Clinical trial NCT05810740
Conditions: Melanoma BRAF V600 Mutation Unresectable Melanoma Metastatic Melanoma
Sponsor: Pierre Fabre Medicament
Start date: 2022-08-31; Completion date: 2023-01-18
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The current commercially available MEKTOVI® (binimetinib) 15 mg tablets are provided as immediate release film-coated tablets for oral administration. For the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600 mutation, the recommended dosing regimen is 45 mg twice daily (bis in die, BID). No food effect with the commercial formulation of 15 mg was demonstrated. In order to reduce the patient's burden, a new strength tablet containing 45 mg of binimetinib as active ingredient is being developed. As a result, the number of tablets to be taken by the patients will be reduced from 6 tablets (6 x 15 mg) to 2 tablets (2 x 45 mg) per day. The evaluation of the bioequivalence between one 45 mg tablet and three 15 mg tablets is therefore required.

Detailed description:
The reference (R) formulation is the currently commercially available tablet containing 15 mg of binimetinib as active substance, administered as three tablets for a total of 45 mg binimetinib. The Test (T) formulation is the tablet containing 45 mg of binimetinib as active substance in one tablet. Participants will be randomized to one of 2 treatment sequences (RT or TR) containing 2 treatment periods, with at least a 7-day washout between each dose.

The study will consist of a screening period between 21 and 2 days before the first study treatment administration on Period (P) 1 Day (D) 1, 2 treatment periods of 5 days each, and a washout of at least 7 days between P1D1 and P2D1.

Study treatments are given by the oral route in fasted condition. The end-of-study (EOS) visit will be performed 30 (± 3) days after the last study treatment administration or discontinuation.

Arms: arm 1: Participants first received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period. arm 2: Participants first received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period.
Interventions: intervention 1: Binimetinib 15 MG intervention 2: Binimetinib 45 MG
Intervention descriptions: intervention 1: Binimetinib 15 mg tablet intervention 2: Binimetinib 45 mg tablet

Protocol documents:
Prot_000.pdf: 
PIERRE FABRE MEDICAMENT
Les Cauquillous
81500 Lavaur FRANCE
Represented by: Institut de Recherche Pierre Fabre 
EudraCT N°: 2022-000610-34 
Clinical Study Protocol N° W00074CI103
Biotrial Code: 1PF74
A randomized, single-center, open-label, single dose, two-period, crossover pivotal 
bioequivalence study comparing binimetinib 3 x 15 mg and 45 mg tablets in healthy 
participants
Short title: Bioequivalence binimetinib 3 x 15 mg and 45 mg formulations
Investigational Medicinal Product Code: 
Binimetinib
Development Phase: 
I
Principal Investigator:
Sponsor:
Marina Klein, MD
7-9 rue Jean-Louis Bertrand
CS 34246
35042 Rennes Cedex
FRANCE
Pierre Fabre Médicament 
Les Cauquillous
81500 Lavaur
FRANCE
Represented by the Institut de Recherche 
Pierre Fabre
Version 2.0
Date: 26 OCT 2022
This information may not be used, published or otherwise disclosed without prior written 
authorization from the Sponsor


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Protocol Approval Form
The protocol entitled "A randomized, single-center, open-label, single dose, two-period, 
crossover pivotal bioequivalence study comparing binimetinib 3 x15 mg and 45 mg tablets in 
healthy participants", version 2.0 dated 26 / OCT / 2022 has been approved for submission to 
the French Ethics Committee and regulatory authorities (CPP and ANSM) by:
Date:
Sponsor's Representative:
Eric Chetaille, MD
Principal Investigator's Approval
I, the undersigned, have examined this protocol and agree to conduct this trial according to this 
protocol, to comply with its requirements, subject to ethical and safety considerations, as set 
out in this protocol, the Declaration of Helsinki 1964 (latest revision Fortaleza 2013) and all 
other laws and regulations on the use of investigational medicinal products.
Date:
Principal Investigator:
Marina Klein, MD
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TABLE OF CONTENTS
1. 
SYNOPSIS.........................................................................................................................7 
2. 
SCHEDULE OF ACTIVITIES (SOA) .........................................................................17 
3. 
INTRODUCTION ..........................................................................................................24 
3.1. 
Study Rationale......................................................................................................................................24 
3.2. 
Introduction ...........................................................................................................................................24 
3.2.1. 
Background.....................................................................................................................................24 
3.2.2. 
Pharmacology .................................................................................................................................24 
3.2.3. 
Non-clinical Metabolism and Pharmacokinetics ............................................................................25 
3.2.4. 
Toxicology......................................................................................................................................25 
3.2.5. 
Previous Human Experience...........................................................................................................26 
3.3. 
Benefit/Risk Assessment........................................................................................................................28 
3.3.1. 
Overall Risk/Benefit Assessment ...................................................................................................28 
3.3.2. 
Coronavirus Disease 2019 (COVID-19) Risk Assessment.............................................................29 
4. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS.....................................................30 
5. 
STUDY DESIGN ............................................................................................................31 
5.1. 
Overall Design........................................................................................................................................31 
5.2. 
Number of Participants.........................................................................................................................31 
5.3. 
Number of Study Centers .....................................................................................................................31 
5.4. 
End of Study Definition and Duration of Participation .....................................................................32 
5.5. 
Scientific Rationale for Study Design ..................................................................................................32 
5.6. 
Justification for Dose.............................................................................................................................32 
5.7. 
Identification of Source Data................................................................................................................33 
6. 
STUDY POPULATION.................................................................................................34 
6.1. 
Inclusion criteria....................................................................................................................................34 
6.2. 
Exclusion criteria...................................................................................................................................35 
6.3. 
Lifestyle restrictions ..............................................................................................................................38 
6.4. 
Screen Failures.......................................................................................................................................39 
7. 
STUDY TREATMENTS................................................................................................40 
7.1. 
Study Treatments Administered ..........................................................................................................40 
7.2. 
Method of Treatment Assignment .......................................................................................................40 


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7.3. 
Dose administration...............................................................................................................................41 
7.4. 
Dose Modification..................................................................................................................................42 
7.5. 
Supply, Packaging and Labeling of the investigational products......................................................42 
7.6. 
Storage of the investigational products................................................................................................43 
7.7. 
Accountability, reconciliation and return of the investigational products .......................................43 
7.8. 
Recall ......................................................................................................................................................43 
7.9. 
Study Treatment Retention ..................................................................................................................44 
7.10. 
Treatment Compliance..........................................................................................................................44 
7.11. 
Prior Treatments ...................................................................................................................................44 
7.12. 
Concomitant Treatments ......................................................................................................................44 
8. 
DISCONTINUATION CRITERIA AND RELATED PROCEDURES....................46 
8.1. 
Withdrawal criteria...............................................................................................................................46 
8.2. 
Stopping rules ........................................................................................................................................46 
8.3. 
Discontinuation of Study Treatment....................................................................................................47 
8.4. 
Lost to Follow Up...................................................................................................................................47 
8.5. 
Withdrawn participant data collection................................................................................................48 
8.6. 
Replacement of participants.................................................................................................................48 
9. 
PROCEDURES...............................................................................................................50 
9.1. 
Investigational schedule ........................................................................................................................50 
9.2. 
Total volume of blood collected............................................................................................................50 
9.3. 
Pharmacokinetic Evaluation ................................................................................................................50 
9.3.1. 
Pharmacokinetic Assessment Methods and Timing .......................................................................50 
9.3.2. 
Sample shipment and storage..........................................................................................................51 
9.3.3. 
Bioanalytical method......................................................................................................................51 
9.3.4. 
Pharmacokinetic Criteria ................................................................................................................51 
9.4. 
Adverse Events and Serious Adverse Events ......................................................................................52 
9.4.1. 
Time Period and Frequency for Collecting AE/SAE Information..................................................52 
9.4.2. 
Method of Detecting, Recording and Reporting AEs and SAEs ....................................................52 
9.4.3. 
Follow-up of AEs and SAEs...........................................................................................................54 
9.4.4. 
Regulatory Reporting of Serious Adverse Events ..........................................................................55 
9.4.5. 
Pregnancy .......................................................................................................................................55 
9.4.6. 
Overdose.........................................................................................................................................56 
9.4.7. 
Medication errors............................................................................................................................57 
9.5. 
Safety Assessment..................................................................................................................................57 
9.5.1. 
Physical Examination .....................................................................................................................57 
9.5.2. 
Visual and Ophthalmological Examinations...................................................................................58 


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9.5.2.1. 
Visual Assessment......................................................................................................................58 
9.5.2.2. 
Ophthalmologic Examination.....................................................................................................58 
9.5.3. 
Vital Signs ......................................................................................................................................58 
9.5.3.1. 
Parameters ..................................................................................................................................58 
9.5.3.2. 
Method of Assessment ...............................................................................................................58 
9.5.4. 
Standard 12-lead ECG ....................................................................................................................58 
9.5.4.1. 
Parameters ..................................................................................................................................58 
9.5.4.2. 
Method of Assessment ...............................................................................................................58 
9.5.5. 
Laboratory safety parameters..........................................................................................................59 
9.5.5.1. 
Blood Safety Analysis................................................................................................................59 
9.5.5.2. 
Urinalysis parameters.................................................................................................................59 
9.5.5.3. 
Method of Assessment ...............................................................................................................59 
9.5.5.4. 
Laboratory Safety Determinations..............................................................................................60 
9.5.6. 
COVID-19 tests ..............................................................................................................................60 
9.6. 
Demographic and Baseline Characteristics.........................................................................................60 
9.6.1. 
Demography and Other Participant Information.............................................................................60 
9.6.2. 
Standard Cardiac Echocardiography...............................................................................................60 
9.6.3. 
Serology, Drug Screen, Alcohol Breath Test, Urine Cotinine Test, and Hormonology .................60 
10. 
DATA MANAGEMENT AND STATISTICS..........................................................62 
10.1. 
Data entry and management ................................................................................................................62 
10.1.1. 
Data collection................................................................................................................................62 
10.1.2. 
Data coding.....................................................................................................................................62 
10.1.3. 
Data validation................................................................................................................................62 
10.2. 
Statistical considerations.......................................................................................................................62 
10.2.1. 
Sample size.....................................................................................................................................62 
10.2.2. 
Statistical methods..........................................................................................................................63 
10.2.3. 
Description of data sets...................................................................................................................64 
10.2.3.1. Definition of data sets.................................................................................................................64 
10.2.3.2. Description of the sets ................................................................................................................64 
10.2.4. 
Demographic and baseline characteristics ......................................................................................64 
10.2.5. 
Protocol deviations .........................................................................................................................65 
10.2.6. 
Pharmacokinetic analysis................................................................................................................65 
10.2.7. 
Safety analysis ................................................................................................................................65 
10.2.7.1. Criteria........................................................................................................................................65 
10.2.7.2. Statistical methodology ..............................................................................................................66 
11. 
REFERENCES............................................................................................................67 
12. 
APPENDICES.............................................................................................................69 


