doublets directed towards the most active kinases always 
exerted great therapeutic efficacy. Doublets targeting non-active kinases lacked efficacy. Of 
note, palbociclib alone was not effective in any case in monotherapy, despite observing 
CDK6 activation. The implications of these observations are mainly two: 
- 
1) we have uncovered the top-codependent signaling axes for tumor survival with 
CDK6 in TNBC; 
- 
2) contrary to what was previously thought, there is a clinical niche for palbociclib 
in TNBC, but always following rationale combinatorial strategies as the one laid 
out here. 
 
 
Summary and considerations 
Our data constitute the first phosphoproteomic taxonomy of TNBC and constitutes a seminal 
manuscript in the field recently published in Nature Communications [1]. 
MDA-MB-157 weeks 
Vehicle 
GDC 
Suni8 nib 
Palbo 
Palbo + 
Sunit 


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This tool allows not only to find novel phosphosites and kinases that account for the biology 
of this disease but also to use this knowledge to accurately classify this disease for the first 
time. We were also able to build a signature that is sufficiently parsimonious and easy to 
measure in daily clinical routine samples embedded in paraffin. More importantly, this 
taxonomy is not only able to provide prognosis information: it also reveals the targets that a 
patient should have modulated with targeted inhibitors in case her taxonomy results classified 
her in the adverse prognosis subgroup. Thus, our taxonomy also provides therapeutic 
solutions. 
Next step is to validate the therapeutic results in humans. To this end, it is necessary to assess 
each of the possible 2-by-2 combinations individually, in advanced TNBC in order to detect 
which of them yield signals of activity. Although for some of these targets (i.e., PNKP, 
p70S6K) there are not clinical-grade available compounds, Pfizer has developed agents that 
effectively inhibit several of the kinases in the list, such as cKIT (sunitinib) or CDK6 
(palbociclib, which according to our preclinical data seems the cornerstone agent for the 
doublets). In addition, a recent partnership with Array Biopharma will allow Pfizer developing 
the MEK inhibitor binimetinib (effective against models with high ERK signaling output). 
Some previous studies have assessed the role of inhibitors against some of the former kinases 
but that have always been performed in monotherapy, without taking into account that the 
maintenance of aggressive TNBC biology, according to our results, requires the activity of 
several of these axes. Thus, it is unlikely to achieve a durable and/or meaningful benefit by 
using single-agent approaches. These agents have to be evaluated at least in 2-by-2 
combinations. 
Among all the combinations tested, CDK+MEK/ERK inhibition was the most powerful [1]. In 
order to set a proof of concept, and prior to launch a multi-arm trial with treatment allocation 
based on the status of each of the six kinases, we propose to launch a single-arm pilot trial 
testing palbociblib + binimetinib (CDK4/6 plus MEK inhibition) in advanced TNBC. Only 
patients within the highest quartiles of activation of CDK4/6 and/or ERK will be candidates 
for the trial. If no signal of activity is detected in this pilot trial, it is unlikely that the other 
combinations will be active. 
In addition, it would make unlikely as well to observe activity outside the subsets of patients 
with CDK4/6/ERK within the highest levels of activation. Although this requires real-time 
determination by a centralized pathology lab during the screening procedures, such biomarker 
enrichment will allow maximizing the chances of success. Real-time patient selection 
assumes a positivity of activated ERK, CDK4/6 or both in 42% of incident TNBC patients 
[1]. Patients candidates for this trial will have sent to CNIO their tumor sample. Two 
duplicates for each staining will be processed and acquired by an automated Ariol Scanning 
Machine after pathologic 


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evaluation. We will set-up a circuit that supports sample shipment/processing twice per week 
coupled with a response time (with final pathologic evaluation and H-score report 
communicated to the CRO) of less than 7 days, in order to avoid delays in the screening 
processes. Should this pilot trial be successful, other doublets may be tested and also different 
cut-off values might be used for trial selection in the future. 
Recent preclinical studies suggest that alternating schedules (continuous palbociclib 
administration plus 3 weeks on/1 off MEK inhibitor, or continuous MEK inhibitor plus 3 
weeks on/1 off palbociclib) are more effective and better tolerated in animals than continuous 
dosing of both agents alone [41]. We propose to use as starting dose that one found as RP2D 
in a similar study ongoing in lung cancer that has already completed the safety lead-in part 
(NCT03170206, data on file). In this study binimetinib 45 mg BID was the recommended 
phase II dose [42]. Another study with binimetinib and palbociclib in colorectal cancer 
(NCT03981614) uses the same starting doses of both drugs without a preceding dose-
escalation phase. A subsequent study in a larger number of patients in advanced melanoma 
showed that a significant number (61%) of patients had to undergo dose reduction to 30 
mg/BID because of the former side effects and others such as hypertension, decreased LVEF 
or elevated CPK [43]. Some of these toxicities partially overlap with those already registered 
for palbociblib, such as diarrhea and decreased blood counts. So we propose to start on 45 
mg/BID (binimetinib, continuous dosage) plus 100 mg daily (palbociclib, days 1-21/28). If 
tolerance is good (no side effects or at most tolerable grade 1 side effects) after a full cycle 
(28 days) patients will be allowed to escalate palbociclib to 125, according to the study 
investigators’ decision. Alternatively, patients with non-tolerable grade 2 events will resume 
at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-on/7-off. 
Depending on the side-effects, in case of clear relationship with palbociclib is established, 
palbociclib - instead of binimetinib – will be reduced to 75 mg daily. 
We propose a single-arm pilot trial testing palbociblib + binimetinib (CDK4/6 plus MEK 
inhibition) in advanced TNBC to evaluate preliminary activity of this combination by 
measuring 3-months PFS. 
 
 
5.3. Study objectives 
Primary objective: 
Primary objective of this study is to determine the 3-months PFS of palbociclib plus 
binimetinib in advanced triple negative breast cancer (TNBC), in patients with activation of 
ERK and/or CDK4/6. 


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Secondary objectives: 
- 
To determine response rate of the combination in advanced TNBC, in patients with 
activation of ERK and/or CDK4/6. 
- 
- 
To assess the safety of the combination in patients with advanced TNBC. 
Exploratory objective: 
- 
 
 
 
 
6. STUDY DESIGN 
6.1. Overall design 
This is an interventional, prospective, multicentric, single-arm, open label, phase IB clinical 
trial. 
The following scheme depicts the basic trial design. 
 
 
 
 
 
Patients diagnosed of metastatic or locally advanced non-curable TNBC that have received 
at least one treatment regimen for advanced disease will be candidates for the trial. A fresh 
tumor sample will be obtained in order to determine the phosphoproteomic profile of the 
tumor preferably obtained after last treatment or the most recent sample as possible (from 
metastatic site or first diagnosis according to sample availability) prior to study inclusion. If 
the patient has not a tumor sample available prior to study inclusion, the patient will not be 
allowed to participate in the study. Activation of the two kinases of interest will be determined 
centrally at CNIO. Only patients with scores above the upper quartile of at least one of them 
will be candidates (according to our series, approximately 40% of the patients are positive 
for CDK4/6 and/or ERK). 
CCI
CCI


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Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 
100 mg daily, 21 days on / 7days off, until disease progression. Tumor evaluation will be 
performed every 8 weeks. Study treatment will continue until disease progression, 
unacceptable toxicity, intercurrent serious disease, consent withdrawal or investigator´s 
decision. 
If treatment tolerance is good (no side effects or at most tolerable grade 1 side effects) after 
a full cycle (28 days) patients will be allowed to escalate palbociclib to 125, according to the 
study investigators’ decision. Alternatively, patients with non- tolerable grade 2 events will 
resume at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-
on/7-off. Depending on the side-effects, in case of clear relationship with palbociclib is 
established, palbociclib -instead of binimetinib – will be reduced to 75 mg daily. 
The study will be conducted at 8 Spanish sites and will enroll 25 patients. 
Study of immune resistance to study drugs 
In addition to evaluate the efficacy of study treatment, it is highly probable that in the long 
term the tumor will grow again, even if promising data on activity are found. It is necessary 
to investigate the reasons that lead to this event, in order to be able to design new therapies 
or therapeutic combinations that delay or prevent the development of resistance. 
To do this, we are working with murine models of breast cancer that mimic the therapeutic 
scenario of advanced breast cancer, but it is necessary to study and validate the possible 
findings in the clinical setting. 
Currently, we are trying to understand how different targeted therapies impact the immune 
system's ability to control tumor growth. 
 
 
 
 
 
 
 
 
 
 
CCI


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6.2. Primary endpoint 
- 
Three-months PFS. 
 
6.3. Secondary endpoints 
- 
Overall response rate. 
- 
 
- 
Number of patients experiencing each AE will be summarized by CTCAE grade 
to evaluate safety profile, according to NCI-CTC v 5 criteria. 
 
6.4. Exploratory endpoints: 
- 
 
 
 
 
7. PATIENT SELECTION 
7.1. Inclusion criteria 
Patients must meet the following criteria for study entry: 
1. Women >18 years-old. 
2. Diagnostic of metastatic or locally advanced non-resectable TNBC. 
3. Patient must have received a minimum of one and a maximum of two treatment lines 
for metastatic TNBC. Previous treatments can be of any nature (chemotherapy, 
immunotherapy, antiangiogenics, experimental therapy, etc.). 
Women with known BRCA1/BRCA2 germline mutations must have received a 
platinum based treatment or treatment with a PARP inhibitor. 
4. Patient must have experienced disease progression to the previous treatment line 
according to the RECIST 1.1 or iRECIST criteria. 
5. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study 
inclusion, preferably obtained after last treatment or the most recent sample as 
possible (from metastatic site or first diagnosis according to sample 
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availability). If the patient has not a tumor sample available prior to study inclusion, 
the patient will not be allowed to participate in the study. 
6. Ability to understand and signing of the written patient information/informed consent 
form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be 
performed centrally at CNIO. 
7. Ability to understand and signing the written PIS/ICF for study treatment eligibility. 
Signed informed consent form must be available before any study- specific procedure 
for the respective study parts may begin. 
8. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-
quartile according to published definitions [1]. 
9. ECOG performance status of 0-1. 
10. Evaluable disease according to RECIST 1.1 criteria. 
11. Life expectancy >24 weeks. 
12. Adequate bone marrow, liver and renal function as assessed by laboratory 
requirements conducted within 7 days before first study drug administration: 
a. Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte colony-
stimulating factor support within 2 weeks before the first study drug 
administration) 
b. Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks 
before the first study drug administration) 
c. Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the 
first study drug administration) 
d. Total bilirubin ≤ 2  the upper limit of normal (ULN). 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 
 ULN (≤ 5 times ULN for patients with liver metastases) 
f. Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the 
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13. Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments 
(excluding neuropathy which can be ≤ Grade 2, and alopecia). 
14. Patients must be able to take oral medications. 
15. Patients must have adequate cardiac function, defined as: 
a. Left ventricular ejection fraction (LVEF) > 50% as determined by 
echocardiogram or multigated acquisition scan (MUGA). 
b. QTc < 480 msec. 
16. Negative serum pregnancy test in women of childbearing potential (performed within 
7 days before the first treatment). Negative results must be available before the first 
study drug administration. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Pregnancy test will not be performed in postmenopausal women. 
17. Women of reproductive potential must agree to use adequate contraception when 
sexually active. This applies for the time period since the signature of the informed 
consent form and until at least 1 month after the last study drug administration. The 
definition of adequate contraception will be based on the judgment of the investigator 
and on local requirements. Acceptable methods of contraception include, but are not 
limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) 
diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-
based contraception. 
Zoledronic acid or denosumab started prior to trial registration is allowed, but in case 
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7.2. Exclusion criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Participants who have had chemotherapy, radiotherapy, or major surgery within 2 
weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. 
2. Patients that received during the metastatic disease setting any of the study drugs, 
palbociclib or binimetinib. 
3. Participants receiving any other study agents concurrently with the study drugs. 
Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to 
enrollment are allowed. 
4. Participants with symptomatic brain metastases that require chronic steroids. Patients 
with a history of brain metastases are permitted to enroll as long as they have been 
treated, are off of steroids, and have been stable for a minimum of one month on 
imaging. 
5. Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is the 
only location of the disease and it has not progressed. Patients with radiated single 
lesions that has progressed are allowed. 
6. Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug 
interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used 
with caution. 
7. Uncontrolled intercurrent illness including, but not limited to: 
a. ongoing or active infection requiring systemic treatment 
b. symptomatic congestive heart failure 
c. cardiac arrhythmia 
d. psychiatric illness/social situations that would limit compliance with 
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e. hypertension, defined as systolic blood pressure > 160 mmHg despite medical 
management 
f. myocardial infarction, unstable angina, coronary artery bypass grafting, 
coronary angioplasty, or stenting < 6 months prior to screening 
8. History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or 
Torsades de Pointes. 
9. History of Gilbert's syndrome. 
10. History of neuromuscular disorders that are associated with elevated CK (e.g. 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy). 
11. Previous or concurrent cancer except: 
a. cervical carcinoma in situ 
b. treated basal-cell carcinoma or squamous cell skin cancer 
c. any other cancer curatively treated > 3 years before the first study drug 
administration 
12. Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may 
interfere with the absorption of oral study medication in the opinion of the investigator. 
13. Pregnant women or breast-feeding. 
14. Known HIV-positive individuals on combination antiretroviral therapy. 
15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive 
hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C 
infection requiring treatment. 
a. Patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
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b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
16. Any condition that in the opinion of the investigator would interfere with evaluation 
of study treatment or interpretation of patient safety or study results, or inability to 
comply with the study and follow-up procedures. 
17. Participation in another clinical study with investigational medicinal products within 
4 weeks before the first study drug administration. 
18. Clinically active infections within 2 weeks before the first study drug administration. 
19. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first study 
drug administration. Patients receiving prophylactic antibiotics (e.g. for prevention of 
a urinary tract infection or to prevent chronic obstructive pulmonary disease 
exacerbation) are eligible. 
20. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 
the formulation. 
21. Current diagnosis of any retinal disorders including retinal detachment, retinal pigment 
epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or risk 
factors for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or 
hypercoagulability syndrome). 
22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher 
23. Major surgery, open biopsy or significant traumatic injury within 4 weeks before the 
first study drug administration (central line surgery is not considered major surgery). 
24. Renal failure requiring peritoneal dialysis or hemodialysis. 
25. Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results. 


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7.3. Randomization procedures 
Not applicable. Single arm, open-label study. 
 
 
7.4. Blinding procedures 
Not applicable. Open-label study. 
 
 
8. WITHDRAWAL CRITERIA 
8.1. Reasons for Withdrawal 
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. 
Reasons for withdrawal from the study may include but are not limited to the following: 
- 
Unacceptable toxicity. 
- 
If, in the investigator’s opinion, continuation of study would be harmful to the 
patient’s well-being. 
- 
Any toxicity requiring dose reduction below 30 mg/BID of binimetinib or 75 mg 
daily of palbociclib. 
- 
Any toxicity requiring dose interruption longer than 28 days to resolve to Grade 
1 or better. 
- 
Any other potential adverse reaction deemed sufficiently serious to warrant 
discontinuation of treatment by the investigator or his designated associate(s). 
- 
Any decrease in visual acuity, or symptomatic or asymptomatic retinal disorders 
including retinal detachment / retinal pigment epithelial detachment / serous 
retinopathy / retinal vein occlusion classified analog to CTCAE v.5 as Grade 
2 or higher. Based on the individual benefit risk assessment and after discussion 
with the sponsor, patient may interrupt treatment until recovery to at least Grade 
1 and then treatment may be resumed at one dose level below. 
- 
Grade 4 non-hematological toxicity (laboratory abnormalities of any grade will not 
be considered toxicity unless deemed clinically significant by the investigator). 
- 
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- 
Subject noncompliance that warrants withdrawal in the opinion of the 
investigator or sponsor. 
- 
Initiation of alternative anticancer therapy including another investigational 
agent. 
- 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with study treatment. 
If the administration of any of the study drugs has to be stopped, the site principal investigator 
will consult with the sponsor to withdraw the patient from the study (depending on the 
duration of treatment, if she has benefit, if the benefit is attributed to the suspended drug, etc.). 
 
 
8.2. Handling of Withdrawals 
The investigator will be requested to collect all patient data until she leave the study treatment. 
If a subject will be withdrawn by the Investigator or withdraws from the study, the 
Investigator will complete and report the observations as thoroughly as possible up to the 
date of withdrawal including the date of last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an adverse event, the Investigator will follow the subject 
until the adverse event has resolved or stabilized. 
All patients who are withdrawn from the study should complete protocol specified 
withdrawal procedures. 
 
 
8.3. Reserve and Replacement Subjects 
Patients who withdraw or are withdrawn from the study prior to completing the first cycle 
for reasons other than toxicity will be replaced. 
 
 
9. INVESTIGATIONAL PRODUCT 
9.1. Investigational product description 
9.1.1. Binimetinib 
9.1.1.1.Description 
Binimetinib is supplied as film-coated tablets in a dosage strength of 15 mg. 


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9.1.1.2. Packaging 
Binimetinib 15 mg are packaged in blister packs containing 12 tablets. Each pack contains 
168 tablets. 
9.1.1.3. Shipping, Storage and Disposal 
Binimetinib film-coated tablets should not be stored above 25°C and should be protected 
from light. 
Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements. 
9.1.1.4. Dosage and administration 
Patients will receive continuous binimetinib at 45 mg/BID. Binimetinib dose may be reduced 
to 30 mg/BID according to tolerance and investigator’s criteria. Dose re- escalation is allowed 
in case toxicities are recovered and no new events are present in at least 28 days. 
Patients should be encouraged to take their dose at approximately the same time each day. If 
the patient vomits or misses a dose, an additional dose should not be taken that day. The next 
prescribed dose should be taken at the usual time. 
Binimetinib tablets are intended for oral administration with water; tablets should be 
swallowed whole and should not be chewed. Binimetinib may be taken without regard to 
food. 
9.1.2. Palbociclib 
9.1.2.1.Description 
Palbociclib are opaque, hard capsules with 75, 100 and 125 mg of palbociclib. 
9.1.2.2. Packaging 
Palbociclib 75 mg, 100 mg and 125 mg are packaged in blister packs of 21 hard capsules. 
PVC/PCTFE/PVC/Al blister strip containing 7 hard capsules (one capsule per cell). Each 
carton contains 21 hard capsules (3 blister strips per pack). 
9.1.2.3. Shipping, Storage and Disposal 
Palbociclib does not require any special storage conditions. 
Any unused medicinal product or waste material should be disposed of in accordance with 
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9.1.2.4. Dosage and administration 
Patients will receive palbociclib on day 1 at 100 mg per day until day 21 followed by a 7-day 
rest. Palbociclib may be escalated to 125 mg per day according to tolerance and investigator’s 
criteria, starting in cycle 2. 
Patients should be encouraged to take their dose at approximately the same time each day. If 
the patient vomits or misses a dose, an additional dose should not be taken that day. The next 
prescribed dose should be taken at the usual time. 
Palbociclib should be taken with food, preferably a meal and should not be opened. Capsules 
are intended for oral administration with a glass of water; capsules should be swallowed 
whole and should not be chewed or crashed. 
 
 
9.2. Treatment duration 
Treatment will continue until disease progression, unacceptable toxicity, significant 
intercurrent disease, consent withdrawal or investigator´s decision. 
In case of discontinuation/interruption for toxicity of one of the 2 drugs of the combination 
therapy during treatment, the continuation of patient in the study with the other drug will be 
agreed with study sponsor (depending on the duration of treatment, if she has benefit, if the 
benefit is attributed to the suspended drug, etc.). 
 
 
9.3. Criteria for dose adjustments 
9.3.1. Palbociclib 
Dose modification of palbociclib is recommended based on individual safety and tolerability. 
Management of some adverse reactions may require temporary dose interruptions/delays, 
and/or dose reductions, or permanent discontinuation as per dose reduction schedules 
provided in Tables 1, 2, and 3. 
 
Palbociclib recommended dose modifications for adverse reactions 
 
Dose level 
Dose 
Recommended dose 
125 mg/day 
First dose reduction 
100 mg/day 
Second dose reduction 
75 mg/day* 
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Complete blood count should be monitored prior to the start of palbociclib therapy and at the 
beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. 
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, 
complete blood counts for subsequent cycles should be monitored every 3 months, prior to 
the beginning of a cycle and as clinically indicated. 
Absolute  neutrophil  counts  (ANC)  of  ≥1.000/mm3  and  platelet  counts  of 
≥50.000/mm3 are recommended to receive palbociclib. 
Palbociclib dose modification and management – Haematological toxicities 
 
CTCAE Grade 
Dose modifications 
Grade 1 or 2 
No dose adjustment is required. 
Grade 3a 
Day 1 of cycle: 
Withhold palbociclib, until recovery to Grade ≤2, and repeat complete blood 
count monitoring within 1 week. When recovered to Grade ≤2, start the next 
cycle at the same dose. 
Day 15 of first 2 cycles: 
If Grade 3 on Day 15, continue palbociclib at the current dose to complete 
cycle and repeat complete blood count on Day 22. 
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. 
Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 
neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles. 
Grade 3 ANCb 
(<1000 to 500/mm3) + 
Fever ≥38.5 ºC and/or 
infection 
At any time: 
Withhold palbociclib until recovery to Grade ≤2 
Resume at next lower dose. 
Grade 4a 
At any time: 
Withhold palbociclib until recovery to Grade ≤2. 
Resume at next lower dose. 
Grading according to CTCAE 4.0. 
ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit 
of normal. 
a Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical events, 
e.g., opportunistic infections). 
b ANC: Grade 1: ANC < LLN - 1500/mm3; Grade 2: ANC 1000 - <1500/mm3; 
Grade 3: ANC 500 - <1000/mm3; Grade 4: ANC <500/mm3. 
 
Table 3. Palbociclib dose modification and management – Non-haematological 
toxicities 
 
CTCAE Grade 
Dose modifications 


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Grade 1 or 2 
No dose adjustment is required. 
Grade ≥3 non-haematological toxicity (if persisting 
despite medical treatment) 
Withhold until symptoms resolve to: 
- Grade ≤1; 
- Grade ≤2 (if not considered a safety risk for 
the patient) 
Resume at the next lower dose. 
Grading according to CTCAE 4.0. 
CTCAE=Common Terminology Criteria for Adverse Events. 
 
Interstitial Lung Disease/Pneumonitis 
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with 
cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, including palbociclib when taken in 
combination with endocrine therapy. 
Across clinical trials, 1.4% of palbociclib -treated patients had ILD/pneumonitis of any grade, 
0.1% had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of 
ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported. 
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (eg, hypoxia, 
cough, dyspnea). In patients who have new or worsening respiratory symptoms and are 
suspected to have developed ILD/pneumonitis, interrupt palbociclib immediately and 
evaluate the patient. Permanently discontinue palbociclib in patients with severe ILD or 
pneumonitis. Permanently discontinue palbociclib in patients with severe 
interstitial lung disease (ILD)/pneumonitis. 
9.3.2. Binimetinib 
For patients receiving 45 mg binimetinib twice daily, the recommended reduced dose of 
binimetinib is 30 mg twice daily. Dose reduction below 30 mg twice daily is not 
recommended. Therapy should be discontinued if the patient is not able to tolerate 30 mg 
orally twice daily. 
If the adverse reaction that resulted in a dose reduction is under effective management, dose 
re-escalation to 45 mg twice daily may be considered. Dose re- escalation to 45 mg twice 
daily is not recommended if the dose reduction is due to left ventricular dysfunction or any 
Grade 4 toxicity. 
Recommended dose modifications for binimetinib for selected adverse 
reaction. 


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Recommended dose modifications for binimetinib for other adverse reactions. 
 
 
 
 
9.4. Accountability 
The trial medication will be sent directly from the sponsor to the investigator's site preceded 
by the Regulatory Green Light. The medication is to be used exclusively in the clinical trial 
according to the instructions of this trial protocol. 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the delivery, drug expiration date, and sign the Receipt of Shipment Form 
provided. The Receipt of Shipment Form should be faxed or emailed to the sponsor and also to 
CRO. The original form will preliminarily be retained at the site and will be collected at the 
next monitoring visit by the monitor and stored in the Centre File of the TMF at CRO. A copy 
remains in the Investigator File at the site. In case of shipment problems the Investigator or 
designee shall contact the CRA as soon as possible. 
A Drug Accountability Record will be provided for the trial medication. The record must be 
continuously updated and contain the dates, quantities and compounds of drugs received, 
medication identification number(s), the patient identification number to whom the trial 
medication was dispensed, date and quantity of medication dispense and date and number of 
returned tablets/blisters/boxes, as well as the initials of the dispenser. 