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LIST OF TABLES
Table 1: Study treatments ........................................................................................................40 
Table 2: Treatment Numbers ...................................................................................................41 
Table 3: Volume of blood........................................................................................................50 
LIST OF APPENDICES
Appendix 1: Regulatory and legal considerations ...................................................................69 
Appendix 2: Adverse event and serious adverse event definitions..........................................74 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information...................77 
Appendix 4: Vital Signs and Electrocardiogram (ECG) normal ranges..................................78 
Appendix 5: Time windows for performing safety and pharmacokinetic (PK) assessments..79 


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1. SYNOPSIS
Name of Company:
PIERRE FABRE MEDICAMENT
Les Cauquillous
81500 Lavaur France
Represented by: Institut de Recherche Pierre Fabre 
Name of Finished Product: binimetinib (MEKTOVI®)
Name of active ingredient: binimetinib
Title of Study: 
A randomized, single-center, open-label, single dose, two-period, crossover pivotal bioequivalence study 
comparing binimetinib 3 x15 mg and 45 mg tablets in healthy participants.
Short title:
Bioequivalence binimetinib 3 x 15 mg and 45 mg formulations.
Principal Investigator:
Marina Klein, MD
Study center:
Biotrial, 7-9 rue Jean-Louis Bertrand, CS 34246, 35042 Rennes Cedex, France.
Publication (reference): 
NA
Clinical Phase:
Phase I
Rationale:
The currently commercially available MEKTOVI® (binimetinib) 15 mg tablets are provided as immediate 
release film-coated tablets for oral administration. For the treatment of adult patients with unresectable or 
metastatic melanoma with virus-induced rapidly accelerated fibrosarcoma murine sarcoma viral oncogene 
homolog B (BRAF) V600 mutation, the recommended dosing regimen is 45 mg twice daily (bis in die, BID). 
No food effect with the commercial formulation of 15 mg was demonstrated.
In order to reduce the patient’s burden, a new strength tablet containing 45 mg of binimetinib as active 
ingredient is being developed. As a result, the number of binimetinib tablets to be taken by the patients will 
be reduced from 6 tablets (6 x 15 mg) to 2 tablets (2 x 45 mg) per day. 
Binimetinib is a Class 4 compound in the Biopharmaceutics Classification System, therefore changes in the 
formulation require a bioequivalence (BE) study in case of post-approval changes.
Given that binimetinib did not reveal any relevant signal of genotoxic or mutagenic risk in preclinical studies 
(binimetinib Investigator’s Brochure latest version), with an acceptable safety profile following single oral 
dose administration up to 45 mg, this study will be performed in healthy participants, a population in which
extrinsic factors influencing the pharmacokinetics (PK) are expected to be minimal.


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Objectives and associated endpoints/estimands:
Objectives
Endpoints
Primary
To demonstrate the bioequivalence of 
binimetinib 
45 mg 
tablet 
Test 
formulation in comparison to 3 x 
15 mg tablet Reference formulation in 
healthy 
participants 
under 
fasted 
conditions.
Plasma concentrations of binimetinib and 
corresponding non-compartmental derived PK 
parameters 
[area 
under 
the 
plasma 
concentration-time curve (AUC) from time of 
administration 
to 
last 
observed 
plasma 
concentration (AUClast), AUC from time of 
administration to infinity (AUCinf), maximum 
observed plasma concentration (Cmax), AUC 
Test (T)/Reference (R) ratios].
Secondary
To measure secondary PK parameters 
of binimetinib and PK parameters of 
the metabolite (AR00426032).
To evaluate the safety and tolerability 
of binimetinib as a 1 x 45 mg Test 
tablet in comparison to 3 x 15 mg 
Reference tablets in healthy 
participants.
•
Secondary PK parameters of binimetinib: 
Time to reach Cmax (Tmax) and terminal 
half-life 
(t1/2,
Oz),
residual 
area 
(AUC_%Extrap_obs),
mean 
residence 
time (MRT).
•
PK parameters of AR00426032: AUClast, 
AUCinf, Cmax, Tmax, t1/2, Oz, mean residence 
time (MRT).
•
Incidence, 
nature 
and 
severity
of 
treatment-emergent 
adverse 
events 
(TEAEs).
•
TEAEs leading to dose interruption or 
discontinuation.
•
Treatment-emergent 
serious 
adverse 
events (treatment-emergent SAEs).
•
Changes in clinical laboratory parameters, 
vital signs, electrocardiograms (ECGs), 
ophthalmologic examinations.
Estimands:
The primary estimands are to demonstrate the bioequivalence of binimetinib 45 mg-tablet in comparison to 
the currently commercialized 3 x 15 mg tablets in healthy participants under fasted conditions. 
Forty (40) healthy participants will be enrolled to obtain a minimum of 36 evaluable healthy participants, who 
will receive within a crossover design the 2 formulations under fasted conditions. 
To demonstrate the bioequivalence between the two formulations, primary PK parameters (AUClast, AUCinf
and Cmax) will be analyzed separately using a linear mixed effects model with the log-transformed PK 
parameter as the dependent variable. Point estimates and 90% confidence intervals (CIs) will be provided for 
the ratio of Test to Reference (45 mg formulation as Test and 3 x 15 mg formulation as Reference). Two one-
sided t-tests will be used to test the ratio of Test to Reference. Bioequivalence will be declared if the 90% CI 
for the ratio of Test to Reference geometric means is within the range of 0.80 to 1.25 for all primary endpoints. 
Tmax will be analyzed using non-parametric methods for paired data.


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Design: 
This will be a randomized, single-center, open-label, 2-sequence, 2-period crossover Phase I study in healthy 
participants. Participants will receive each treatment after a washout period. 
The Reference (R) formulation will be the currently commercially available tablet containing 15 mg of 
binimetinib as active substance, administered as three tablets for a total of 45 mg binimetinib. The Test (T) 
formulation will be the tablet containing 45 mg of binimetinib as active substance, administered as one tablet.
Participants will be randomized into one of 2 treatment sequences (RT or TR) containing 2 treatment periods, 
with at least a 7-day washout between each dose. 
Thus, the study will consist of:
x
A screening period between 21 and 2 days before the first study treatment administration on Period 
(P) 1 Day (D) 1, 
x
2 treatment periods of 5 days each (including one ambulatory visit at D4 per period),
x
A washout of at least 7 days between P1D1 and P2D1,
x
An End-of-Study (EOS) visit to be performed 30 (± 3) days after the last study treatment 
administration or discontinuation.
Study treatments will be given by oral route in fasted conditions.
Details of the timing of each clinical visit and the assessments to be performed at each visit are summarized 
in the schedule of activities (SoA).
Number of participants:
A total of 40 healthy participants will be included in the study to allow for the completion of 36 participants
evaluable for PK.
Rationale for Number of Participants:
The primary objective of this study is to demonstrate bioequivalence between the test 45 mg-binimetinib tablet 
and the reference 3 x 15 mg binimetinib commercial tablets, based on PK endpoints Cmax, AUCinf and AUClast.
The null hypothesis is that the true ratio of the geometric mean of the test treatment to the geometric mean of 
the reference treatment, P(Test)/ P(Reference), for the Cmax, AUClast, and AUCinf is either <0.80 or >1.25. 
The alternate hypothesis is that the true ratio of the geometric mean of the test treatment to the geometric mean 
of the reference treatment for the Cmax, AUCinf and AUClast, is either t0.80 or d1.25. 
For each PK parameter designated as a primary endpoint, a two one-sided t-test (TOST) [Schuirmann et.al.,
1987] procedure with D=0.05 for each one-sided test will be used to test this set of hypotheses. 
Bioequivalence will be declared if the 90% CI for the true ratio of test to reference geometric means falls entirely 
within the range of 0.80 to 1.25 for all primary parameters (i.e., the null hypothesis must be rejected), in 
accordance with the EMA guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 
1/ Corr **. 20 Jan 2010).
Based on these criteria, assuming intra participant CV (CVintra) of Cmax to be around 25% as observed on the 
pilot study (W00074CI101) and a “Test/Reference” geometric mean ratio of 1.05; thirty-six healthy participants 
are needed to achieve a power of 90% at an alpha of 0.05.
Up to 40 participants will be included into the study to complete the study with at least 36 evaluable participants. 
Duration of participation:
The duration of study participation by participant will be approximately 2 months and this will include a 
screening evaluation up to 21 days before the first administration, 2 treatment periods of 5 days each 
(including one ambulatory visit on D4 per period) with at least a 7-day wash-out period between P1D1 and 
P2D1, and an EOS visit 30 (±3) days after the last study treatment administration or discontinuation of the 
last participant.
End-of-study definition:
The study will be completed when all participants have undergone the EOS visit [i.e., 30 (± 3) days after the 
last study treatment administration or discontinuation].


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Study products, dose and mode of administration:
Study treatment will be administered orally on D1 in the morning under fasted conditions.
Dosing: participants will fast from 10 hours before dosing until 4 hours after dosing where they will be served 
lunch. Dinner will be served approximately 12 hours after dosing.
Study treatment / Pharmaceutical form / Dose Strength 
Dose
Mode of administration
Test (T) formulation 
Binimetinib, oral film-coated tablet, 45 mg 
45 mg (1 tablet)
Oral, in fasted conditions
Reference (R) formulation 
Binimetinib, oral film-coated tablet, 15 mg
45 mg (3 tablets)
Oral, in fasted conditions
Participants will receive 2 single oral administrations of 45 mg binimetinib, separated by a washout of at 
least 7 days between 2 study treatment intakes.


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Criteria for inclusion / exclusion:
Inclusion:
All the following inclusion criteria must be met for a participant to be eligible to be included in this study:
1.
Provide a signed and dated informed consent form.
2.
Healthy participant.
Note: defined as an absence of clinically significant abnormalities and any active medical 
conditions, as identified by a detailed medical history, complete physical examination, vital signs, 
clinical laboratory tests, cardiac and ophthalmologic evaluation as assessed by the Investigator.
3.
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4.
Female participants must be postmenopausal or sterilized.
Note: due to preclinical data of teratogenicity and lack of data on human pregnancies with 
binimetinib, women of childbearing potential are excluded from this study.
Women are considered postmenopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum 
follicle stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL [except if treated 
with hormone replacement therapy (HRT)] or have had surgical bilateral oophorectomy (with or 
without hysterectomy) at least six weeks prior to dosing. In case of doubt on the menopausal status, 
the participant will not be included. In the case of oophorectomy alone, the reproductive status of 
the woman should be confirmed by a follow-up hormone level assessment to consider her of non-
childbearing potential.
5.
Men with a female partner of childbearing potential will be required to use an effective method of birth 
control or practice abstinence for the entire study duration, and for up to 30 days following the last dose 
of the study treatment. 
Note: the following birth control is recommended: condom for the male participant and an 
intrauterine device with spermicide or oral or implanted hormonal contraception for the female 
partner.
6.
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7.
Vital signs within the following ranges or if out of normal ranges, considered as not clinically significant 
by the Investigator except for high diastolic blood pressure (BP): 
(After at least 5 minutes rest in the supine position)
a.
Supine systolic BP PP+JDQG0 mmHg
b.
Supine diastolic BP PP+JDQGPP+J
c.
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d.
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e.
Orthostatic hypotension has to be ruled out based on the following criteria after standing for 
5 minutes:
i.
More than a 20 mmHg decrease in systolic BP or 10 mmHg decrease in diastolic BP.
ii.
Clinical signs/symptoms of postural hypotension (dizziness, syncope, etc.), regardless of 
vital signs.
8.
Participants must have safety laboratory values within the normal ranges or if out of normal ranges 
considered as not clinically significant by the Investigator except for the following parameters:
a.
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b.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase 
(GGT) 8/1 and alkaline phosphatase (ALP) 1.1 X ULN.
c.
Serum creatinine within normal range, except on PID-1 and P2D-1 ( 1.1 X ULN).
d.
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e.
Fasting glucose, coagulation panel (prothrombin ratio) within normal range and activated partial 
thromboplastin time (aPTT)  1.1 X ULN.
NB: It should be noted that for the parameters acceptable at  1.1 X ULN, if more than one 
parameter exceeds ULN, the subject will be excluded.