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Trial medication will be monitored by the CRA at the respective hospital pharmacy prior to 
destruction after having completed a final inventory. Local or institutional regulations may 
require immediate destruction of the study drug used for safety reasons, e.g., cytotoxicity or 
to maintain the storage capacity and functionality of the storage at the site. In these cases, it 
may be acceptable to destroy it by the research staff, including partially used and empty vials, 
dispensed before a monitoring inspection, if the verification of original documents of empty 
boxes that indicate the information of batch number and dispensing date to the patient on the 
label. This documentation will be verified against the quantity shipped, dispensed, returned 
and destroyed. 
Prior to the destruction a final trial medication reconciliation statement must be completed. 
Drug supplies will be destroyed according to the legal requirements in Spain. 
All trial medication inventory forms must be made available for inspection by a Sponsor-
authorized representative or designee and regulatory agency inspectors. The Investigator is 
responsible for the accountability of all used and unused study supplies at the site. 
9.5. Auxiliary Medicinal Products 
Not applicable 
9.6. Concomitant medication 
Overall, the risk for binimetinib to be a cause of or be affected by significant drug- drug 
interactions is predicted to be low. However, given the predominant role of UGT1A1 in the 
metabolism of binimetinib, special consideration should be taken for co-administration of 
drugs that are UGT1A1 inhibitors or inducers, and administration of binimetinib to patients 
with low UGT1A1 activity. 
Binimetinib has been shown to be a substrate for P-gp and BCRP in vitro. The impact of P-
gp/BCRP inhibitors on the PK of binimetinib in vivo is unknown; therefore, it is 
recommended that P-gp and BCRP inhibitors are dosed with caution. 
The following concomitant treatments are allowed: 
1. Zoledronic acid or denosumab for bone metastases, started at least 28 days prior to 
enrollment. 
2. Low dose corticosteroids (with or without anti-seizure drugs) - equivalent to 10mg 
prednisone per day, although this situation can be addressed in a case- by-case basis 
through discussion with the trial coordinators, that has been stable for more than 28 days 
for brain metastases currently non-uncontrolled. 
3. Supportive measures such as pain drugs, eritropoetin, antiemetics, antidiarrhea, etc 
- according to current standards of care. 


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4. Appropriate treatments for intercurrent conditions as long as not deemed severe 
enough by the investigator to justify coming off trial (i.e., antibiotics for an intercurrent 
infection, etc). 
9.7. Prohibited drugs 
Concomitant therapy with the following medication is prohibited: 
- 
Concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are 
not permitted for 2 weeks prior to start of study treatment or during the study. 
- 
Concomitant use of moderate and weak CYP3A4 inducers should be avoided. 
- 
Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John’s 
Wort) are not permitted during the study. 
- 
Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not 
permitted during the study. 
- 
Patients may not receive other investigational treatment or other approved anti-
tumor therapy while on this protocol. 


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10. STUDY SCHEDULE 
 
Procedure 
Screening 
(-28 to -1) 
Cycle 1 and 2 
(± 2 days) 
Cycle 3+ 
(± 2 days) 
EOT / Early 
withdrawal 
Safety FU visit 
D1 
D8 
D15 
D22 
D1 
D15 
Informed consent 
X 
Demographic data 
X 
Selection criteria 
X 
Medical history1 
X 
Physical exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological examination 
X 
X 
X3 
X 
X3 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
ECOG PS 
X 
X 
X 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG (qTC) 
X 
If clinically indicated 
LVEF (ECHO/MUGA)5 
X 
X 
X5 
X 
X 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, fT3 y fT48 
X 
X 
X 
X 
X 
Urinalysis9 
X 
X 
X 
X 
X 
Coagulation10 
X 
X 
X 
X 
X 
Serology11 
X 
If clinically indicated 
Serum pregnancy test 12 
X 
X 
X 
X 
X 
Archival and fresh tumor biopsy13 
X 
Blood sample (correlative studies) 18 
X 
X 
Tumor sample (correlative studies) 19 
X 
Tumor evaluation (PET-CT/CT/MRI) 
X 
X14 
X14 
X 
Binimetinib administration 
X 
X 
X 
X 
X 
X 
Palbociclib administration13 
X 
X 
X 
X 
X 
X 
Adverse events16 
X 
Concomitant medications 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
1. Medical history, including prior treatments for BC. 


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2. A complete physical exam will be carried out during the screening visit and thereafter targeting symptoms in subsequent study visits. 
3. Only cycle 1. 
4. Vital Signs: pulse, blood pressure and temperature. 
5. ECHO/MUGA will be performed before start binimetinib treatment, 1 month after the start of treatment and every 3 months thereafter. 
6. Hematology include absolute red blood cell count (RBC), hemoglobin, hematocrit, platelet count, white blood cell count (WBC), with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils). Hematology will be performed in the 14 days previous to start study treatment. 
7. Alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), total bilirubin; blood urea/blood urea nitrogen (BUN), 
creatinine: creatinine clearance; glucose, albumin, cholesterol, triglyceride, phosphorus, lactate dehydrogenase (LDH), total protein, uric acid, creatinine phosphokinase 
(CPK); Sodium, potassium, calcium, magnesium, chloride, bicarbonate (HCO3). Biochemistry will be performed in the 14 days previous to start study treatment. 
8. Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine system. In 
the 14 days previous to start study treatment. 
9. Urinalysis: bilirubin, blood, glucose, ketones, PH, protein specific gravity, colour and appearance. Dipstick test every cycle. Additional analyses will be done at investigator 
criteria in case of abnormal results. Urinalysis will be performed in the 14 days previous to start study treatment. 
10. 
Coagulation tests: prothrombin time, APTT and INR. In the 14 days previous to start study treatment. 
11. Serology: hepatitis B surface antigen, hepatitis C antibody, HIV antibody. In the 14 days previous to start study treatment and if clinically indicated thereafter. 
12. Serum pregnancy test only pre-menopausal female subjects of childbearing potential. At study entry, every 4 weeks during the study treatment and at the end of study 
treatment. 
13. All formalin-fixed, paraffin-embedded (FFPE) tissue samples block and one hematoxylin and eosin (H&E) stained tumor slide, both obtained in the 15 days before patient 
inclusion in the study, will be sent to CNIO in order to determine positivity of ERK and/or CDK4/6, preferably obtained after last treatment or the most recent sample as 
possible (from metastatic site or first diagnosis according to sample availability). 
14. Tumor evaluation will be performed every 8 weeks until confirmed PD. 
15. 21 days-on/7 days-off. 
16. This applies to all non-serious AEs and SAEs that occur at any time during the administration of the study drug and up to 30 days after end of treatment. 
17. Concurrent medications administered within the 28 days preceding day 1. 
18. Blood sample: two CPT tubes of 7 ml will be obtained at baseline visit before treatment administration, at C2D1 and at disease progression (a 2 weeks window is allowed 
from confirmation of disease progression). 
19. An image-guided biopsy will be done upon progression. The biopsy is allowed within 4 weeks after the confirmation of disease progression and in any case before starting the 
next line of treatment. 


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10.1. Pre-study visit (screening) 
For patient registration, site staff should complete the registration form at the eCRF. The CRO will 
send confirmation e-mail of registration of the patient's number assigned within 24 hours from 
receipt of the information. 
The following procedures will be performed within 28 days prior to registration: 
 Informed consent for in order to determine positivity of ERK and/or CDK4/6 for study 
treatment eligibility will be obtained prior to any study procedures being performed. Each 
participant will be given a copy of the signed informed consent forms (ICF). The ICF must 
be approved by an Independent Ethics Committee (IEC). Only patients ERK and/or 
CDK4/6 positive will be invited to participate in the study and sign the ICF for study 
treatment eligibility 
 Tumor sample (FFPE block and H&E slide) for ERK and CDK4/6 analysis. ERK and 
CDK4/6 analysis will be performed at CNIO. Preferably obtained after last treatment or 
the most recent sample as possible (from metastasis or first diagnosis according to sample 
availability) prior to study inclusion. If the patient has not a tumor sample available prior 
to study inclusion, the patient will not be allowed to participate in the study 
 Review selection criteria 
 Demographics 
 Tumor evaluation: PET-CT, CT and/or MRI 
 Complete medical history (including prior treatments for breast cancer) 
 Physical examination will be conducted on each patient for a review of systems and 
determination of any concurrent symptoms or conditions prior to the first dose of study drug 
 Ophthalmological examination 
 Vital Signs: pulse, blood pressure and temperature 
 Height, weight 
 ECOG performance status 
 12-lead ECG, including qTC 
 ECHO / MUGA 
 Concurrent medications: Record all concurrent medications administered within the 28 
days preceding Day 1 
 
The following procedures should be performed within 14 days prior to registration: 


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 Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white 
blood cell (WBC) count, and percent and absolute differential count (neutrophils, 
eosinophils, lymphocytes, monocytes, basophils). 
 Biochemistry: (glucose, urea/BUN, creatinine, sodium, potassium, magnesium, chloride, 
bicarbonate, calcium, total protein, uric acid, albumin, cholesterol, triglyceride, serum total 
bilirubin, alkaline phosphatase, LDH, CPK, AST, ALT and GGT). 
 Coagulation: basic coagulation study following each center standards, including 
prothrombin time, aPTT and INR. 
 TSH, fT3 y fT4. Free T3 and free T4 will only be measured if TSH is abnormal. 
 Urinalysis: bilirubin, blood, glucose, ketones, PH, protein specific gravity, colour and 
appearance. 
 Serologies: hepatitis B surface antigen, hepatitis C antibody, HIV antibody. 
 
The following procedure should be performed within 7 days prior to Day 1: 
 Pregnancy Testing. Pre-menopausal women of childbearing potential only are 
required to have a negative serum pregnancy test. 
10.2. Study treatment visits 
Study patients will be evaluated weekly during the first 2 months and every 2 weeks thereafter. 
The following procedures will be performed during study treatment: 
 Tumor evaluation: PET-CT, CT and/or MRI (every 8 weeks) 
 Physical examination: will be performed at screening and thereafter targeting symptoms 
in subsequent study visits 
 Ophthalmological examination: Ask patient for changes in vision at every visit. If change 
in vision is reported, an ophthalmological examination must be performed preferably 
within 3 days. Ophthalmologic examination will be performed weekly during first cycle, 
biweekly during second cycle and every 4 weeks thereafter. Particularly for patients who 
experience any decrease in visual acuity, or symptomatic or asymptomatic retinal disorders 
including retinal detachment / RPED / serous retinopathy / retinal vein occlusion (Grade 1 
analog to CTCAE v.5) have to undergo ophthalmologic examinations on day 1 of every 
cycle. 
 Weight: in all study visits 


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 Vital Signs: pulse, blood pressure and temperature; every week during first two cycles, 
and days 1 and 15 of each cycle thereafter 
 ECOG performance status (day 1 of every cycle) 
 12-lead ECG: if clinically indicated 
 ECHO/MUGA: before start binimetinib treatment, 4 weeks after the start of treatment and 
every 12 weeks thereafter. 
 Hematology: every week during first two cycles, and days 1 and 15 of each cycle thereafter 
 Biochemistry: every week during first two cycles, and days 1 and 15 of each cycle 
thereafter. Safety laboratory tests can be collected up to 2 days prior to drug administration. 
 TSH, fT3 y fT4: day 1 of every cycle. Free T3 and free T4 will only be measured if TSH is 
abnormal. 
 Coagulation: day 1 of every cycle 
 Urinalysis: day 1 of every cycle 
 Serologies: if clinically indicated 
 Pregnancy Testing: every 4 weeks (day 1 of each cycle). Pre-menopausal women of 
childbearing potential only 
 Adverse events: in all study visits 
 Concomitant medications: in all study visits 
 Blood sample: two CPT tubes of 7 ml will be obtained before treatment 
administration at D1C1 and D1C2. 
10.3. End of treatment / early withdrawal 
The following procedures will be performed at end of treatment / early withdrawal visit: 
 Tumor evaluation: PET-CT, CT and/or MRI, if patient stops study treatment for any 
reason other than disease progression 
 Physical examination 
 Ophthalmological examination 
 Weight 
 Vital Signs 
 ECOG performance status 
 12-lead ECG: if clinically indicated 
 ECHO/MUGA 


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 Hematology 
 Biochemistry 
 Serology 
 TSH, fT3 y fT4 
 Coagulation 
 Urinalysis 
 Pregnancy test 
 Adverse events 
 Concomitant medications 
 Blood sample: two CPT tubes of 7 ml will be obtained at disease progression (a 2 weeks 
window is allowed from confirmation of disease progression). 
 An image-guided biopsy will be done upon progression. The biopsy is allowed within 4 
weeks after the confirmation of disease progression and in any case before starting the next 
line of treatment. 
10.4. Safety follow-up visit 
The following procedures will be performed at Safety follow-up visit at day 30 and 6 months 
after last study dosage: 
 Physical examination 
 Ophthalmological examination 
 Weight 
 Vital Signs 
 ECOG performance status 
 12-lead ECG: if clinically indicated 
 ECHO/MUGA 
 Hematology 
 Biochemistry 
 TSH, fT3 y fT4 
 Coagulation 
 Urinalysis 
 Pregnancy test 
 Adverse events 
 Concomitant medications 


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11. ASSESSMENT OF SAFETY / ADVERSE EVENTS 
Safety information should be collected in clinical studies in an efficient and consistent way. 
Adverse events must be identified and notified rapidly to identify possible risks to patients and 
satisfy regulatory requirements for notification of adverse events. 
11.1. Definitions 
11.1.1. Adverse event (AE) 
An AE is any undesired experience that occurs in a patient participating in clinical research that 
is associated in time with the use of a medicinal product, whether or not it is considered to be 
related to the investigational products. Therefore, an adverse event can be any unintentional 
unfavorable sign (including an anomalous laboratory result), symptom or disease that is associated 
in time with the use of a medicinal product, whether or not it is considered to be related to the 
product. Pre-existing diseases that worsen during the study shall be notified as Adverse Events. 
AEs include pre- or post-treatment events that occur as a result of study procedures (e.g. invasive 
procedures or modification of the patient’s previous medication). 
11.1.2. Serious adverse event (SAE) 
A SAE is an undesired medical experience that, at any dose: 
 Results in death. 
 Is life-threatening: (NOTE: The term "life-threatening" refers to the fact that, according 
investigator criteria, the patient is at risk of death as a result of this event. Nevertheless, 
this definition does not consider the situation in if the AE had been more severe, patients 
had been in an immediate risk of death). 
 Results in the patient’s hospitalization or prolongs a previous hospitalization (NOTE: In 
general, hospitalization means that the patient has remained [at least 24 hours] in the 
hospital or emergency room. Complications that occur during a hospitalization are AEs. If 
a complication prolongs hospitalization or satisfies any of the other criteria for seriousness, 
then the event will be considered SAE. When any doubt exists as to whether a 
"hospitalization" has taken place or was necessary, the AE will be considered serious. The 
hospitalization to implement scheduled treatment of a disease present before the subject 
entered the study and that has not worsened with respect to baseline is not considered an 
AE) Hospitalizations for social reason are not consider an AE. 
 It produces disability or incapacity (NOTE: Disability refers to an important alteration in 
a person’s capacity to carry out his or her own daily living tasks, not minor clinical 
ailments such as headaches, nausea, vomiting, diarrhea, flu or accidental injuries (such as 
a sprained ankle), that can interfere with the functions of daily life, but do not alter them in 
an important way). 
 It originates a congenital anomaly or birth defect. 
 It is medically important, meaning medically important adverse event that the investigator 
regards as serious that did not strictly meet the criteria above but may have jeopardized the 
patient or required intervention to prevent one of the outcomes listed above. 


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11.1.3. Additional considerations 
Alterations in laboratory parameters (hematology, biochemistry or urine analysis), as well as 
anomalous results of other studies (such as ECGs, radiology, measurements of vital constants), 
including those that deteriorate in relation to baseline, should be recorded as AEs or SAEs if, in the 
medical and scientific opinion of the investigator, they are clinically relevant. 
On the contrary, clinically significant alterations in safety parameters that are associated with the 
study disease are not characterized as AEs or SAEs unless the investigator thinks that they are 
more serious than would be expected considering the state of the patient. 
Lack of efficacy (i.e., disease progression) is a disease-related event and should not be classified 
as a SAE. Death as a result of disease progression is also excluded from the definition of SAEs. 
11.1.4. Adverse reaction 
Any harmful and non-intended response to a drug including adverse reactions derivative from any 
use apart from terms of commercialization authorization, abuse, and medication error. It exists a 
confirmed causality relationship with the administered medication. 
11.2. Characteristics of an adverse event 
11.2.1. Seriousness 
See Serious Adverse Event definition (11.1.2 Serious Adverse Event (SAE)). 
11.2.2. Causality assessment 
The investigator has the obligation to establish the relation of causality between the investigational 
product administration and the adverse event(serious or not). "A reasonable possibility" is 
proposed to define cases in which there are facts/proof or arguments suggesting a causal relation, 
more than a relation that cannot be excluded. The investigator will use his or her clinical judgment 
to determine the relation. Alternative causes, such as the natural history of underlying diseases, 
concomitant treatment, other risk factors and the temporal relation between the event and the 
investigational drug will be considered and investigated. The investigator will also consult the 
investigator's brochure/summary of product characteristics in making the evaluation. 
There may be situations in which a SAE occurs and the investigator has only minimal information 
to include in the initial report to the Sponsor. Nevertheless, it is very important that the investigator 
evaluate the causality of each event before the initial transmission of data to the Sponsor. The 
investigator can change his or her opinion about causality based on the information that appears 
during follow-up, which is why the SAE report may have to be modified. The evaluation of 
causality is one of the criteria that determine whether a case is compliant or not with the criteria of 
notification of the Health Authorities. 


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11.2.3. Expectedness 
An unexpected adverse reaction is any untoward and unintended response that is related to study 
drug at any dose that is not described in the applicable product information (eg, investigators 
brochure for an unauthorized investigational medicinal product or summary of product 
characteristics for an authorized product). 
APICES/Sponsor will classify a Serious Adverse Reaction as expected or unexpected according 
to the Reference Safety Information collected in investigator brochure or summary of product 
characteristics of investigational product, as appropriate. 
11.2.4. Severity 
The severity of any AEs will be graded using the CTCAE vs 5.0 (see Annex 4). If the CTCAE has 
no code that matches, the following guide should be used: 
Grade Description 
0 
No adverse event 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only 
2 
Moderate; minimal, local or noninvasive intervention indicated 
3 
Severe  or  medically 
significant 
but  not  immediately 
life-threatening; 
hospitalization or prolongation of hospitalization indicated 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to adverse event 
 
Grading of AEs is based on specific clinical criteria that will require evaluation by the study site 
Investigator. Should an AE stop and then restart, it will be considered two separate events and the 
severity assessed as described above. 
 
11.3. Reporting procedures 
11.3.1. Reporting of adverse events (AEs) 
The investigator will try to obtain information about any adverse events that have occurred in all 
visits by examining or directly interrogating the patient. All information referring to adverse 
events must be recorded in the respective section of the CRF. AEs should be recorded according 
CTCAE v5.0. All adverse events that occur during the period comprehended from the start of 
study treatment to 30 days after last dose of the investigational products will be recorded. When 
one or more signs or symptoms correspond to a disease, the main diagnosis or syndrome will be 
notified. All adverse events will be followed until resolution or stabilization, or until it is 
determined that the study treatment or the patient’s participation in the study has not been the 
cause. All adverse events still present at the end of the study period will be monitored until their 
final outcome is determined. 


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11.3.2. Reporting of serious adverse events (SAEs) 
The investigator will notify CRO of all serious adverse events that occur during the period 
comprehended from the start of study treatment to 30 days after last dose within 24 h of receiving 
knowledge of the same or, at the latest, on the next working day. 
ATT. SAFETY DEPARTMENT 
e-mail: 
The investigator will collect information about the SAE on the respective form. At least these four 
elements are mandatory always to report any adverse event must include the following: 
 
Name or any identifier of a reporter 
 
Subject ID number 
 
At least one suspect drug: current dose, route, dates 
 
Adverse Event information: 
o Adverse Event Term Seriousness Criteria 
o Causality assessment 
11.3.3. Reporting of serious adverse events (SAEs) to Health Authorities 
The sponsor is responsible for notifying to the Regulatory Health Authorities according to 
applicable regulations of all suspected unexpected serious adverse reactions and which occurred 
in the clinical trial. This communication shall be made within the time limits established by 
legislation. 
 
 
11.3.4. Follow-up of AEs and SAEs 
After the initial notification of an AE or SAE, the investigator is required to follow up each case 
and obtain more data on the patient’s state. All the AEs and SAEs documented in previous visits 
must be reviewed in subsequent visits. All AEs and SAEs must be monitored until their resolution. 
This is applicable to all the patients, including those who withdraw early. 
 
 
11.3.5. AEs or SAEs that occur after the study ends 
Post-study AEs or SAEs are defined as any event that occurs outside the Follow-up period of 
detection defined in the protocol. The investigator is not required to actively seek out AEs or SAEs 
in patients who have participated in the clinical trial in the past. Nevertheless, if the investigator 
comes to know of the existence of any AE or SAE, including the death of the patient at any time 
after a patient has left the study, and this AE or SAE is considered related to the study drug, the 
investigator must notify the sponsor promptly. 
CCI


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11.3.6. Events of special interest 
Binimetinib is an investigational drug and current knowledge of the AEs associated with this 
compound is limited. As with any new chemical entity, there is always potential for unexpected 
AEs, including hypersensitivity reactions. 
The most frequently reported AESI for binimetinib groupings (≥ 20.0% of patients in either 
population) were retinopathy excluding RVO, muscle enzyme/protein changes, liver function test 
abnormalities and rash. Grade 3/4 AESIs reported for ≥ 5.0% of patients in either population were 
in the groupings of liver function test abnormalities, muscle enzyme/protein changes and 
hypertension. 
Ocular AESIs 
Retinopathy excluding RVO events were the most common AESI grouping reported. Retinopathy 
excluding RVO events reported in > 5.0% of patients were vision blurred, retinopathy, subretinal 
fluid, retinal detachment, visual field defect and macular edema. Events in the RVO grouping 
were uncommon. 
Muscle Enzyme/Protein Changes and Myopathy/Rhabdomyolysis-Related AESIs 
Muscle enzyme/protein changes were frequently observed, although Grade 3/4 events were less 
common in patients. All patients with an event in the muscle enzyme/protein changes grouping 
had at least 1 event reported under the PT of blood CK increased. No other muscle enzyme/protein 
changes by PT were reported in > 5.0% of patients in either population. 
Events in the myopathy grouping were reported; few patients had a Grade 3/4 event. The myopathy 
event reported in > 5.0% of patients in either population by PT was myalgia. 
Events in the rhabdomyolysis grouping were uncommon. 
Symptomatic muscle-related AEs reported in the myopathy and rhabdomyolysis groupings that 
occurred within 15 days before to 30 days after the worst laboratory CK elevation were analyzed. 
Around 6% of patients with a worst post-baseline laboratory CK value ≥ Grade 1 had at least one 
symptomatic muscle-related AE reported. 
Liver-related AESIs 
Events in the liver function test abnormalities grouping were reported (between 20-26%) and about 
half of the patients with an event in the liver function test abnormalities grouping experienced at 
least 1 Grade 3/4 event. The events in the liver function test abnormalities grouping reported in > 
5.0% of patients were GGT increased, ALT increased and AST increased. 
Events in the hepatic failure grouping were uncommon. 
Dermatologic-related AESIs 
Rash events are frequently reported with single-agent binimetinib treatment. 


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Events in the skin infections grouping were reported; few patients had a Grade 3/4 event. The skin 
infection events reported in >2.0% of patients in either population by PT were folliculitis and 
cellulitis. 
Nail disorder events were infrequently reported; no patients had a Grade 3/4 event in this grouping. 
Severe cutaneous adverse reactions were rarely observed. No severe cutaneous reaction events 
were Grade 3/4 in severity. These events were reported under the PTs of dermatitis exfoliative, 
erythema multiforme, toxic skin eruption, dermatitis bullous and erythema multiforme. 
Hemorrhage AESIs 
Hemorrhage events were reported; Grade 3/4 events were less common. The hemorrhage events 
reported in >2.0% of patients in either population were hematuria, rectal hemorrhage and 
hematochezia. 
Peripheral Edema AESIs 
Peripheral edema events were reported in 11-16% of patients; few patients had a Grade 3/4 event. 
The peripheral edema event reported in >2.0% of patients was edema peripheral. 
Hypertension AESIs 
Hypertension events were reported in 9-12% of patients and about half of the patients with an 
event in the hypertension grouping experienced at least 1 Grade 3/4 event. The PT of hypertension 
was the most frequently reported event (> 2.0% of patients) in the grouping. 
Cardiac-related AESIs 
Left ventricular dysfunction events were reported in 6-8% of patients, with few patients 
experiencing a Grade 3/4 event. The most frequently reported event was ejection fraction decreased. 
Bradycardia events were infrequently reported (around 1%); none were reported as Grade 3/4. 
The most frequently reported event was sinus bradycardia. 
Venous thromboembolism AESIs 
Venous thromboembolism events were reported in 2-4% of patients, with few patients (around 
1%) experiencing a Grade 3/4 event. The most frequently reported event was pulmonary 
embolism. 
Pneumonitis AESIs 
Events in the pneumonitis grouping were uncommon and were reported in 2 patients (interstitial 
lung disease and pneumonitis). 