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Criteria for inclusion / exclusion:
Inclusion (continued):
9.
Able to communicate well with the Investigator and comply with the requirements of the study.
10. Participants must be willing to comply with dietary and fluid restrictions (from D-7 to 72 hours after the 
last study treatment administration).
11. Willing to remain in the clinical research unit as required by the protocol.
12. Covered by a health insurance system where applicable, and/or in compliance with the recommendations 
of the national laws in force relating to biomedical research.
Exclusion:
Participants meeting any of the following criteria will not be eligible to be included in this study:
1.
Concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or 
uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with 
protocol.
2.
Pregnant or currently breastfeeding women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin
(hCG) laboratory test.
3.
A past medical history of clinically significant ECG abnormalities or a family history (grandparents, 
parents, and siblings) of prolonged QT interval syndrome.
4.
Impaired cardiovascular function.
Note: including any one of the following:
a.
Left ventricular ejection fraction (LVEF) < 50% or below the institutional lower limit 
of the normal range (whichever was higher), as determined by standard cardiac 
echocardiography.
b.
Inability to determine the QT interval on ECG.
c.
Complete left bundle branch block.
d.
Use of a ventricular-paced pacemaker.
e.
Congenital long QT syndrome.
f.
History of or presence of clinically significant ventricular or atrial tachyarrhythmia.
g.
Clinically significant resting bradycardia (< 45 bpm).
h.
History of clinically documented myocardial infarction.
i.
History of angina pectoris.
j.
History of known structural abnormalities (i.e., cardiomyopathy).
k.
Other clinically significant cardiovascular disease (e.g., congestive heart failure,
atherosclerosis, labile hypertension or uncontrolled hypertension).
l.
Abnormal ECG defined as:
i.
PR interval > 220 msec, QRS complex > 110 msec, QT interval corrected 
using Fridericia’s method (QTcF) > 450 msec (male) and > 470 msec 
(female).
ii.
Any ST/T wave abnormalities.
iii.
Any atrial or ventricular arrhythmias, which are of clinical significance and 
may have had an impact on the safety of the participant or the study as 
determined by the Investigator.
iv.
Any cardiac conduction abnormalities.


Study Protocol W00074CI103
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Criteria for inclusion / exclusion:
Exclusion (continued):
5.
History of fainting spells or orthostatic hypotension episodes.
6.
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism 
or excretion of drugs or which may jeopardize the participant in case of participation in the study. 
Note: The Investigator should be guided by evidence of any of the following:
a.
History of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal 
bleeding.
b.
History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, 
cholecystectomy or bowel resection.
c.
History of, or clinical evidence of, pancreatic injury or pancreatitis.
d.
Clinical evidence of liver disease or liver injury as indicated by abnormal liver function 
tests such as ALT, AST, GGT, ALP, or serum bilirubin.
e.
Malabsorption syndrome.
f.
History of impaired renal function or elevated creatinine values indicating impaired renal 
function.
g.
Evidence of urinary tract obstruction or difficulty in voiding at screening.
7.
History of autonomic dysfunction or Gilbert syndrome.
8.
History of immunocompromised status, including a positive human immunodeficiency virus (HIV) 
infection (detected by enzyme-linked immunosorbent assay and western blot) test result.
9.
A positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), positive 
coronavirus disease 2019 (COVID-19) test result or other clinically relevant viral infections. 
10. Significant illness within the 2 weeks prior to dosing.
11. History of clinically significant drug allergy.
12. History of atopic allergy (asthma, urticaria, and eczematous dermatitis).
13. Use of any prescription drugs or over-the-counter (OTC) medications (except acetaminophen, i.e., 
paracetamol) and vitamins, supplements, and herbal remedies within 2 weeks prior to dosing. 
14. Participants taking acetaminophen (i.e., paracetamol) on a daily basis for more than 2 consecutive days 
within 1 week prior to dosing should not be enrolled.
15. History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or 
ophthalmopathy, as assessed by ophthalmologic examination at baseline that would be considered a risk 
factor for CSR/RVO [e.g., optic disc cupping, visual field defects, intraocular pressure (IOP) > 21 mmHg].
16. Subfoveal choroidal thickness outside of 40μm - 475μm range.
17. Neuromuscular disorders that were associated with elevated creatine kinase (CK) (e.g., inflammatory 
myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
18. 8QGHUZHQWPDMRUVXUJHU\ZHHNVSULRUWRVWDUWLQJVWXG\WUHDWPHQWRUZKRKDGQRWUHFRYHUHGIURPVLGH
effects of such a procedure.
19. Known history or ongoing alcohol abuse within 4 weeks prior to dosing of study treatment.
Note: alcohol consumption is prohibited 1 week prior to dosing.
20. Known regular use of recreational drugs within 4 weeks prior to dosing of study treatment. 
Note: evidence of alcohol abuse/drug use (criterion No. 19 and including this criterion No. 20) as 
indicated by the laboratory tests conducted during screening or baseline evaluations. 
21. Smoker or use of tobacco products or products containing nicotine in the last 4 weeks prior to first dosing 
of study treatment. 
Note: smokers will be defined as any participant who reports the use of a product containing 
nicotine during the preceding 30 days or has a positive urine cotinine test > 200 ng/mL.
22. Medical, psychiatric, cognitive or other conditions that may have compromised the participant's ability to 
understand the participant information, give informed consent, comply with the study protocol or complete 
the study.


Study Protocol W00074CI103
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Criteria for inclusion / exclusion:
Exclusion (continued):
23. Malignancy with the following exceptions:
a.
Adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing 
is required prior to study entry).
b.
Primary malignancy which had been completely resected and was in complete remission for 
 5 years.
24. History of retinal degenerative disease.
25. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local 
regulation, or within seven half-lives of the investigational agent taken (whichever is longer). 
Note: participants who had taken part in a clinical investigation receiving any form of binimetinib 
should have completed a 3-week washout prior to baseline.
26. Donation or loss of 400 mL or more of blood within 4 weeks prior to dosing.
27. Inability to swallow.
28. Any vaccination within 4 weeks prior to dosing.
29. Participant is under any administrative or legal supervision.
During the time window authorized for the screening visit (i.e., between 21 and 2 days before admission to the 
first treatment period), the Investigator may order a re-test of any parameter evaluated during the initial 
screening visit if he/she needs to evaluate the evolution of said parameter(s) or to confirm the value observed.
Rechecking of any parameter is to be limited to one time except when the measurement has not been obtained 
in accurate conditions.
Concomitant medications and study restrictions:
Concomitant treatments are not permitted throughout the study (i.e., until after the PK blood sampling and 
safety evaluations at time (t) 72h after the last study treatment administration), except HRT for 
postmenopausal women.
Participants will be requested to abstain from consumption of grapefruit, grapefruit hybrids, pomelos, 
pomegranate, star fruit, Seville oranges and charbroiled meats for 7 days (D-7) prior to the first dosing and 
throughout the study (i.e., up to t72h after the last study treatment administration). Juices and products 
containing the above-mentioned fruits are also required to be avoided during this time. 
Smokers (as defined in exclusion criterion No. 21) will not be included in this study. The use of tobacco 
products or products containing nicotine is prohibited for 4 weeks before the first dosing and throughout the 
study (i.e., up to t72h after the last study treatment administration). 
Alcohol consumption is prohibited for 1 week before the first dosing (D-7) and throughout the study (i.e., up 
to t72h after the last study treatment administration).
Participants will be requested to abstain from strenuous physical activity and consumption of food and 
stimulating beverages containing xanthine derivatives (i.e., no coffee, tea, chocolate or cola drinks) for 
48 hours prior to dosing (D-2) and throughout the study (i.e., up to t72h after the last study treatment
administration).
Study Schedule:
Screening:
Participants will be screened for eligibility between 21 and 2 days before the first study treatment 
administration of the first period.
Written informed consent will be obtained before any study procedure is performed. 
The screening will consist of verification of inclusion and exclusion criteria, demography (sex, age at 
screening, year of birth
and
ethnicity), medical history, alcohol history, smoking history, 
drug/alcohol/tobacco/substance usage (i.e., urine drug screen, alcohol breath test and urine cotinine test), prior 
medications/therapies/procedures, COVID-19 vaccination status, height and weight (to calculate BMI),
complete physical examination, vital signs (supine and standing systolic and diastolic BP and PR, body 
temperature), visual examination, ophthalmologic examination, 12-lead ECG, standard cardiac 
echocardiography, HBsAg, HCV Ab and HIV tests, COVID-19 test, serum FSH and estradiol for 
postmenopausal women (except if treated with HRT), serum pregnancy test for all female participants,
hematology, clinical chemistry, coagulation, urinalysis, assessment of concomitant medications/therapies; 
adverse event (AE) assessment.