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11.3.7. Pregnancy 
The investigator must report all pregnancies during the study, including follow up outcomes, 
within 24 hours of awareness. 
Each pregnancy must be reported on a Pregnancy Report Form within 24 hours of becoming aware 
of the pregnancy. Pregnancy is not an AE, and therefore does not need to be reported as an AE 
unless there is a suspicion that the study drug may have interfered with the effectiveness of a 
contraceptive medication. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Report Form, reported 
as an SAE on the SAE Report Form (e.g., maternal serious complications, therapeutic abortion, 
ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) and reported to the 
Sponsor within 24 hours. Hospitalization for normal delivery of a healthy newborn should not be 
considered an SAE. 
Any exposure during breast feeding must also be reported. 
11.3.8. Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental or 
Occupational Exposure 
 Abuse: is the persistent or sporadic, intentional excessive use of the study treatment which 
is accompanied by harmful physical or psychological effects. 
 Misuse: medicinal product is intentionally and inappropriately used not in accordance with 
the authorized/approved product information. 
 Medication error: is any preventable incident that may cause or lead to inappropriate study 
treatment use or patient harm while the study treatment is in the control of the health care 
professionals or patients. Such incident may be due to health care professional practice, 
product labeling, packaging and preparation, procedures for administration, and systems, 
including the following: prescribing, order communication, nomenclature, compounding, 
dispensing, distribution, administration, education, monitoring, and use. 
 Overdose: is a deliberate or accidental administration of study treatment to a study patient, 
at a dose greater than that which was assigned to that patient per the study protocol and 
under the direction of the Investigator. Study investigator should notified overdose 
immediately, and the patient should be observed closely for AEs. Associated AEs should 
be treated and monitored by the Investigator. 
 Accidental /Occupational exposure: is the unintentional exposure to a study treatment as 
a result of one’s professional or non-professional occupation, or accidental exposure to a 
non-professional to whom exposure was not intended (i.e., study product given to wrong 
patient). 
Reporting Special Situations: All occurrences of abuse, misuse, medication error, overdose, and 
accidental or occupational exposure of study treatment must be reported on a Serious Adverse 
Event Report Form to the Sponsor within 24 hours of awareness regardless of whether or not an 
AE or SAE has occurred. If the abuse, misuse, medication error, overdose, or accidental / 
occupational exposure is associated with an AE, an SAE Report Form must also be submitted to 
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12. STATISTICAL CONSIDERATIONS 
12.1. General considerations 
A comprehensive statistical analysis plan (SAP) will be prepared before database closure. 
Continuous variables will be described by the mean, median, standard deviation, minimum and 
maximum. Categorical variables will be shown as absolute and relative distribution of frequencies 
and percentage. Also a 95% CI will be presented if this information is considered relevant to 
describe a singular variable. 
12.2. Sample size 
Patients with advanced TNBC that have received and experienced disease progression to the 
first/second line treatment are candidates to this trial. Patients that have received three or more 
treatment lines would be excluded. 
Sample size has been calculated based on the primary objective of this clinical trial, to determine 
3-months PFS of the palbociclib plus binimetinib in advanced TNBC, in patients with activation 
of ERK and/or CDK4/6. 
Previous studies shown that the 3-months PFS in patients receiving chemotherapy in advanced 
TNBC was about 25% [44]. To accept the treatment efficacy we will assume that the 3-months 
PFS in patients treated with palbociclib plus binimetinib will be at least 50%. An overall sample 
size of 25 patients achieves 80% power at a 0.05 significance level (alpha) to accept the efficacy 
of palbociclib plus binimetinib in advanced TNBC. An accrual time of 12 months and follow-up 
time of 12 months (treatment and follow-up time) and 2 sided test have been considered in the 
sample size calculation. 
Sample size has been calculated with one-sample survival method [45]. 
12.3. Analytical Populations 
Safety population consists of all patients included in this study who received at least one dose of 
study treatment. 
The efficacy population will be the basis for the primary endpoint analysis in this study; it consists 
of all patients included in this study that received at least one dose of study treatment and have at 
least one evaluation visit after received the first dose of treatment. This will also be the patient 
population used for the analysis of the secondary endpoints. 
12.4. Analysis of Primary Objective 
Progression free survival (PFS) is defined as the time from the date of start treatment until 
objective tumor progression or death from any reason. Patients who have not progressed or died 
at the time of analysis will be censored at the time of the latest date of assessment from their last 
evaluable RECIST 1.1 assessment. PFS will be analysed according to the Kaplan-Meier method. 
Kaplan-Meier survival curves and median will be reported, along with associated 95% CI. 


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Three months PFS and the corresponding 95% CI will be provided. 
12.5. Analysis of Secondary Objectives 
12.5.1. Secondary Efficacy evaluations 
Objective response rate of the combination TNBC patients with metastatic disease that have 
received and experienced disease progression to the first/second line treatment will be measured 
according RECIST 1.1 criteria. Objective response rate (complete response + partial response) 
will be described using frequencies and percentages with its corresponding 95% CI. 
 
 
12.5.2. Secondary Safety evaluations 
AEs and toxicity will be evaluated according NCI CTCAE vs 5.0 criteria. AEs and toxicities will be 
presented by frequency distribution and percentage according to CTCAE grade. 
 
 
13. DATA HANDLING AND QUALITY ASSURANCE 
 
13.1. Monitoring of the trial 
The clinical monitors are employees of CRO, and representatives of the sponsor. As such, they 
have the obligation to follow the trial closely so that all aspects of the trial are carefully monitored 
for compliance with applicable government regulations and with ICH E6(R2) guidelines. 
The clinical monitors will visit the study sites and Investigators at intervals as defined in the 
monitoring plan, in addition to maintaining necessary contact through telephone, e- mail, and 
letter. The clinical monitors will maintain current personal knowledge of the trial through 
observation, review of trial records and source documentation, and discussion of the conduct of 
the trial with the study site Investigators and staff. 
13.2. Audits 
The sponsor may choose to schedule and conduct periodic audits of ongoing clinical studies. 
Audits are independent of, and separate from, routine monitoring or quality control functions and 
are conducted to assure accuracy and compliance with the protocol, governing regulatory 
authorities and/or ICH E6(R2) guidelines. 
13.3. Reporting of serious breaches 
Serious breaches of the authorized protocol or of the Royal Decree 1090/2015 occurring in Spain 
must be reported by the sponsor without undue delay and no later than seven 
CCI
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calendar days from becoming aware of the breach to the Spanish Agency of Medicines and 
Medical Devices (AEMPS) and the CEIm. 
To this end, a serious breach shall be defined as a breach that may significantly affect the safety 
and rights of the trial subjects or the reliability and robustness of the data generated in the clinical 
trial. 
Only serious breaches should be notified to the AEMPS and the CEIm, and the breaches that do not 
constitute a serious breach should not be notified. 
Each study site Investigator must document and explain in the subject’s source documentation 
any breaches from the approved protocol and / or the Royal Decree 1090/2015. Investigators may 
implement a breach to eliminate an immediate hazard to trial subjects without prior IEC informed 
consent approval, but the breach must be reported to the monitor/CRA within 1 working day. 
Such incidents will be evaluated for potential safety hazards of the ongoing study, and if deemed 
appropriate, a protocol amendment will be issued. 
The monitor/CRA will document breaches throughout the course of monitoring visits. The monitor 
will notify the Investigator during a visit and a “Breach Form” will be completed and signed by 
the investigator and by the monitor. 
13.4. Data Management 
CRO will be responsible for processing and quality control of the data. Data will be handled in 
accordance with the Data Management Plan, Standard Operating Procedures and applicable 
regulatory guidelines. 
Data management based on GCP refers to activities defined to achieve safe routines for efficient 
entry of subject information into a database, avoiding errors. The routines include procedures for 
handling of eCRFs, database set-up and management, data entry and verification, data validation, 
quality control (QC) of database, and documentation of the performed activities, including 
information of discrepancies in the process. The database, the data entry screens and the program, 
will be designed in accordance with the clinical study protocol by CRO. 
13.5. Electronic Case Report Forms (eCRFs) 
Data collection for this study will consist of electronic data capture for all eCRF information. 
CRO will supply the eCRF. 
All study site Investigators agree to maintain accurate eCRFs and source documentation as part of 
the case histories. 
All information is to be filled in the subject’s eCRF. If an enroled subject is not randomized into the 
study (ie, fails screening), only minimum data (such as demographics and consent date) and the 
reason for failing screening should be reported on the eCRF. In general, no queries for missing 
data on these subjects will be issued for procedures indicated as ‘Not done’. 


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For randomized subjects, information captured on the source documents will be entered into the 
subject’s eCRF by study site personnel and monitored at the study site. If an item is not available 
or is not applicable, this fact should be indicated by a missing reason. Blank spaces should not be 
present unless otherwise directed. Any corrections should be made using the procedure outlined 
in the Case Report Form Completion Guide of the study manual and will be recorded in the eCRF. 
Each completed eCRF must be reviewed, signed, and dated by the study site Investigator in a 
timely manner. The completed eCRF will be reviewed by the study Monitor as soon as practical 
after completion. A copy of the final, approved and signed eCRF will be provided to the site and 
should be stored in the appropriate files. 
13.6. Web-based eCRF 
Clinical data (including AEs and concomitant medications) will be entered into an Electronic 
Data Capture (EDC) application. The data system is password protected and includes internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete or inaccurate. Clinical data will be entered directly from the source documents. Roles 
and rights of the study site personnel responsible for entering the study data into the eCRF will 
be determined in advance. Only authorized study site personnel designated by each study site 
Investigator will complete data collection. Appropriate training and security measures will be 
completed with the Investigator and all authorized study site personnel, prior to the study 
initiation, and before any study data is entered into the system. 
13.7. Entering of Data into the eCRF 
The eCRFs should always reflect the latest observations on the subjects participating in the study. 
Therefore, the eCRFs should be completed as soon as possible during or after the subject’s visit. 
Each study site Investigator must verify that all data entries in the eCRFs are accurate and correct. 
If some assessments are not done, or if certain information is not available, not applicable or 
unknown, the Investigator or authorized designee should indicate this in the eCRF. The 
investigator will approve the data using an electronic signature, and this approval is used to 
confirm the accuracy of the data recorded. 
13.8. The Query Process 
Each monitor will review the eCRFs and evaluate them for completeness and consistency. Each 
eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections and alterations are to be made by the 
Investigator or his/her authorized designee. The monitor cannot enter data in the eCRFs. 
Once clinical data of the eCRF have been submitted to the central server, corrections to the data 
fields will be audit trailed (ie, the reason for any change, the name of the person who performed 
the change, and time and date will be logged). If additional corrections are needed, the 
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application. The appropriate investigational staff will answer queries generated in the application. 
This process is audit trailed meaning that the name of investigational staff, time, and date is 
logged. 
13.9. Source Documents 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the Investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria, and all records covering the subject’s 
participation in the study. They include enrolment and randomization log, investigational product 
accountability log, laboratory notes, memoranda, material dispensing records, subject files, etc. 
Each Investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. All supportive documentation 
submitted with the eCRF, such as laboratory data should be clearly identified with the study, visit 
and subject number. Any personal information (e.g., subject name, initials) should be removed or 
rendered illegible to preserve individual confidentiality. 
13.10. User ID 
eCRF records will be automatically appended with the identification of the creator, by means of 
their unique User ID. Specified records will be electronically signed by the Investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will be 
facilitated by means of the Investigator’s unique User ID and password; date and time stamps will 
be added automatically at time of electronic signature. If an entry in an eCRF requires change, 
the correction should be made in accordance with the relevant software procedures. 
13.11. Audit Trail 
To meet regulatory requirements, the eCRF data will be electronically stored at sites. All changes 
will be fully recorded in a protected audit trail, and a reason for the change will be required. Once 
all data have been entered, verified, and validated, the database will be locked to prevent any 
further changes in the clinical study data. 
13.12. Inspection of Records 
The Investigators and institutions involved in the trial will permit trial-related monitoring, audits, 
IEC review, and regulatory inspection(s) by providing direct access to all trial records. In the 
event of an audit, the Investigator agrees to allow the sponsor, representatives of the sponsor, and 
the governing regulatory agency access to all trial records. 
The Investigator should promptly notify the sponsor of any inspections scheduled by any 
regulatory authorities and promptly forward copies of any inspection reports received to the 
sponsor. 


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13.13. Trial Record Retention 
Essential documents and eCRF data should be retained during 25 years. 
 
 
14. ADMINISTRATIVE CONSIDERATIONS 
The following administrative items are meant to guide each study site Investigator in the conduct 
of the study but may be subject to change based on industry and government SOPs or working 
practice documents or guidelines. 
14.1. Legal Considerations 
The current clinical trial will be conducted in accordance with the protocol, the principles 
established in the current revised version of the Declaration of Helsinki (Annex 1) and the 
applicable regulatory requirements, particularly the ICH Tripartite Harmonized Guidelines for 
good clinical practice (1996), the Regulation (EU) 536/2014 relative to clinical trials on medicinal 
products for human use and the locally applicable regulations (e.g., In Spain, the Royal Decree on 
Clinical Trials 1090/2015). 
14.2. Ethics committee review 
ICH guidelines require that approval be obtained from Health Authorities and an Ethics 
Committee before human subjects can participate in research studies. Prior to the trial onset, the 
protocol, informed consent, advertisements to be used for subject recruitment (if applicable), and 
any other written information regarding this trial to be provided to the subject will be approved by 
the Ethics Committee. The clinical study will only be started when both the Health Authorities 
and an Ethics Committee have considered that the expected benefits for the trial subject and 
society justify the risks; in addition, the trial will only be continued if compliance with this 
criterion is constantly supervised. 
CRO will obtain Ethics Committee approvals on behalf of the sponsor and investigators. All 
regulatory approvals should be signed by the Ethics Committee Chairman or designee and must 
identify the Ethics Committee name and address, the clinical protocol by title and/or protocol 
number and the date approval and/or favorable opinion was granted. Documentation of all Health 
Authorities and Ethics Committee approvals and of the Ethics Committee compliance with ICH 
E6(2) will be maintained by the site and will be available for review. 
14.3. Modifications of the protocol 
Any change in the approved protocol will require a Protocol amendment. The Investigator must not 
make any change in the study without favourable opinion from the Ethics Committee and 
authorization from the Health Authorities, except as necessary to eliminate an impending and 
obvious risk for the subjects except when necessary to remove an apparent, immediate hazard to 
subjects. Protocol changes introduced to eliminate an impending and obvious risk may be 
implemented immediately, but must subsequently be documented in an amendment, reported to 
the Ethics Committee and be submitted to the relevant Health Authorities within the required 
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Any substantial amendments to the protocol must be submitted in writing to the Ethics Committee 
and the Health Authorities for approval before the changes proposed in the amendment are 
implemented. Depending on the magnitude of the change, the recruitment may be temporally 
halted. 
The sponsor does not have to notify non-substantial amendments to the Health Authorities or the 
Ethics Committee. However, any non-substantial amendments will be recorded and contained in 
the documentation when it is subsequently submitted, for example in the subsequent notification 
of a substantial amendment. Documentation of any non-substantial amendments will be available 
on request for inspection at the trial site or the sponsor premises as appropriate. 
14.4. Informed consent 
A written informed consent in compliance with ICH E6 guidelines shall be obtained from each 
subject before being included in the study or performing any study specific procedures. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the Ethics Committee prior to being provided to potential subjects. 
The written Informed Consent Form (ICF) should be prepared in the local language(s) of the 
potential subject population. 
An approved informed consent form will be provided by the sponsor to investigative site. 
Before a subject’s participation in the study, it is the Principal Investigator’s (or their designee) 
responsibility to obtain freely given consent in writing, from the subject after adequate 
explanation of the aims, methods, anticipated benefits, and potential risks of the study and before 
any protocol-specific screening procedures or any study drugs are administered. Subjects must 
have the opportunity to ask questions and receive answers and will have adequate time to decide 
whether or not to participate in the study. Once the Investigator is assured that the subject 
understands the implications of participating in the trial, the subject will be asked to give consent 
to participate in the trial by signing the informed consent. 
The ICF should be signed and personally dated by the subject and by the physician who conducted 
the informed consent discussion (Principal Investigator or designee). The subject’s written 
informed consent should also be documented in the subject’s medical records. 
The Investigator shall provide a copy of the signed informed consent to the subject. A second 
original form shall be maintained in the Investigator study file at the site. 


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If the informed consent is revised during the course of the trial, all active participating subjects 
must sign the revised form approved by the Ethics Committee. 
The subject participating in a clinical trial, or his/her legal representative, may withdraw consent 
at any time without giving any reason and without this involving any penalty or prejudice for the 
participating subject. 
14.5. Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. Each Investigator will ensure that all site 
personnel involved will respect the confidentiality of any information about trial subjects. 
Management of personal data from subjects participating in the trial, particularly as regards 
consent, will comply with Regulation (EU) 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data and local laws. 
At each site, all records will be kept in a secure storage area with limited access. Clinical 
information will not be released without the written permission of the subject. Subject identity is 
confidential and may only be known by the Investigator, trial personnel, appointed auditors and 
monitors, and Health Authorities. 
Each Investigator and all employees and coworkers involved with this trial may not disclose or 
use for any purpose other than performance of the trial, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the trial. Prior written 
agreement from the sponsor or its designee must be collected for the disclosure of any said 
confidential information to other parties. 
14.6. Insurance 
The sponsor has contracted an insurance policy to cover the responsibilities of the investigator 
and other parties participating in the study, according to the applicable legislation. 
 Insurance company: QBE Europe SA/NV 
 Policy Number: 063 0000488 
 
14.7. Publications 
The sponsor commits to responsible publication of both the positive and negative results from its 
clinical trials as required by all governing regulatory and health authorities. 
Investigators will not publish the global study results (all sites) unless the sponsor has not done 
so in a suitable time period after the clinical study report (CSR) has been available. Should the 
Investigator(s) independently seek to publish results of this study which occur at their study 
site(s), they must inform the study sponsor of any/all drafts (including, but not limited to papers, 
manuscripts or abstracts) at least 60 days before submission to the congress, meeting or journal. 
The sponsor and Investigator(s) will 


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agree with all aspects related to any proposed publications with regards to the following: 
1) any proposed publications will be drafted in agreement with international recommendations, 
such as those from the International Committee of Medical Journal Editors (ICMJE) and all 
elements of the Consort Statement, to maintain integrity of the trial results in all communications; 
2) any proposed publications will state the Clinical Research Ethics Committees which approved 
the trial and the funding sources of the trial; 3) any proposed publications will occur before 
disclosure of results to lay people; 4) any proposed publications will not report premature or partial 
data prior to completion of the analysis of the overall results of the trial. 


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15. SPONSOR’S SIGNATURE PAGE 
 
Study title: Phase IB Clinical trial of palbociclib and binimetinib in advanced triple negative 
breast cancer with hyperactivation of ERK and/or CDK4/6 
Study code: PALBOBIN 
Version number and date: 3.0, 16th June 2021 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
 
 
 
 
 
 
 
Position 
(pre-printed name) 
Signature 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
 
Position 
(pre-printed name) 
Signature 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Position 
(pre-printed name) 
Signature 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Position 
(pre-printed name) 
Signature 
Signature date 
(DD-Mmm-YYYY) 


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16. INVESTIGATOR’S SIGNATURE PAGE 
 
Study title: Phase IB Clinical trial of palbociclib and binimetinib in advanced triple negative 
breast cancer with hyperactivation of ERK and/or CDK4/6 
Study code: PALBOBIN 
Version number and date: 3.0, 16th June 2020 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines. 
 
 
 
 
 
Principal Investigator’s signature 
Signature date 
(DD-Mmm-
YYYY) 
Investigator’s name (capital letters) 
 
 
 
 
 
Investigator’s signature 
Signature date 
(DD-Mmm-
YYYY) 
Investigator’s name (capital letters) 
 
 
 
 
 
Investigator’s signature 
Signature date 
(DD-Mmm-
YYYY) 
Investigator’s name (capital letters) 


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Anal Chem 2016; 88(1): 74-94. 
38. Deribe YL, Pawson T, Dikic I. Post-translational modifications in signal integration. Nat 
Struct Mol Biol 2010; 17(6): 666-72. 
39. Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer 
whole-genome sequences. Nature 2016; 534(7605): 47-54. 
40. Bossi D, Cicalese A, Dellino GI, et al. In Vivo Genetic Screens of Patient-Derived Tumors 
Revealed Unexpected Frailty of the Transformed Phenotype. Cancer Discov 2016; 6(6): 
650-63. 
41. Teh JLF, Cheng PF, Purwin TJ, et al. In Vivo E2F Reporting Reveals Efficacious 
Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms. Cancer 
Discov 2018; 8(5): 568-81. 
42. Bendell JC, Javle M, Bekaii-Saab TS, et al. A phase 1 dose-escalation and expansion study 
of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer 2017; 
116(5): 575-83. 
43. Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients 
with advanced NRAS-mutant melanoma (NEMO): a multicentre, open- label, randomised, 
phase 3 trial. Lancet Oncol 2017; 18(4): 435-45. 
44. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in metastatic triple-
negative breast cancer. N Engl J Med; 384 (16): 1529-41, 2021. 
45. Lawless, Jerald F. Statistical Models and Methods for Lifetime Data. 2nd ed. John Wiley & 
Sons, 2003. 


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Annex 1. Declaration of Helsinki 
 
WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and 
amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th 
WMA General Assembly, Venice, Italy, October 1983 41st WMA 
General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA 
General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 55th 
WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 64th 
WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with 
consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my 
first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient's 
best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, development and 
effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect 
their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence 
over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right 
to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for 
the protection of research subjects must always rest with the physician or 


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other health care professionals and never with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and 
scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision 
of a competent and appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to participation in 
research. 
14. Physicians who combine medical research with medical care should involve their patients in research only to the 
extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the patients who serve 
as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must 
be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective outweighs the 
risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks and 
burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and 
to other individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and 
documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are confident that the 
risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, 
physicians must assess whether to continue, modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged 
or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or 
priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should 
stand to benefit from the knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on 
a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, 
as appropriate, animal experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how the principles 
in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 


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information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned 
research ethics committee before the study begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information 
to the committee, especially information about any serious adverse events. No amendment to the protocol may be 
made without consideration and approval by the committee. After the end of the study, the researchers must submit a 
final report to the committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal 
information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no individual capable of giving 
informed consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome and results of 
the study. 
27. When seeking informed consent for participation in a research study the physician must be particularly cautious if 
the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed 
consent from the legally authorised representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing informed consent, and the research 
entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is 
a necessary characteristic of the research group. In such circumstances the physician must seek informed consent 
from the legally authorised representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent 


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have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a 
patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data contained in 
biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There 
may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In 
such situations the research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven 
intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than 
the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an 
intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for 
post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information 
must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication 
and dissemination of the results of research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest 
must be declared in the publication. Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known interventions 
have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorised representative, may use an unproven intervention if in the physician's judgement it offers hope of saving 
life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of 
research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where 
appropriate, made publicly available. 


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Annex 2. List of Sites / Principal Investigators 
 
Separate attachment. 


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Annex 3. Informed Consent Form 
 
Separate attachment. 


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Annex 4. NCI-CTC AE Criteria 
 
Common terminology criteria for classification of adverse events version 5.0 (NCI CTC AEv5) are 
available at the following Internet address: 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_ 
Quick_Reference_8.5x11.pdf 

SAP_001.pdf: 
 
 
 
 
 
 PALBOBIN Statistical Analysis Plan 
 
 
 
 
 Phase IB Clinical trial of palbociclib and binimetinib in 
advanced triple negative breast cancer with 
hyperactivation of ERK and/or CDK4/6. 
 