Study Protocol W00074CI103
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Screening (continued):
During the time window authorized for the screening visit (i.e., between 21 and 2 days before admission to 
the first treatment period), the Investigator may order a re-test of any parameter evaluated during the initial 
screening visit if he/she needs to evaluate the evolution of said parameter(s) or to confirm the value 
observed.
Rechecking of any parameter is to be limited to one time except when the measurement has not been 
obtained in accurate conditions.
The results of screening must be known to the Investigator prior to the participant’s admission to the first 
treatment period.
Treatment periods:
In each treatment period (P1 and P2), eligible participants will be admitted to the research facilities on D-1, 1 
day prior to receiving the dose of study medication, and the following procedures will be performed: 
verification of inclusion and exclusion criteria, drug/alcohol/tobacco/substance usage (i.e., urine drug screen, 
alcohol breath test and urine cotinine test), prior medications/therapies/procedures (P1D-1 only), weight, 
complete physical examination, vital signs (supine and standing systolic and diastolic BP and PR, body 
temperature), visual examination, 12-lead ECG, COVID-19 test, serum pregnancy test for all female 
participants, hematology, clinical chemistry, coagulation, urinalysis, assessment of concomitant 
medications/therapies, AE assessment and sequence randomization (P1D1 only). Rechecking of any 
parameter is to be limited to one time except when the measurement has not been obtained in accurate 
conditions.
In the morning of D1, allocated treatment will be administered following at least 10 hours of fasting.
Vital signs will be assessed at pre-dose and on D2 and D4 (24 and 72h post-dose) and 12-lead ECGs will be 
performed at pre-dose and on D2 (24h post-dose). Complete physical examination will be performed on D2 
(24h post-dose) and visual examination will be performed on D2 and D4 (24 and 72h post-dose). Hematology, 
clinical chemistry, coagulation and urinalysis will be performed on D2 and D3 (24 and 48h post-dose). PK 
blood samples will be taken at pre-dose within 15 min before treatment administration (0h), and at t +0.5, 
0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 and 72h post-dose. 
Concomitant medications/therapies and AEs will be assessed continuously, from when the participant first 
provides informed consent until the EOS visit.
Meals will be served as indicated in the schedule of assessments.
Following the 48h post-dose procedures, the participants will be discharged and will return for an ambulatory 
visit on D4, and then return for the next treatment period or an EOS visit.
Follow-up:
An EOS visit will occur 30 (± 3) days after the last study treatment administration or discontinuation. The 
EOS visit will cover weight, complete physical examination, vital signs (supine and standing systolic and 
diastolic BP and PR, body temperature), visual examination, ophthalmologic examination, 12-lead ECG,
COVID-19 test, serum pregnancy test for all female participants, hematology, clinical chemistry, coagulation, 
urinalysis, assessment of concomitant medications/therapies, and AE assessment.
Criteria for evaluation:
Pharmacokinetic 
Assessments
Blood samples (4 mL) will be drawn for the assay of plasma binimetinib and its 
metabolite AR00426032 at the following time-points: within 15 min before 
treatment administration (0h), and at t+0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 
12, 24, 36, 48 and 72h post-dose in each dosing period.
The following parameters will be derived by non-compartmental analysis from 
the plasma binimetinib concentration-time profiles: Cmax, Tmax, AUClast, AUCinf
(primary parameters); and apparent terminal HOLPLQDWLRQ UDWH FRQVWDQW Ȝz),
terminal elimination half-life (t½), time of last observed plasma concentration 
(Tlast), apparent total body clearance (CL/F), residual area in percentage
(AUC_%Extrap_obs), apparent volume of distribution (Vz/F) and mean 
residence time (MRT) (secondary parameters).
Additionally, the following PK parameters will be derived by non-
compartmental analysis from the plasma AR00426032 concentration-time 
profiles: Cmax, Tmax, AUClast, AUCinf; t½, Tlast, Ȝz, MRT.
The PK parameters will be determined using Phoenix® WinNonlin® version 8.1 
or higher (Certara USA, Inc., Princeton, NJ).


Study Protocol W00074CI103
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Safety Assessments
Safety will be evaluated from:
•
Clinical safety (reported AEs, complete physical examinations, weight, vital 
signs, visual examinations, ophthalmologic examinations, standard 12-lead 
ECGs).
•
Laboratory safety assessments (standard hematology, clinical chemistry,
coagulation analyses, urinalysis and COVID-19 tests).
A serum pregnancy test will be performed for all female participants at 
screening, on D-1 of each period and at the EOS visit.
AEs will be monitored throughout the study, i.e., from when the participant first 
provides informed consent until the EOS visit [30 (± 3) days after the last study 
treatment administration or discontinuation].
Statistical methods:
Statistical analysis of clinical parameters and PK parameters will be performed 
under the responsibility of Biotrial.
PK analysis:
Plasma concentrations (binimetinib and AR00426032) will be summarized over 
time by formulation and corresponding listings will be prepared. 
Concentration-time profile plots will be prepared on linear and log-linear 
coordinates for each participant with both formulations on the same graph, as 
well as arithmetic mean (± standard deviation [SD]) with both formulations on 
the same graph.
Binimetinib and AR00426032 PK parameters will be summarized by 
formulation and corresponding listings will be prepared.
For binimetinib only:
•
Scatter plots and box whisker plots will be generated for the comparison of 
Cmax, AUClast and AUCinf.
•
To demonstrate the bioequivalence between the two formulations, primary 
PK parameters (AUClast, AUCinf and Cmax) will be analyzed separately using 
linear mixed effects model with log-transformed PK parameter as the 
dependent variable, sequence, period and formulation as fixed effects and 
participant with sequence as random effect. Point estimates and 90% CIs will 
be provided for the ratio of Test to Reference (3 x 15 mg formulation as 
Reference and 45 mg formulation as Test). Bioequivalence will be declared 
if the 90% CI for the ratio of Test to Reference geometric means is within 
the range of 0.80 to 1.25 for all primary endpoints.
•
Tmax will be analyzed using non-parametric tests for paired data.
Safety Analysis
All AEs and TEAEs will be described by preferred term and system organ class.
TEAEs will be described by formulation and overall and all AEs will be listed.
Summary descriptive statistics will be provided for other safety parameters (vital 
signs measurements, ECG, complete physical examination, weight, COVID-19
tests, visual examination, ophthalmologic examination, and laboratory tests).


Study Protocol W00074CI103
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2. SCHEDULE OF ACTIVITIES (SOA)
Treatment Phase
Epoch
Screening
Treatment Period 1
Washout
Treatment Period 2
Follow-up
Procedure/Assessment
Screening
Run-in
Period 1
Washout
perioda
Run-in
Period 2
End of Studyb
D-21 to 
D-2
D-1
D1
D2
D3
D4
At least 
7 days
D-1
D1
D2
D3
D4
30 (±3) days 
after last dosing
Relative time (h)
Screening 
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h
t72h
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h t72h
Ambulatory visits
X
X
X
X
Stay in center
<----------------------------------------------------------------->
<------------------------------------------------------------>
Discharge
X
X
Informed consent 
X
Sequence randomization
X
Inclusion 
and 
exclusion
criteria
X
X
X c
Demographyd
X
Medical history
X
Alcohol history
X
Smoking history
X
Drug / alcohol / tobacco /
substance usagee
X
X
X
Prior medications / therapies
/ procedures
X
X
COVID-19 
vaccination
status
X
Height
X
Weight
X
X
X
X
Complete 
physical 
examination
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X


Study Protocol W00074CI103
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Treatment Phase
Epoch
Screening
Treatment Period 1
Washout
Treatment Period 2
Follow-up
Procedure/Assessment
Screening
Run-in
Period 1
Washout
perioda
Run-in
Period 2
End of Studyb
D-21 to 
D-2
D-1
D1
D2
D3
D4
At least 
7 days
D-1
D1
D2
D3
D4
30 (±3) days 
after last dosing
Relative time (h)
Screening 
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h
t72h
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h t72h
Visual examinationg
X
X
X
X
X
X
X
X
Ophthalmologic 
examinationh
X
X
Standard 12-Lead ECGi
X
X
X
X
X
X
X
X
Standard cardiac 
echocardiographyj
X
Hepatitis B surface antigen,
hepatitis C antibody and HIV
X
COVID-19 testk
X
X
X
X
FSH and estradioll
X
Pregnancy testm
X
X
X
X
Hematologyn
X
X
X
X
X
X
X
X
Clinical chemistryo
X
X
X
X
X
X
X
X
Coagulationp
X
X
X
X
X
X
X
X
Urinalysisq
X
X
X
X
X
X
X
X
PK blood samplesr
<------------------------------------------------------------>
<-------------------------------------------------------->
Concomitant 
medications/therapies
X
Assess continuously
Adverse eventss
X
Assess continuously
Study 
treatment  
administration
X
X
Meals: B=Breakfast, 
Lu=Lunch, Di=Dinnert
Lu, Di
Lu
Di
B
Di
B
Lu, Di
Lu
Di
B
Di
B


Study Protocol W00074CI103
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1PF74 / Version 2.0 / 26 OCT 2022 
a.
At least 7 days between P1D1 and P2D1.
b.
The end-of-study (EOS) visit [30 (± 3 days) after the last study treatment administration or discontinuation] must be done for all the included participants, except participants who did 
not receive any dose of study treatment, for whom the EOS visit is not required. 
c.
For P2D-1: exclusion criteria and only inclusion criteria 7 (vital sign) and 8 (safety lab) will be checked. Clinical relevance of abnormal value could be discussed for the participant’s 
participation in the second period of the trial. However, and among the exclusion criteria PR interval >220ms is acceptable, if not clinically significant (NCS).
d.
Sex, age at screening, year of birth and ethnicity.
e.
Urine drug screen, alcohol breath test and urine cotinine test.
f.
Supine and standing systolic and diastolic BP and PR (after at least 5 minutes at rest in the supine position and after standing for 5 minutes), and body temperature. At screening visit and 
D-1, 3 supine BP measurements will be performed within 5 minutes. An average for each parameter (SBP, DBP, HR) will be obtained.
g.
Visual assessment (general inspection of the eyes, examination of motility and alignment, any visual disturbances such as blurred vision or loss of vision) to be performed on site by the 
Investigator.
h.
Full ophthalmologic examination by ophthalmologist to be performed at screening (within 2 weeks before randomization) and EOS (within 1 week up to EOS) and in case of emergency, 
including best corrected visual acuity for distance testing, optical coherence tomography and/or fluorescein angiography, slit lamp examination, intraocular pressure and fundoscopy with 
attention to retinal abnormalities.
i.
ECGs are to be performed in triplicate (conducted within approximately 5 to 10 minutes total time). ECGs should be performed before blood collection at equivalent nominal time 
points.
j.
Within 2 weeks before randomization .
k.
COVID-19 antigenic test is to be performed at screening and D-1 of each treatment period and at the EOS visit. COVID-19 polymerase chain reaction (PCR) test is to be performed on 
P1D-1, if required.
l.
For postmenopausal female participants, serum FSH and estradiol to be performed at screening to confirm postmenopausal status (except if the participant is treated with HRT).
m.
For all female participants, serum pregnancy tests are to be performed at screening, D-1 of each period and at the EOS visit.
n.
Erythrocytes (red blood cells, RBC), hematocrit, hemoglobin, platelets; leukocyte count with differential: basophils, eosinophils, lymphocytes, monocytes, neutrophils/absolute 
neutrophil count; RBC indices: mean corpuscular hemoglobin, mean corpuscular volume, reticulocytes/erythrocytes.
o.
ALT, albumin, ALP, AST, GGT, bicarbonate, bilirubin (total and indirect), urea, calcium, chloride, CK, creatinine, amylase, lipase, total cholesterol, glucose, lactate dehydrogenase, 
magnesium, potassium, sodium, total protein, uric acid.
p.
aPTT and prothrombin ratio.
q.
Urinalysis (dipstick: pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrites and leukocyte esterase) will be performed. In case of positive results for white blood cells, red 
blood cells and/or nitrites, urine will be sent to the laboratory for microscopy and culture. If there is an explanation for the positive dipstick results (e.g., menses), this will have to be 
discussed with the Sponsor and should be recorded, and there might be no need to perform microscopy and culture)
r.
Serial PK blood samples will be collected at pre-dose within 15 min before treatment administration (0h), and t+0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12h post-dose, as well as at 
24, 36, 48 and 72h post-dose. 1 min, 3 min and 5 min time windows will be authorized up to 0.75 h, up to 1.5 h and up to 12 h, respectively. 15 min, 30 min and 120 min time windows 
will be authorized at 24h, 36h and 48h-72h, respectively. 
s.
All AEs are collected from when the participant first provides informed consent until the EOS visit [30 (± 3) days after the last study treatment administration or discontinuation]. 
t.
In addition, a snack will be provided in the afternoon of D1 and lunch will be provided on D2. 


Study Protocol W00074CI103
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LIST OF ABBREVIATIONS
ACSF
Array clinical service form
ADME
Absorption, distribution, metabolism and excretion
ADR
Adverse drug reaction 
AE
Adverse event
AESI
Adverse event of specific interest
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
ANSM
Agence Nationale de Sécurité du Médicament et des produits de santé 
(French Drug Agency)
aPTT
Activated partial thromboplastin time
ARS
Agence Régionale de Santé (Regional Health Agency)
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve 
AUClast
Area under the plasma concentration-time curve from time of administration
to the last observed plasma concentration
AUCinf
Area under the plasma concentration-time curve from time of administration
to infinity
B
Breakfast
BE
Bioequivalence
BID
Twice daily (bis in die)
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BRAF
Virus-induced rapidly accelerated fibrosarcoma murine sarcoma viral 
oncogene homolog B
°C
Degree Celsius
CDER
Food and Drug Administration Center for Drug Evaluation and Research
CI
Confidence interval
CK
Creatine kinase
CL/F
Apparent total body clearance
Cmax
Maximum observed plasma concentration
COVID-19
Coronavirus disease 2019
CPMP
Committee for Proprietary Medicinal Products
CPP
Comité de Protection des Personnes (Independent Ethics Committee)


Study Protocol W00074CI103
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Page 21
1PF74 / Version 2.0 / 26 OCT 2022
CRA
Clinical research associate
CSR
Central serous retinopathy; or Clinical study report 
CTD
Clinical Trial Document
CVintra
IQWUDဨLQGLYLGXDOYDULDWLRQV
CYP
Cytochrome P450
D
Day
Di
Dinner
ECG
Electrocardiogram
eCRF
Electronic case report form 
EDC
Electronic data capture 
e.g.
Exempli gratia (for example)
EMA
European Medicines Agency
EOS
End-of-study
ERK
Extracellular signal-regulated kinase
etc.
Et cetera (and the rest)
EudraCT
European Clinical Trials Database 
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GLP
Good Laboratory Practice
hCG
Human chorionic gonadotropin
H
Hour
HBs Ag
Hepatitis B surface antigen
HCV Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormone replacement therapy
ICF
Informed consent form
ICH
International Council on Harmonization
i.e.
Id est (that is)
IEC
Independent Ethics Committee
IOP
Intraocular pressure
IRPF
Institut de Recherche Pierre Fabre
IV
Intravenous


Study Protocol W00074CI103
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1PF74 / Version 2.0 / 26 OCT 2022
K2EDTA
Dipotassium ethylenediaminetetraacetic acid
kg
Kilogram
L
Liter
LLOQ
Below the lower limit of quantification
Lu
Lunch
LVEF
Left ventricular ejection fraction
Ȝz
Apparent terminal elimination rate constant
m2
Square meter
MedDRA
Medical Dictionary for Regulatory Activities
MEK
Mitogen-activated protein kinase kinase
mg
Milligram
min
Minute
mIU
Milli-international unit
mL
Milliliter
mmHg
Millimeter of mercury
MRT
Mean residence time 
msec
Millisecond
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
NCSF
Novartis clinical service form
NCS
Not clinically significant
ng
Nanogram
NOAEL
No observed adverse effect level
OTC
Over-the-counter
P
Period
P3-MI
Phase 3-market image
PCR
Polymerase chain reaction
PCSA
Potentially clinically significant abnormal(ity)
pg
Picogram
PK
Pharmacokinetics
PR
Pulse rate
QTcF
QT interval corrected using Fridericia’s method
R
Reference
RAF
Rapidly accelerated fibrosarcoma
RAS
Rat sarcoma virus


Study Protocol W00074CI103
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1PF74 / Version 2.0 / 26 OCT 2022
RBC
Red blood cell (erythrocyte)
RVO
Retinal vein occlusion
SADR
Serious adverse drug reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation 
SEM
Standard error of the mean
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reaction
t
Time
T
Test
t1/2
Terminal elimination half-life
Tlast
Time of last observed plasma concentration
Tmax
Time to reach Cmax (time at peak plasma level)
TEAE
Treatment-emergent adverse event
TOST
Two one-sided t-test
UGT1A1
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1
ULN
Upper limit of normal range
Vz/F
Apparent volume of distribution
WOCBP
Woman of childbearing potential 
WHO
World Health Organization
WMA
World Medical Association


Study Protocol W00074CI103
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3. INTRODUCTION
3.1.
Study Rationale
The current commercially available MEKTOVI® (binimetinib) 15 mg tablets are provided as 
immediate release film-coated tablets for oral administration. For the treatment of adult patients 
with unresectable or metastatic melanoma with virus-induced rapidly accelerated fibrosarcoma 
murine sarcoma viral oncogene homolog B (BRAF) V600 mutation, the recommended dosing 
regimen is 45 mg twice daily (bis in die, BID). No food effect with the commercial formulation 
of 15 mg was demonstrated.
In order to reduce the patient’s burden, a new strength tablet containing 45 mg of binimetinib 
as active ingredient is being developed. As a result, the number of binimetinib tablets to be 
taken by the patients will be reduced from 6 tablets (6 x 15 mg) to 2 tablets (2 x 45 mg) per 
day. 
Binimetinib is a Class 4 compound in the Biopharmaceutics Classification System, therefore 
changes in the formulation require a bioequivalence (BE) study in case of post-approval 
changes.
Given that binimetinib did not reveal any relevant signal of genotoxic or mutagenic risk in 
preclinical studies, with an acceptable safety profile following single oral dose administration 
up to 45 mg (binimetinib Investigator’s Brochure latest version [1]), this study will be 
performed in healthy participants, a population in which extrinsic factors influencing the 
pharmacokinetics (PK) are expected to be at a minimum.
3.2.
Introduction
3.2.1. Background
Binimetinib is an orally bioavailable, selective and potent mitogen-activated protein kinase 
kinase (MEK) 1 and MEK 2 inhibitor. As a MEK inhibitor, this compound has the potential to 
benefit participants with advanced cancers by inhibiting the oncogene rat sarcoma (RAS) /
rapidly accelerated fibrosarcoma (RAF) / MEK / extracellular signal-regulated kinase (ERK)
pathway. Binimetinib has previously been examined in the treatment of rheumatoid arthritis 
based on the role of the RAS/RAF/MEK/ERK pathway in inflammatory processes.
3.2.2. Pharmacology
Binimetinib in combination with encorafenib is approved in Europe for the treatment of adult 
patients with unresectable or metastatic melanoma with a BRAF V600 mutation. In addition, 
binimetinib in combination with encorafenib and cetuximab is approved in Japan for the 
treatment of unresectable advanced or recurrent colorectal cancer with BRAF mutations
progressing after chemotherapy.
Binimetinib has been or is also currently being investigated mainly in combination with a 
variety of additional compounds, including encorafenib, paclitaxel and inhibitors of 
phosphoinositide 3-kinase, RAF, epidermal growth factor receptor, protein kinase C, 
cyclin-dependent kinase 4/6 and type 1 insulin-like growth factor receptor in patients with 
selected advanced or metastatic solid tumors, including, among other tumors, melanoma, 
biliary, colorectal, and ovarian cancers. The clinical development program of binimetinib 
encompasses patients with selected advanced or metastatic solid tumors, including 
neuroblastoma RAS viral oncogene homolog- and BRAF-mutant melanoma, BRAF- and 
Kirsten RAS viral oncogene homolog-mutant non-small cell lung cancer, high-grade platinum-


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resistant ovarian cancer, low-grade serous ovarian cancer, biliary, colorectal, and pancreatic 
cancers.
Numerous in vitro and in vivo studies were performed to evaluate and confirm the ability of 
binimetinib to affect its intended targets, MEK1/2, and produce beneficial pharmacodynamics 
and efficacy outcomes.
For more details, please see the Investigator’s Brochure [1].
3.2.3. Non-clinical Metabolism and Pharmacokinetics
In rat and monkey absorption, distribution, metabolism and excretion (ADME) studies, with 
radiolabeled binimetinib administered orally as a suspension as well as intravenously (IV), the 
average absorption was ~50% in rat and ~50-100% in monkey. The rate of absorption was 
faster in the monkey ADME study [time to reach maximum observed plasma concentration 
(Tmax) = 0.67h] than in the rat ADME study (Tmax = 4.7h), although in other rat single-dose PK 
studies the rate of absorption has been higher (Tmax as low as 0.33h).
Binimetinib is highly bound to plasma proteins across species (97.2% in humans), and 
preferentially distributes to the plasma.
The average oral bioavailability in both nonclinical ADME studies was similar to absorption, 
indicating a minimal first pass effect in rats and monkeys. In single-dose PK studies, oral 
bioavailability in preclinical species (mice, rats, dogs and monkeys) ranged from 26.7% in 
monkeys to 76% in rats. Overall, the area under the plasma concentration-time curve (AUC) 
and maximum observed plasma concentration (Cmax) values increased in an approximately 
dose-proportional manner in mice, rats and monkeys.
Following single- and repeat-dose administration of binimetinib to Sprague-Dawley rats for up 
to 6 months, females had approximately 2-fold higher exposures than males at equivalent 
doses. Cmax and AUC from time of administration to infinity (AUCinf) values increased with
the dose, but the increase was less than dose proportional. Cynomolgus monkeys receiving 
binimetinib for 28 days or 9 months showed no consistent differences in exposure between 
females and males. No significant changes in exposure versus day were observed.
The primary metabolites of binimetinib across species and in vitro systems occurred through 
direct glucuronidation, oxidative N-demethylation (AR00426032), and cleavage of the N-O
bond of the alkyl sidechain to form an amide. In human liver microsomes and recombinant 
cytochrome P450s (CYPs), the major oxidative metabolite was AR00426032. In vitro,
CYP1A2 and CYP2C19 catalyzed the formation of AR00426032.
For more details, please see the Investigator’s Brochure [1].
3.2.4. Toxicology
The safety of binimetinib has been evaluated in acute and repeat-dose studies in 
Sprague-Dawley rats and cynomolgus monkeys in accordance with international regulatory 
guidelines for preclinical toxicity studies and in adherence to current Good Laboratory Practice 
(GLP). In general, administration of binimetinib at doses up to 100 mg/kg was tolerated in rats 
and up to 3 mg/kg was tolerated in monkeys in a panel of safety studies.
There was no evidence of a genotoxic potential seen in the GLP bacterial reverse mutation 
(Ames) test, in the in vitro mouse lymphoma assay or the in vivo mouse micronucleus study.
In the rat embryo-fetal developmental toxicity study, no binimetinib-related mortality was seen. 
Binimetinib was well tolerated at 10 mg/kg; gestational body weight gain and fetal body 
weights were significantly reduced in the 30 and 100 mg/kg dose groups and food consumption 