NCT: NCT04494958  
 
 
 
 
 
 
  
Version 1.0 - 08-Jan-2024 


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative 
breast cancer with hyperactivation or ERK 
and/or CDK4/6” 
 
PALBOBIN Study 
APICES Project No. ONC227009 
Statistical Analysis Plan 
(Final analysis) 
Version 1.0 
January 8th, 2024 
 
 
Prepared by: 
Reviewed by: 
(Name) 
/ (Role) 
/ 
(Company) 
Signature / Date 
(Name) 
/ (Role) 
/ 
(Company) 
Signature / Date 
Approved by: 
Approved by: 
(Name) 
/ (Role) 
/ 
(Company) 
Signature / Date 
(Name) 
/ (Role) 
/ 
(Company) 
Signature / Date 
 
 
 
 
 
 
STP-703-E1 Statistical Analysis Plan template Rev02.4 
www.apices.es 
CCI


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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1. HISTORY OF REVISION (Documentation of changes) 
 
 
SECTIONS 
VERSION 
DATE 
REVISED 
REVISED BY 
DESCRIPTION OF 
CHANGES 


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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INDEX 
1. 
HISTORY OF REVISION (Documentation of changes) ........................................... 2 
2. 
INTRODUCTION ..................................................................................................... 4 
3. 
SYNOPSIS .............................................................................................................. 5 
3.1. 
Study title .......................................................................................................... 5 
3.2. 
Study Code ....................................................................................................... 5 
3.3. 
Protocol Version and Amendments .................................................................. 5 
3.4. 
Sponsor ............................................................................................................ 5 
3.5. 
Design .............................................................................................................. 5 
3.6. 
Objectives ......................................................................................................... 6 
3.7. 
Total number of subjects .................................................................................. 6 
3.8. 
Inclusion Criteria ............................................................................................... 7 
3.9. 
Exclusion Criteria .............................................................................................. 9 
3.10. 
Study treatment ........................................................................................... 11 
4. 
GENERAL CONSIDERATIONS ............................................................................ 11 
5. 
STUDY POPULATIONS ........................................................................................ 12 
5.1. 
Definition of study populations to analyze ....................................................... 12 
5.2. 
Study recruitment period ................................................................................. 12 
5.3. 
Disposition of subjects .................................................................................... 12 
5.4. 
Study Discontinuations ................................................................................... 13 
5.5. 
Deaths ............................................................................................................ 13 
6. 
SUBJECT DESCRIPTION ..................................................................................... 13 
6.1. 
Demographic and baseline description. General considerations .................... 13 
6.2. 
Subject Characteristics ................................................................................... 13 
7. 
TREATMENT ADMINISTRATION ......................................................................... 15 
7.1. 
Treatment description. General considerations .............................................. 15 
7.2. 
Treatment administration ................................................................................ 15 
7.3. 
Dose intensity ................................................................................................. 16 
8. 
EFFICACY ASSESSMENT .................................................................................... 16 
8.1. 
Efficacy Assessment; general considerations ................................................. 16 
8.2. 
Primary efficacy endpoint. PFS....................................................................... 16 
8.3. 
Secondary efficacy endpoints ......................................................................... 17 
9. 
SAFETY ASSESSMENT ....................................................................................... 18 
9.1. 
Safety Assessment; general considerations ................................................... 18 
9.2. 
Adverse Events ............................................................................................... 18 
9.3. 
Adverse reactions ........................................................................................... 18 
9.4. 
Serious Adverse Events (SAEs) ..................................................................... 18 
9.5. 
Adverse Events of Special Interest (AESI)...................................................... 19 


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
with hyperactivation or ERK and/or CDK4/6” 
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2. INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analysis for PALBOBIN study. In it is 
described all consideration over study data and are defined the tables, figures and listing (TLFs) 
that will be presented as result of the study. 
Additionally includes definition of the different population and missing data consideration. 
The statistical analysis plan will be signed and per protocol dataset will be defined before 
database lock. 
Table of abbreviations 
 
 
95% CI 
95% confident interval 
AEs 
Adverse events 
AESI 
Adverse events of special interest 
BID 
“Bis in die” twice a day 
CR 
Complete response 
CTC AE 
Common terminology criteria for adverse events 
HIV 
Human immunodeficiency virus 
MedDRA 
Medical dictionary for regulatory activities 
ORR 
Overall response rate 
PD 
Progression disease 
PFS 
Progression-free survival 
PR 
Partial response 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
TNBC 
Triple negative breast cancer 


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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3. SYNOPSIS 
 
3.1. Study title 
“Phase IB Clinical trial of palbociclib and binimetinib in advanced triple negative breast cancer 
with hyperactivation or ERK and/or CDK4/6” 
 
3.2. Study Code 
PALBOBIN. 
 
 
3.3. Protocol Version and Amendments 
 
Previous protocol versions / amendments (number and date): 
 Version 1.0, 14/Jul/2020 
 Version 2.0, 07/Sep/2020 
Current version (number and date): 
- 
Version 3.0, 16/Jun/2021 
 
 
3.4. Sponsor 
Fundación OncoSur 
Address: Gran Vía Marqués del Turia nº65, 3º-11. 46005 Valencia 
Office: Medical Oncology Service 
Hospital 12 de Octubre 
Avda de Córdoba s.n. 
e-mail: secretaria_tecnica@oncosur.org 
 
3.5. Design 
This is an interventional, prospective, multicentric, single-arm, open label, phase IB clinical trial. 
The following scheme depicts the basic trial design. 
CCI


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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Patients diagnosed of metastatic or locally advanced non-curable TNBC that have received one 
or two treatment regimens for advanced disease will be candidates for the trial. 
 
3.6. Objectives 
Primary objective: 
Primary objective of this study is to determine the 3-months PFS of palbociclib plus binimetinib in 
advanced triple negative breast cancer (TNBC), in patients with activation of ERK and/or CDK4/6. 
Secondary objectives: 
- 
To determine response rate of the combination in advanced TNBC, in patients with 
activation of ERK and/or CDK4/6. 
- 
- 
To assess the safety of the combination in patients with advanced TNBC. 
 
 
 
 
 
 
 
3.7. Total number of subjects 
It is expected to include 25 patients in this trial. Patients diagnosed of metastatic or locally 
advanced non-curable TNBC that have received one or two treatment regimens for advanced 
disease will be included in this study. 
CCI
CCI


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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3.8. Inclusion Criteria 
1. Women >18 years-old. 
2. Diagnostic of metastatic or locally advanced non-resectable TNBC. 
3. Patient must have received a minimum of one and a maximum of two treatment lines 
for metastatic TNBC. Previous treatments can be of any nature (chemotherapy, 
immunotherapy, antiangiogenics, experimental therapy, etc.). 
Women with known BRCA1/BRCA2 germline mutations must have received a 
platinum-based treatment or treatment with a PARP inhibitor. 
4. Patient must have experienced disease progression to the previous treatment line 
according to the RECIST 1.1 or iRECIST criteria. 
5. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study 
inclusion, preferably obtained after last treatment or the most recent sample as 
possible (from metastatic site or first diagnosis according to sample availability). If the 
patient has not a tumor sample available prior to study inclusion, the patient will not 
be allowed to participate in the study. 
6. Ability to understand and signing of the written patient information/informed consent 
form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be 
performed centrally at CNIO. 
7. Ability to understand and signing the written PIS/ICF for study treatment eligibility. 
Signed informed consent form must be available before any study-specific procedure 
for the respective study parts may begin. 
8. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top- 
quartile according to published definitions. 
9. ECOG performance status of 0-1. 
10. Evaluable disease according to RECIST 1.1 criteria. 
11. Life expectancy >24 weeks. 
12.  Adequate bone marrow, liver and renal function as assessed by laboratory 
requirements conducted within 7 days before first study drug administration: 
a. Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte colony- 
stimulating factor support within 2 weeks before the first study drug 
administration). 
b. Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks 
before the first study drug administration). 
c. Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the 
first study drug administration). 


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binimetinib in advanced triple negative breast cancer 
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d. Total bilirubin ≤ 2  the upper limit of normal (ULN). 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 
 ULN (≤ 5 times ULN for patients with liver metastases). 
f. 
Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the 
modification of diet in renal disease (MDRD) abbreviated formula. 
13. Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments 
(excluding neuropathy which can be ≤ Grade 2, and alopecia). 
14. Patients must be able to take oral medications. 
15. Patients must have adequate cardiac function, defined as: 
a. Left ventricular ejection fraction (LVEF) > 50% as determined by 
echocardiogram or multigated acquisition scan (MUGA). 
b. QTc < 480 msec. 
16.  Negative serum pregnancy test in women of childbearing potential (performed within 
7 days before the first treatment). Negative results must be available before the first 
study drug administration. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
Pregnancy test will not be performed in postmenopausal women. 
17. Women of reproductive potential must agree to use adequate contraception when 
sexually active. This applies for the time period since the signature of the informed 
consent form and until at least 1 month after the last study drug administration. The 
definition of adequate contraception will be based on the judgment of the investigator 
and on local requirements. Acceptable methods of contraception include, but are not 
limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) 
diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone- 
based contraception. 
Zoledronic acid or denosumab started prior to trial registration is allowed, but in case 
they are required after initiation of trial procedures, adequate justification is required. 


“Phase IB Clinical trial of palbociclib and 
binimetinib in advanced triple negative breast cancer 
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3.9. Exclusion Criteria 
1.  Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks 
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study. 
2.  Patients that received during the metastatic disease setting any of the study 
drugs, palbociclib or binimetinib. 
3.  Participants receiving any other study agents concurrently with the study drugs. 
Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to 
enrollment are allowed. 
4.  Participants with symptomatic brain metastases that require chronic steroids. Patients 
with a history of brain metastases are permitted to enroll as long as they have been 
treated, are off of steroids, and have been stable for a minimum of one month on imaging. 
5.  Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is the only 
location of the disease and it has not progressed. Patients with radiated single lesions that 
has progressed are allowed. 
6.  Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug 
interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with 
caution. 
7. 
Uncontrolled intercurrent illness including, but not limited to: 
a. ongoing or active infection requiring systemic treatment. 
b. symptomatic congestive heart failure. 
c. cardiac arrhythmia. 
d. psychiatric illness/social situations that would limit compliance with study 
requirements. 
e. hypertension, defined as systolic blood pressure > 160 mmHg despite medical 
management. 
f. 
myocardial infarction, unstable angina, coronary artery bypass grafting, coronary 
angioplasty, or stenting < 6 months prior to screening. 
8.  History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or 
Torsades de Pointes. 
9. History of Gilbert's syndrome. 
10.  History of neuromuscular disorders that are associated with elevated CK (e.g. 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy). 
11. Previous or concurrent cancer except: 
a. 
cervical carcinoma in situ. 


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b. 
treated basal-cell carcinoma or squamous cell skin cancer. 
c. any other cancer curatively treated > 3 years before the first study drug 
administration. 
12.  Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere 
with the absorption of oral study medication in the opinion of the investigator. 
13. Pregnant women or breast-feeding. 
14. Known HIV-positive individuals on combination antiretroviral therapy. 
15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive 
hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C infection 
requiring treatment. 
a.  Patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible 
if HBV DNA is negative. 
b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA. 
16.  Any condition that in the opinion of the investigator would interfere with evaluation of study 
treatment or interpretation of patient safety or study results, or inability to comply with the 
study and follow-up procedures. 
17.  Participation in another clinical study with investigational medicinal products within 4 
weeks before the first study drug administration. 
18. Clinically active infections within 2 weeks before the first study drug administration. 
19.  Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first study drug 
administration. Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary 
tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
20.  Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the 
formulation. 
21.  Current diagnosis of any retinal disorders including retinal detachment, retinal pigment 
epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or risk factors 
for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or hypercoagulability 
syndrome). 
22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher. 
23.  Major surgery, open biopsy or significant traumatic injury within 4 weeks before the first 
study drug administration (central line surgery is not considered major surgery). 
24. Renal failure requiring peritoneal dialysis or hemodialysis. 


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25.  Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results. 
 
 
 
3.10. Study treatment 
 
Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 100 
mg daily, 21 days on / 7days off, until disease progression. Study treatment will continue until 
disease progression, unacceptable toxicity, intercurrent serious disease, consent withdrawal or 
investigator´s decision. 
 
 
 
4. GENERAL CONSIDERATIONS 
 
The statistical analysis will be performed using SPSS software vs 26. 
 
Data will be generally provided with one decimal. In those cases that a greater accuracy is 
required, as much decimals as needed will be provided. 
Adverse events will be codified using MedDRA dictionary (latest version available). 
 
Continuous variables will be described by mean, median, standard deviation, minimum, 
maximum, Q1 and Q3. Categorical variables will be shown as distribution of frequencies and 
percentage 
All available efficacy and safety data will be included in data listings and tabulations. No imputation 
of values for missing data will be performed unless otherwise stated. Data that are potentially 
spurious or erroneous will be examined according to standard data management operating 
procedures. 


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5. STUDY POPULATIONS 
 
5.1. Definition of study populations to analyze 
The following describes the different populations that will be used in the analyses process: 
 
Efficacy population: consists of all patients included in this study that received at least 
one dose of study treatment and have at least one evaluation visit after received the first 
dose of treatment. The efficacy population will be the basis for the primary endpoint 
analysis in this study. This will also be the patient population used for the analysis of the 
secondary endpoints. 
 
Safety population: consists of all patients who received at least one dose of the study 
treatment and had at least one valid post baseline safety assessment. 
 
 
5.2. Study recruitment period 
The date of informed consent form for the first subject and the last subject included in the study 
will be provided. 
 
 
5.3. Disposition of subjects 
 
Figure 1: Disposition of subjects 
 
 
 
*Discrepancies between the number of analysed patients and number of recruitment patients into 
the database will be described. 
The frequency distribution and percentage of patients analysed will be provided by site. 
Recruitment patients (n=) 
Safety 
(n=) 
Efficacy 
(n=) 
Patient’s description 
(n=) 
Analyzed patients (n=*) 


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5.4. Study Discontinuations 
Number and percentage of patients who discontinued the study and their reasons will be 
described. Those patients who leave the study for reasons related to study medication will be 
described in detail. 
 
5.5. Deaths 
Number and percentage of patients who died during the study and their reasons will be provided 
per treatment group. Patients who have died due to adverse events or adverse reactions will be 
described in detail. 
 
 
6. SUBJECT DESCRIPTION 
 
6.1. Demographic and baseline description. General considerations 
All demographics and baseline characteristics will be described for efficacy population. 
 
6.2. Subject Characteristics 
 
a) Demographics 
 
The following variables will be described: 
o Age, years (continuous). 
o Ethnicity (categorical). 
 
b) Baseline characteristics 
 
The following variables will be described: 
o Vital signs: 
 
Weight (Kg) (continuous). 
 
Height (cm) (continuous). 
 
Systolic blood pressure (mmHg) (SBP) (continuous). 
 
Diastolic blood pressure (mmHg) (DBP) (continuous). 
 
Pulse rate (b.p.m) (continuous). 
 
Temperature (ºC) (continuous). 
o 12-lead ECG (Done/not done) (categorical), if performed: 
 
Result (Normal/ abnormal not clinically significant / abnormal clinically significant). 
o ECO/MUGA (Done/not done) (categorical), if performed: 
 
Result (Normal/ abnormal not clinically significant / abnormal clinically significant). 


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o Hepatitis B surface antigen (Positive / Negative / Not done) (categorical). 
o Hepatitis C antibody (Positive / Negative / Not done) (categorical). 
o HIV (Positive / Negative / Not done) (categorical). 
 
c) Cancer history 
 
The following variables will be described: 
o Performance status at screening (ECOG-PS) (categorical). 
o Time from initial diagnosis, defined as the elapsed time in months between the initial 
diagnose date to informed consent date (continuous). 
o TNM & Stage at initial diagnosis (categorical). 
o Current disease status (Advanced/Metastatic) (categorical). 
o Time from advanced/metastatic disease, defined as the elapsed time, in months, between 
the advanced/metastatic disease date to informed consent date (continuous). 
o Histology (categorical). 
o Histologic grade (differentiation): GX: Grade cannot be assessed, G1: Well differentiated 
(Low grade), G2: Moderately differentiated (Intermediate grade), G3: Poorly differentiated 
(High grade), G4: Undifferentiated (High grade), Not Available (differentiation) 
(categorical). 
o Actual TNM & Stage (categorical). 
o Breast cancer previous treatments: 
 
Previous surgeries (Yes/No) (categorical), if affirmative: surgery description by 
patient (categorical). 
 
Previous chemotherapy-based treatment (Yes/No) (categorical), if affirmative: 
 
Localized disease chemotherapy (Yes/No) (categorical), if affirmative: 
chemotherapy scheme by patient (categorical). 
 
Metastatic disease chemotherapy (Yes/No) (categorical) , if affirmative: 
chemotherapy scheme by patient (categorical). 
 
Previous radiotherapy (as primary therapy) (Yes/No). 
 
Previous hormonal therapy (Yes/No) if affirmative: hormonal treatment by patient 
(categorical). 
 
Previous immunotherapy (Yes/No) if affirmative: immunotherapy treatment by 
patient (categorical). 
 
Other previous treatments (Yes/No) if affirmative: treatment by patient 
(categorical). 


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d) Baseline lesions: 
 
The analysis of target and non-target baseline lesions will be performed together. 
 
It will be considered affected location when the patient presents at least one lesion in one organ 
or system, regardless of the number of lesions in the organ or system is more than one. It will be 
provided: 
 
The number and percentage of patients with each affected location (categorical). 
 
The number and percentage of patients by number of affected locations (categorical). 
 
 
7. TREATMENT ADMINISTRATION 
 
7.1. Treatment description. General considerations 
 
The information related to treatment descriptions, dose intensity and subsequent treatments will 
be presented for the efficacy population defined in section 5.1.. 
 
7.2. Treatment administration 
 
It will be considered as cycle administered when the patient receives at least one treatment 
dose. Number of cycles administered will be described as continuous variable. 
 
The following data will be described for each drug (palbociclib and binimetinib): 
 
● Treatment interruption (Yes, No): If affirmative: 
o Number and percentage of patients by the no. interruptions (Categorical). 
o Reason for interruption (Categorical). 
o Total number of cycles interrupted and percentage regarding total cycles 
(Categorical). 
 
● Dose reductions (Yes, No): If affirmative: 
o Number and percentage of patients by the no. dose reduction (Categorical). 
o Reason for reduction (Categorical). 


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The exposure treatment time will be defined as the elapsed time, in months, between the date of 
first administered dose of study treatment (binimetinib or palbociclib) and the end of treatment 
date. For patients with treatment ongoing or without end of treatment date, the last administration 
date of any drug will be considered. 
 
7.3. Dose intensity 
Dose intensity will be defined as the total of each study drug received by the patient with respect 
to the exposure treatment time. The dose intensity will be described as mg/week. 
The relative dose intensity will be defined as the total dose of each drug received by the patient 
in relation to the theoretical total dose that patient should had received per protocol. 
The dose intensity and relative dose intensity will be evaluated as continuous variables. 
 
 
 
8. EFFICACY ASSESSMENT 
 
8.1. Efficacy Assessment; general considerations 
Efficacy assessment will be performed for efficacy population defined in section 5.1. 
Time-to-event variables will be analyzed according to the Kaplan-Meier method. Kaplan-Meier 
survival curves, median, 95% CI, number of events and censored and number of patients at risk 
will be presented. 
The follow-up time is defined as the elapsed time, in months, between the date of first 
administered dose of study treatment (binimetinib or palbociclib) and the end of study date. For 
patients without end of study, the last follow-up date will be taken into account. 
The swimmer pool plot will be provided displaying the follow-up time, the treatment exposure time 
and the moment of progression disease. 
 
 
8.2. Primary efficacy endpoint. PFS 
 
Progression-free survival (PFS) is defined as the elapsed time, in months, between the start of 
treatment until the documentation of disease progression (radiological RECIST v1.1 or clinical) 
or death due to any cause, whichever occurs first. For subjects who are alive and not present 
disease progression at the time of data cut-off for analysis, PFS will be censored at the last tumor 
assessment date, if no one tumor assessment date is available PFS will be censored at start of 
treatment date. 


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PFS will be analyzed according to the Kaplan-Meier method. Kaplan-Meier survival curves and 
the median estimation will be reported, along with associated 95% CI. In order to response to 
primary end point, PFS rate at 3 month will be estimated and the 95% CI will be reported. In 
addition, PFS rate at 1 year with 95% CI will be calculated. 
In addition, PFS will be evaluated by mutation ERK and CDK4/6. 
 
 
8.3. Secondary efficacy endpoints 
 
 
● Overall response rate (ORR) per RECIST v1.1 as assessed by investigator. ORR is 
defined as the proportion of patients with an overall response of complete or partial 
response, as per local investigator´s assessment and according to Response Evaluation 
Criteria in Solid Tumours (RECIST) version 1.1 criteria. The table below provides a 
summary of the overall response calculation. 
 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
CR 
Not-evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Counts and percentages of ORR will be reported, along with associated 95% confidence interval 
(CI). 
In addition, the response rate and ORR will be provided by mutation ERK and/or CDK4/6. 
 
A waterfall plot will be provided with the percentual change of tumoral change between baseline 
evaluation and the patient's evaluation with the best response tumor assessment. Additionally, a 
spider plot with the percent change of tumoral size respect baseline evaluation in each patient's 
evaluation performed will be provided. 


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9. SAFETY ASSESSMENT 
 
9.1. Safety Assessment; general considerations 
The assessment will be performed for safety population defined in section 5.1. Adverse events 
will be evaluated according to NCI CTCAE vs 5 criteria. Adverse events will be coded by the latest 
available version of MedDRA dictionary. AEs will be evaluated with the MedDRA code by system 
organ class (SOC) and preferred term (PT). 
The analysis will be performed with the information completed into the adverse event eCRF 
section. 
The analysis of adverse events will be performed per patient, for that the maximum grade for each 
adverse event completed of each patient will be calculated. 
 
9.2. Adverse Events 
 
All adverse events evaluated will be described. The analysis of AEs will be described the 
following: 
 
 
The number and percentage of patients with at least one adverse event. 
 
The number and percentage of patients with each adverse event by grades (1-5). 
 
9.3. Adverse reactions 
 
All adverse event indicated as related with any study treatment drug in the eCRF adverse event 
section will be considered. The analysis of toxicities will be provided: 
 
 
The number and percentage of patients with at least one toxicity. 
 
The number and percentage of patients with each toxicity by grade (1-5). 
 
9.4. Serious Adverse Events (SAEs) 
Serious adverse events listing will be provided the following information: 
 
 
Site 
 
Subject ID 
 
AE description 
 
PT Term 
 
Grade (1-5) NCI CTC AE v5 
 
Start date 
 
End date 


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binimetinib in advanced triple negative breast cancer 
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 
AESI (Yes/No) 
 
Action taken (None / Delay / Dose reduction / Dose interruption / Withdrawn / Not 
applicable / Unknown / Other) 
 
Relationship (Palbociclib / Binimetinib / Concomitant medication or procedure / Other / Not 
related) 
 
Seriousness criteria (Death / Life-threatening / Hospitalization / Prolonged hospitalization 
/ Persistent or significant disability/incapacity / Congenital anomaly or birth defect / 
Medically important) 
 
Outcome (Recovered / Recovered with sequelae / Not recovered/ongoing / Death / 
unknown) 
 
DLT (Yes/No) 
 
Serious adverse events analysis includes the following: 
 
 
The number and percentage of patients with at least one serious adverse. 
 
The number and percentage of patients with each serious adverse event by grade (1-5). 
 
9.5. Adverse Events of Special Interest (AESI) 
Serious adverse events listing will be provided the following information: 
 
 
Site 
 
Subject ID 
 
AE description 
 
PT Term 
 
Grade (1-5) NCI CTC AE v5 
 
Start date 
 
End date 
 
Serious (Yes/No) 
 
Action taken (None / Delay / Dose reduction / Dose interruption / Withdrawn / Not 
applicable / Unknown / Other) 
 
Relationship (Palbociclib / Binimetinib / Concomitant medication or procedure / Other / Not 
related) 
 
Seriousness criteria (Death / Life-threatening / Hospitalization / Prolonged hospitalization 
/ Persistent or significant disability/incapacity / Congenital anomaly or birth defect / 
Medically important) 


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 
Outcome (Recovered / Recovered with sequelae / Not recovered/ongoing / Death / 
unknown) 
 
DLT (Yes/No) 
 
Serious adverse events analysis includes the following: 
 
 
The number and percentage of patients with at least one serious adverse. 
 
The number and percentage of patients with each serious adverse event by grade (1-5).