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was reduced in all dose groups. The number of ossified fetal sternebrae was significantly 
decreased in the 30 and 100 mg/kg dose groups. Based on the results, the no observed adverse 
event level (NOAEL) in rats with respect to embryo-fetal developmental abnormalities is 10 
mg/kg binimetinib. In the rabbit embryo-fetal developmental toxicity study, binimetinib 
related-mortality was seen in the 10 and 20 mg/kg dose groups. 
Based on the results, the NOAEL in rabbit with respect to embryo-fetal developmental 
abnormalities is 2 mg/kg binimetinib.
No fertility or multi-generational reproductive toxicology studies have been performed with 
binimetinib.
For more details, please see the Investigator’s Brochure [1].
3.2.5. Previous Human Experience
As of 20 January 2022, a total of 3483 participants 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 participants constitute the binimetinib safety 
population, which includes 243 healthy participants, 17 participants with hepatic dysfunction, 
6 participants with renal dysfunction, 164 participants with rheumatoid arthritis and 
3053 participants with advanced cancer. For more details, please see the Investigator’s 
Brochure [1].
ADME studies:
The PK of binimetinib is characterized by moderate to high variability, accumulation of 
approximately 1.5-fold, and steady state concentrations reached within 15 days. Binimetinib 
Tmax tends to range from 1.5 to 2 hours. Binimetinib PK has been shown to be approximately 
dose-proportional from 30 mg BID to 80 mg BID (Study ARRAY-162-111 [2]).
The human ADME study (CMEK162A2102 [3]) indicated that approximately 50% of the 
binimetinib dose was absorbed. The primary metabolic pathways include glucuronidation [up 
to 61.2% via uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 
(UGT1A1)], N-dealkylation, amide hydrolysis [up to 17.8% via CYP1A2 and CYP2C19]. The 
excretion route was 31.7% of unchanged binimetinib in feces and 18.4% in urine. Estimated 
renal clearance of unchanged binimetinib was 6.3% of the total dose. The impact of UGT1A1 
inhibitors or inducers has not been clinically assessed.
The active metabolite AR00426032 has been monitored in several clinical studies; the results 
indicate that AR00426032 is <20% of binimetinib exposure.
Based on a population PK analysis, age, body weight and gender do not have a clinically 
important effect on the systemic exposure of binimetinib.
Four relative bioavailability studies were carried out:
x
Clinical Study ARRAY-162-104 [4] assessed the relative bioavailability of single dose 
40 mg binimetinib capsules and formulated binimetinib tablets in healthy participants in a 
fasted state, with no statistically or clinically significant difference in binimetinib exposure 
observed.
x
Clinical Study CMEK162A2101J [5] assessed the relative bioavailability of binimetinib 
Novartis clinical service form (NCSF) and Array clinical service form (ACSF) tablets 
following a single oral dose given as 3 × 15 mg tablets in healthy participants. The ACSF 
and NCSF drug product formulations are identical except that the drug substance used in 


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NCSF drug product was made with a slightly different process and at a different 
manufacturer. Binimetinib exposure was similar between the NCSF and ACSF tablets. The 
Phase 3-market image (P3-MI) formulation used in pivotal clinical studies is identical to 
the ACSF/NCSF formulation except that P3-MI drug product is coated with a slightly lower 
quantity of cosmetic film coat.
x
Clinical Study CMEK162A2110 [6] evaluated the relative bioavailability of a binimetinib 
liquid formulation (crushed tablets in suspension) and 3 × 15 mg tablets following a single 
oral dose in healthy participants. A slightly higher peak plasma binimetinib concentration 
was observed following the liquid formulation, while total exposure (AUC) remained 
unchanged. These results indicate that binimetinib administered as a 45 mg single dose 
using the liquid formulation is an adequate formulation to be used in future clinical studies, 
including those conducted in a pediatric population.
x
Clinical study W00074CI101 [7] investigated the relative bioavailability of binimetinib 3
x 15 mg and 45 mg tablets in fourteen (14) healthy participants under fasted condition. The 
preliminary results demonstrated that the geometric mean ratios (Test/Reference) for 
binimetinib Cmax, AUClast and AUCinf between 0.98 and 1.05 indicated that the 
bioavailability of the test formulation is not different from the reference formulation. 
Moreover, median Tmax values observed were not different between the 2 formulations.
Overall, the plasma PK profiles of binimetinib appear to be similar with the new strength 
tablet (Test: 1 x 45 mg tablet) and the currently commercialized formulation (Reference: 3 
x 15 mg tablets).
Single oral administrations of 45 mg binimetinib, as 1 x 45 mg tablet and 3 x 15 mg tablets 
in a crossover design with a washout of 7 days between the 2 administrations, were safe 
and well tolerated for the majority of participants. One (1) out of the 14 participants
presented, after receiving these single doses, an AE of moderate severity (already described 
and potentially expected for this class of family treatment, i.e., MEK inhibitors), considered 
emergent and related to IMP (retinal exudates), which resolved spontaneously without 
treatment and without sequelae. Overall, this pilot study has given appropriate results to 
design the current pivotal bioequivalence study.
Food effect and drug interaction studies:
Food-effect clinical studies have indicated that the influence of food on the PK of binimetinib 
is mild and not clinically relevant; therefore, binimetinib can be taken without regard to food 
(ARRAY-162-104 [4] and CMEK162A2103 [8]). Results from a drug interaction study with 
binimetinib and midazolam suggested that continuous intake of binimetinib produced no 
relevant CYP3A4 induction (CMEK162A2105 [9]). Binimetinib solubility in vitro has been 
shown to be pH-dependent. Results from a drug interaction study in healthy participants
indicate that the extent of binimetinib exposure is not altered in the presence of the proton-
pump inhibitor rabeprazole (ARRAY-162-105 [10]). In vitro studies also demonstrated that 
binimetinib is a P-glycoprotein and breast cancer resistance protein substrate, but the effects of 
inhibitors of these substrates on the PK of binimetinib in vivo are unknown. 
Although encorafenib is a relatively potent reversible inhibitor of UGT1A1, when binimetinib 
was co-administered with encorafenib no differences in binimetinib exposure were observed 
clinically.


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Safety:
Data collected in the nonclinical and clinical programs, as well as class effects with MEK 
inhibitors overall, indicate that binimetinib exposure may be associated with rash-like events, 
gastrointestinal events (including diarrhea, nausea and vomiting, stomatitis/mucositis), 
reversible elevations of creatine kinase (CK), aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), hemorrhage, edema, cardiac events, retinal events, and interstitial 
lung disease or non-infectious pneumonitis. Ocular toxic effects occurred infrequently, with 
blurred vision being the most frequent single ocular event (4%). The vast majority of events 
were grade 1-2 and either asymptomatic, managed with supportive care or improved or 
resolved with dose reduction or temporary interruption of binimetinib. Less frequently, ejection 
fraction decrease and hypertension have also been observed with binimetinib [11].
For more details, please see the Investigator’s Brochure [1].
3.3.
Benefit/Risk Assessment
3.3.1. Overall Risk/Benefit Assessment
The inclusion and exclusion criteria have been chosen to enable a uniform study population 
and to minimize possible risks due to the administration of binimetinib.
In the completed clinical studies, single doses of 45 mg/kg have been tested and well tolerated
[1]. In addition, the recommended dose of binimetinib, which has had marketing authorization 
since September 2018, is 45 mg BID [12].
The participants in this study will receive a single dose of binimetinib as 3 x 15 mg tablets and 
a single dose of binimetinib as one 45 mg tablet.
The participants will not benefit from taking part in this study; the data from this study will 
support the development of binimetinib as a 45 mg tablet in order to reduce the burden on 
patients who must currently take 6 x 15 mg tablets daily.
Given that this study involves single dose administration in healthy participants, the main 
adverse events (AEs) that may be anticipated based on the safety profile of binimetinib are 
gastrointestinal events (nausea, diarrhea), nervous system disorders (headache, presyncope), 
dermatologic events (rash, acne) and eye events (vision blurred) [13].
Other common to very common identified risks with binimetinib mainly after repeated doses
are blood and lymphatic system disorders (anemia), cardiac disorders (ejection fraction 
decreased, left ventricular dysfunction), eye disorders (chorioretinopathy, detachment of retinal 
pigment epithelium, eyelid edema, macular edema, periorbital edema, retinal detachment,
retinal vein occlusion, retinopathy, serous retinal detachment, subretinal fluid, blurred vision,
visual acuity reduced, visual impairment), gastrointestinal disorders (abdominal pain, diarrhea,
nausea, vomiting), general disorders and administration site conditions (fatigue, peripheral 
edema, pyrexia, asthenia, face edema, generalized edema, edema, xerosis), investigations (AST 
increased, blood CK increased, ALT increased), musculoskeletal and connective tissue 
disorders (muscle spasms, muscular weakness, musculoskeletal pain, myalgia), nervous system 
disorders (dizziness, dysgeusia), respiratory, thoracic and mediastinal disorders (epistaxis, 
pulmonary embolism), skin and subcutaneous disorders (dermatitis acneiform, dry skin, rash, 
erythema, erythematous rash, macular rash, maculo-papular rash, papular rash, skin fissures), 
and vascular disorders (hypertension) [1]. Other potential risks are listed in the Investigator’s 
Brochure [1]. These AEs are unlikely to occur with the administration of single doses of 
binimetinib.


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There can be risks, special discomforts or symptoms in connection with the measures 
performed in this study. Specifically, these are, e.g., risks associated with blood draws or skin 
reactions to electrocardiogram (ECG) adhesive electrodes.
The risks resulting from blood draws are circulatory reactions that may result in changes in 
blood pressure (BP), dizziness, or nausea, or possibly fainting or seizure. Some blood draws 
will be taken using an indwelling venous cannula. This may occasionally cause local irritation 
such as swelling, hardening or inflammation of the vein, formation of blood clots, or bleeding 
into the surrounding tissue (bruising). Nerve damage may occur that may lead in rare instances 
to long-lasting paresthesia, impaired touch sensation and to persistent pain. In this regard motor 
disturbances such as impaired mobility of the affected arm may also occur. When using 
adhesive ECG electrodes, people with overly sensitive skin may experience itching and redness 
beneath the adhesive patches (electronic leads). These reactions are usually harmless and 
resolve once the electrode leads are removed. 
The study will be carried out in a center specialized in early phase studies with experienced 
medical staff and adequate facilities. From admission on Day (D)-1, until discharge on D3 of 
each of the 2 treatment periods, the participants will be confined and under constant medical 
monitoring. To ensure the safety of the participants, AEs, vital signs parameters, ECG and 
laboratory parameters will be carefully monitored. 
Participants with a known history of clinically significant drug allergies are excluded from the 
study, as are participants with a history or current evidence of central serious retinopathy 
(CSR), retinal vein occlusion (RVO) or ophthalmopathy that may be considered a risk for either 
of those conditions, a history of retinal disease, or a history of neuromuscular disorders 
associated with elevated CK.
The risks associated with this study are considered elucidated and well controlled by cautionary 
measures.
3.3.2.
Coronavirus Disease 2019 (COVID-19) Risk Assessment
The risk of exposure to people infected with COVID-19 cannot be completely excluded, as the 
participants may need to be exposed to public areas (e.g., commute to the site and at the site).
Risk mitigation:
x
Risk assessment by the Investigator and Sponsor before deciding to start the trial.
x
Record participants’ COVID-19 vaccination status at screening.
x
Test for COVID-19 prior to each stay at the study site.
x
Closely monitor symptoms and signs for COVID-19.
x
Reduce the public exposure while ambulatory.
COVID-19 screening procedures will be performed according to Biotrial procedures as deemed 
necessary by the Investigator. COVID-19 tests will be performed at screening, D-1 of each 
period and at the end-of-study (EOS) visit.


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4. OBJECTIVES, ENDPOINTS AND ESTIMANDS
Objectives
Endpoints
Primary
x
To demonstrate the bioequivalence 
of binimetinib 45 mg tablet Test 
formulation in comparison to 3 x 
15 mg tablet Reference formulation 
in healthy participants under fasted 
conditions.
x
Plasma concentrations of binimetinib and 
corresponding 
non-compartmental 
derived PK parameters [area under the 
plasma concentration-time curve (AUC) 
from time of administration to last 
observed plasma concentration (AUClast), 
AUC from time of administration to 
infinity (AUCinf), maximum observed 
plasma concentration (Cmax), AUC Test 
(T)/Reference (R) ratios].
Secondary
x
To 
measure 
secondary 
PK 
parameters of binimetinib and PK 
parameters 
of 
the 
metabolite 
(AR00426032).
x
To 
evaluate 
the 
safety 
and 
tolerability of binimetinib as a 1 x 
45 mg Test tablet in comparison to 3 
x 15 mg Reference tablets in healthy 
participants.
x
Secondary PK parameters of binimetinib: 
Time to reach Cmax (Tmax) and terminal 
half-life 
(t1/2,
Oz), 
residual 
area 
(AUC_%Extrap_obs), mean residence time
(MRT).
x
PK parameters of AR00426032: AUClast,
AUCinf, Cmax, Tmax, t1/2, Oz, mean residence 
time (MRT).
x
Incidence, 
nature 
and 
severity 
of 
treatment-emergent 
adverse 
events 
(TEAEs).
x
TEAEs leading to dose interruption or 
discontinuation.
x
Treatment-emergent 
serious 
adverse 
events (treatment-emergent SAEs).
x
Changes in clinical laboratory parameters, 
vital signs, electrocardiograms (ECGs), 
ophthalmologic examinations.
Estimands:
The primary estimands are to demonstrate the bioequivalence of binimetinib 45 mg-tablet in 
comparison to the currently commercialized 3 x 15 mg tablets in healthy participants under 
fasted conditions. 
Forty (40) healthy participants will be enrolled to obtain a minimum of 36 evaluable healthy 
participants, who will receive within a crossover design the 2 formulations under fasted 
conditions. 
To demonstrate the bioequivalence between the two formulations, primary PK parameters 
(AUClast, AUCinf and Cmax) will be analyzed separately using linear mixed effects model with 
log-transformed PK parameter as the dependent variable. Point estimates and 90% confidence 
intervals (CIs) will be provided for the ratio of Test to Reference (45 mg formulation as Test


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and 3 x 15 mg formulation as Reference). Two one-sided t-tests will be used to test the ratio of 
Test to Reference. Bioequivalence will be declared if the 90% CI for the ratio of Test to 
Reference geometric means is within the range of 0.80 to 1.25 for all primary endpoints. Tmax
will be analyzed using non-parametric methods for paired data.
5.
STUDY DESIGN
5.1.
Overall Design
This will be a randomized, single-center, open-label, 2-sequence, 2-period crossover Phase I 
study in healthy participants. The aim is to demonstrate the bioequivalence of binimetinib 
45 mg tablets Test formulation in comparison to 3 x 15 mg tablet Reference formulation in 
healthy participants under fasted conditions.
The Reference (R) formulation will be the currently commercially available tablet containing 
15 mg of binimetinib as active substance, administered as three tablets for a total of 45 mg 
binimetinib. The Test (T) formulation will be the tablet containing 45 mg of binimetinib as 
active substance, administered as one tablet. 
Participants will be randomized into one of 2 treatment sequences (RT or TR) containing 2 
treatment periods, with at least a 7-day washout between each dose. 
Thus, the study will consist of:
x
A screening period between 21 and 2 days before the first study treatment 
administration on Period (P) 1 Day (D) 1, 
x
2 treatment periods of 5 days each (including one ambulatory visit at D4 per period),
x
A washout of at least 7 days between P1D1 and P2D1,
x
An End-of-Study (EOS) visit to be performed 30 (± 3) days after the last study treatment 
administration or discontinuation.
Study treatments will be given by oral route in fasted conditions.
In each treatment period, following the 48h post-dose procedures, the participants will be 
discharged and will return for an ambulatory visit on D4, and then return for the next treatment 
period or an EOS visit.
Details of the timing of each clinical visit and the assessments to be performed at each visit are 
summarized in the schedule of activities (SoA, Section 2).
5.2.
Number of Participants
A total of 40 healthy participants will be included in the study to allow for the completion of 
36 participants evaluable for PK.
Participants who drop out may be replaced as described in Section 8.6. Replacement 
participants will be assigned to the same treatment sequence as the participants they are 
replacing, in order to allow for the completion of 36 evaluable participants.
5.3.
Number of Study Centers
The study will be performed at one investigational site in France.


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5.4.
End of Study Definition and Duration of Participation
The study will be completed when all participants will have undergone the end of study visit 
[i.e., 30 (± 3 days) after the last study treatment administration or discontinuation of the last 
participant].
The maximum duration of the study for a participant will be approximately 2 months between 
the screening visit and the EOS visit. Following the completion of the study, a 3-month 
exclusion period will apply to the participant before they are allowed to take part in another 
clinical study.
5.5.
Scientific Rationale for Study Design
Binimetinib is a Class 4 compound in the Biopharmaceutics Classification System, therefore 
changes in the formulation require a bioequivalence (BE) study in case of post approval 
changes [14]. Thus, this study will be conducted as a randomized, open-label, two-period 
crossover design to demonstrate the bioequivalence of binimetinib 45 mg tablets Test 
formulation in comparison to 3 x 15 mg tablet Reference formulation in healthy participants 
under fasted conditions.
This study design is also standard for a BE study and is consistent with Food and Drug 
Administration (FDA) and EMA guidelines.
Based on the half-life of 15 mg binimetinib tablets, a washout period of at least 7 days will be 
used between each dosing days in the 2 treatment periods, in order to ensure that drug 
concentrations are below the lower limit of quantification (LLOQ) prior to the next dose 
administration.
Healthy participants will be included in this study. The binimetinib safety profile is well known 
as described in the Investigator’s Brochure [1]. In addition, preliminary results of clinical study 
W00074CI101 (see section 3.2.5) in healthy participants has demonstrated that the 2 single oral 
administrations binimetinib at 45mg (as 1 x 45 mg tablet and 3 x 15 mg tablets) separated by a 
7-day washout period were safe and was well tolerated.
The primary estimands are described in Section 4.
The primary objective of this study is to demonstrate bioequivalence between the test 45 mg-
binimetinib tablet and the reference 3 x 15 mg binimetinib commercial tablets, based on 
PK endpoints Cmax, AUCinf and AUClast.
The study design is open-label without placebo control because the primary estimand is an 
objective measurement (PK), investigating the Bioequivalence, that does not require blinding 
or a placebo control.
5.6.
Justification for Dose
For the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600 
mutation, the recommended dosing regimen is 45 mg BID [12]. A single dose of 45 mg, i.e.,
half the recommended daily dose, is appropriate with this type of study design as it provides 
sufficient information for the extent of absorption and will thus be investigated in the present 
bioequivalence study.


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5.7.
Identification of Source Data
Electronic data capture (EDC) via electronic case report forms (eCRFs) will be used for this 
study, as described in Section 10.1.1. Data will be collected on source documents and entered 
by the study personnel into the eCRFs in a timely manner.


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6.
STUDY POPULATION
Each participant must take part in the informed consent process and sign and date the informed 
consent form (ICF) before any procedures specified in this protocol are performed.
Nevertheless, if necessary and after agreement of the Sponsor, any measures identical to those 
planned in the protocol for the participants’ screening that have already been performed within 
the protocol time window authorized for the screening examinations could be used in the study,
in order to minimize the constraints on the participants.
6.1.
Inclusion criteria
All the following inclusion criteria must be met for a participant to be eligible to be included 
in this study:
1. Provide a signed and dated ICF.
2. Healthy participant.
Note: defined as an absence of clinically significant abnormalities and any active 
medical conditions, as identified by a detailed medical history, complete physical 
examination, vital signs, clinical laboratory tests, cardiac and ophthalmologic
evaluation as assessed by the Investigator.
3. 0DOHDQGIHPDOHEHWZHHQDQG\HDUVRIDJHDWWKHGD\RIFRQVHQWVLJQDWXUH
4. Female participants must be postmenopausal or sterilized. 
Note: due to preclinical data of teratogenicity and lack of data on human pregnancies 
with binimetinib, women of childbearing potential are excluded from this study.
Women are considered postmenopausal and not of childbearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months 
of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 
40 mIU/mL and estradiol < 20 pg/mL [except if treated with hormone replacement 
therapy (HRT)] or have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six weeks prior to dosing. In case of doubt on the menopausal 
status, the participant will not be included. In the case of oophorectomy alone, the 
reproductive status of the woman should be confirmed by a follow-up hormone level 
assessment to consider her of non-childbearing potential.
5. Men with a female partner of childbearing potential will be required to use an effective 
method of birth control or practice abstinence for the entire study duration and for up to 
30 days following the last dose of the study treatment. 
Note: the following birth control is recommended: condom for the male participant and 
an intrauterine device with spermicide or oral or implanted hormonal contraception for 
the female partner.
6. %RG\PDVVLQGH[%0,RIWRNJP2ZLWKERG\ZHLJKWNJand < 100 kg.


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7. Vital signs within the following ranges or if out of normal ranges, considered as not 
clinically significant by the Investigator except for high diastolic BP:
(After at least 5 minutes rest in the supine position)
a.
SXSLQHV\VWROLF%3PP+JDQGPP+J
b. 6XSLQHGLDVWROLF%3PP+JDQGPP+J
c.
Supine pulse rate (PR)  45 to  100 beats per minute (bpm).
d. BRG\WHPSHUDWXUHEHWZHHQ&DQG&.
e.
Orthostatic hypotension has to be ruled out based on the following criteria after 
standing for 5 minutes:
i.
More than a 20 mmHg decrease in systolic BP or 10 mmHg decrease in 
diastolic BP.
ii.
Clinical signs/symptoms of postural hypotension (dizziness, syncope, etc.), 
regardless of vital signs.
8. Participants must have safety laboratory values within the normal ranges or if out of 
normal ranges considered as not clinically significant by the Investigator except for the 
following parameters:
a.
7RWDOELOLUXELQXSSHUOLPLWRIQRUPDO8/1
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyltransferase (GGT) 8/1 and alkaline phosphatase (ALP) 1.1 X ULN.
c.
Serum creatinine within normal range, except on P1D-1 and P2D-1 (1.1 X 
ULN).
d. 6HUXPDP\ODVHDQGOLSDVH8/1
e.
Fasting glucose, coagulation panel (prothrombin ratio) within normal range and 
activated partial thromboplastin time (aPTT) 1.1 X ULN.
NB: ,WVKRXOGEHQRWHGWKDWIRUWKHSDUDPHWHUVDFFHSWDEOHDW;8/1if more than one 
parameter exceeds ULN, the subject will be excluded.
9. Able to communicate well with the Investigator and comply with the requirements of the 
study.
10. Participants must be willing to comply with dietary and fluid restrictions (from D-7 to 
72 hours after the last study treatment administration, see Section 6.3).
11. Willing to remain in the clinical research unit as required by the protocol.
12. Covered by a health insurance system where applicable, and/or in compliance with the 
recommendations of the national laws in force relating to biomedical research.
6.2.
Exclusion criteria
Participants meeting any of the following criteria will not be eligible to be included in this 
study:
1. Concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, 
active or uncontrolled infection) that could cause unacceptable safety risks or compromise 
compliance with protocol.


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2. Pregnant or currently breastfeeding women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) laboratory test.
3. A past medical history of clinically significant ECG abnormalities or a family history 
(grandparents, parents, and siblings) of prolonged QT interval syndrome.
4. Impaired cardiovascular function.
Note: including any one of the following:
a.
Left ventricular ejection fraction (LVEF) < 50% or below the institutional 
lower limit of the normal range (whichever was higher) as determined by 
standard cardiac echocardiography.
b. Inability to determine the QT interval on ECG.
c.
Complete left bundle branch block.
d. Use of a ventricular-paced pacemaker.
e.
Congenital long QT syndrome.
f.
History of or presence of clinically significant ventricular or atrial 
tachyarrhythmia.
g. Clinically significant resting bradycardia (< 40 bpm).
h. History of clinically documented myocardial infarction.
i.
History of angina pectoris.
j.
History of known structural abnormalities (i.e., cardiomyopathy).
k. Other clinically significant cardiovascular disease (e.g., congestive heart 
failure, atherosclerosis, labile hypertension or uncontrolled hypertension).
l.
Abnormal ECG defined as:
i. PR interval > 220 msec, QRS complex > 110 msec, QT interval 
corrected using Fridericia’s method (QTcF) > 450 msec (male) and 
> 470 msec (female).
ii. Any ST/T wave abnormalities.
iii. Any atrial or ventricular arrhythmias, which are of clinical significance 
and may have had an impact on the safety of the participant or the 
study as determined by the Investigator.
iv. Any cardiac conduction abnormalities.
5. History of fainting spells or orthostatic hypotension episodes.
6. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism or excretion of drugs or which may jeopardize the participant in 
case of participation in the study. 
Note: The Investigator should be guided by evidence of any of the following:
a.
History of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or 
rectal bleeding.
b. History of major gastrointestinal tract surgery such as gastrectomy, 
gastroenterostomy, cholecystectomy or bowel resection.


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c.
History of, or clinical evidence of, pancreatic injury or pancreatitis.
d. Clinical evidence of liver disease or liver injury as indicated by abnormal liver 
function tests such as ALT, AST, GGT, ALP, or serum bilirubin.
e.
Malabsorption syndrome.
f.
History of impaired renal function or elevated creatinine values indicating 
impaired renal function.
g. Evidence of urinary tract obstruction or difficulty in voiding at screening.
7. History of autonomic dysfunction or Gilbert syndrome.
8. History of immunocompromised status, including a positive human immunodeficiency 
virus (HIV) infection (enzyme-linked immunosorbent assay and western blot) test result.
9. A positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV 
Ab) or positive COVID-19 test result or other clinically relevant viral infections. 
10. Significant illness within the 2 weeks prior to dosing.
11. History of clinically significant drug allergy.
12. History of atopic allergy (asthma, urticaria, and eczematous dermatitis).
13. Use of any prescription drugs or over-the-counter (OTC) medications (except 
acetaminophen, i.e., paracetamol) and vitamins, supplements, and herbal remedies within 
2 weeks prior to dosing. 
14. Participants taking acetaminophen (i.e., paracetamol) on a daily basis for more than 
2 consecutive days within 1 week prior to dosing should not be enrolled.
15. History or current evidence of central serous retinopathy (CSR), retinal vein occlusion 
(RVO) or ophthalmopathy as assessed by ophthalmologic examination at baseline that 
would be considered a risk factor for CSR/RVO [e.g., optic disc cupping, visual field 
defects, intraocular pressure (IOP) > 21 mmHg].
16. Subfoveal choroidal thickness outside of 40μm - 475μm range. 
17. Neuromuscular disorders that were associated with elevated CK (e.g., inflammatory 
myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
18. 8QGHUZHQW PDMRU VXUJHU\   ZHHNV SULRU WR VWDUWLQJ VWXG\ WUHDWPHQW or who had not 
recovered from side effects of such a procedure.
19. Known history or ongoing alcohol abuse within 4 weeks prior to dosing of study treatment.
Note: alcohol consumption is prohibited 1 week prior to dosing.
20. Known regular use of recreational drugs within 4 weeks prior to dosing of study treatment. 
Note: evidence of alcohol abuse/drug use (criterion No. 19 and including this criterion
No. 20) as indicated by the laboratory tests conducted during screening or baseline 
evaluations. 
21. Smoker or use of tobacco products or products containing nicotine in the last 4 weeks prior 
to first dosing of study treatment. 
Note: smokers will be defined as any participant who reports the use of a product 
containing nicotine during the preceding 30 days or has a positive urine cotinine test
> 200 ng/mL.


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22. Medical, psychiatric, cognitive or other conditions that may have compromised the 
participant's ability to understand the patient information, give informed consent, comply 
with the study protocol or complete the study.
23. Malignancy with the following exceptions:
a. Adequately treated basal cell or squamous cell carcinoma of the skin (adequate 
wound healing is required prior to study entry).
b. Primary malignancy which had been completely resected and was in complete 
UHPLVVLRQIRU 5 years.
24. History of retinal degenerative disease.
25. Participation in any clinical investigation within 4 weeks prior to dosing or longer if 
required by local regulation, or within seven half-lives of the investigational agent taken 
(whichever is longer). 
Note: participants who had taken part in a clinical investigation receiving any form of 
binimetinib should have completed a 3-week washout prior to baseline.
26. Donation or loss of 400 mL or more of blood within 4 weeks prior to dosing.
27. Inability to swallow.
28. Any vaccination within 4 weeks prior to dosing.
29. Participant is under any administrative or legal supervision.
During the time window authorized for the screening visit (i.e., between 21 and 2 days before 
admission to the first treatment period), the Investigator may order a re-test of any parameter 
evaluated during the initial screening visit if he/she needs to evaluate the evolution of said 
parameter(s) or to confirm the value observed.
Rechecking of any parameter is to be limited to one time except when the measurement has 
not been obtained in accurate conditions.
6.3.
Lifestyle restrictions
Participants will be requested to abstain from consumption of grapefruit, grapefruit hybrids, 
pomelos, pomegranate, star fruit, Seville oranges and charbroiled meats for 7 days (D-7) prior 
to the first dosing and throughout the study. Juices and products containing the above-
mentioned fruits, as well as orange juice, are also required to be avoided during this time. 
Smokers (as defined in exclusion criterion No. 21, see Section 6.2) will not be included in this 
study. The use of tobacco products or products containing nicotine is prohibited for 4 weeks
before the first dosing and throughout the study (i.e., up to t72h after the last study treatment
administration).
Alcohol consumption is prohibited for 1 week before the first dosing (D-7) and throughout the 
study.
Participants will be requested to abstain from strenuous physical activity and consumption of 
food and stimulating beverages containing xanthine derivatives (i.e., no coffee, tea, chocolate 
or cola drinks) for 48 hours prior to dosing (D-2) and throughout the study. 
An overnight fast will be imposed so that no food is taken within at least 10 hours before study 
treatment administration. Participants will remain fasted for at least 4 hours after dosing.


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For each treatment period, meals will be served in the unit: lunch at an appropriate time on 
D-1, dinner on D-1 ending at least 10 hours before dosing, lunch on D1 4 hours after dosing, a 
snack in the afternoon of D1, and dinner on D1 approximately 12 hours after dosing, and 
breakfast, lunch and dinner at appropriate times on D2, and breakfast on D3.
All meal times during hospitalization will be reported in the eCRF.
All meals and fluids taken after the treatment will be standardized with regards to composition 
and time of administration during the sampling period.
During the in-house periods, meals will be standardized and identical for all participants and 
all periods.
The start time and end time of the standardized dinner meal consumed and the percentage of 
the meal consumed on the day prior to dosing (D-1 of each period) will be documented on the 
eCRF. 
The start time and end time of meals consumed and the percentage of the meals consumed for 
lunch and dinner on the dosing days (P1D1 and P2D1) will also be recorded.
Drinking of water will be allowed ad libitum except from 1 h before up until 2 h after dosing.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized (i.e., participants who do not meet one or more of the 
inclusion/exclusion criteria at screening or on P1D-1, or who are not randomized for other 
reasons, e.g., consent withdrawal). A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes informed consent and visit date, demography, screen 
failure details, eligibility criteria, and any adverse event (AE/SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, and a complete screening assessment panel will be performed.


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7. STUDY TREATMENTS
7.1.
Study Treatments Administered
Table 1 provides an overall summary of the study treatment administered during the study, 
further information is provided in the Investigator’s Brochure [1].
Table 1: Study treatments
Study Treatment 
Name:
Test Formulation: 
Binimetinib 45 mg, film-coated 
tablet
Reference Formulation:
Binimetinib film coated tablet
(MEKTOVI®) [12]
Active ingredients
Binimetinib
Binimetinib
Excipients
Tablet core:
Lactose monohydrate, cellulose 
microcrystalline, croscarmellose 
sodium, magnesium stearate, silica 
colloidal anhydrous
Film-coating (Opadry II TF-White):
Polyvinyl alcohol – part hydrolyzed, 
macrogol 4000, talc
Tablet core:
Lactose monohydrate, cellulose 
microcrystalline, silica colloidal 
anhydrous, croscarmellose sodium, 
magnesium stearate
Film-coating (Opadry II Yellow):
Polyvinyl alcohol, macrogol 3350, 
titanium dioxide, talc, iron oxide 
yellow, iron oxide black
Dosage formulation:
Film-coated tablet
Film-coated tablet
Unit dose 
strength/Dosage level:
45 mg / 45 mg (1 tablet)
15 mg / 45 mg (3 tablets)
Route of Administration
Oral
Oral
Dosing instructions:
Study treatments will be administered orally on D1 in the morning.
Participants should be instructed to take binimetinib with approximately 240
mL of water. Participants should be instructed to swallow the tablet(s) whole 
and not to chew or crush them.
Participants will fast from 10 hours before dosing until 4 hours after dosing 
where they will be served lunch. Dinner will be served approximately 12 
hours after dosing.
Packaging and Labeling
Study treatments will be provided as treatment units each comprised of 
1 blister of 14 film-coated tablets of binimetinib 45 mg and 1 blister of 
12 film-coated tablets of binimetinib 15 mg. Each pack and blister will be 
labeled as required per country requirements in local languages.
Details of labeling are provided in Section 7.5.
7.2.
Method of Treatment Assignment
Each participant will be identified in the study by a participant code that will be assigned upon 
enrolment. Participants will be considered enrolled in the study as soon as they have signed an 
ICF.
The participant code will contain 8 digits, corresponding to the country number, the center 
number and the participant’s number according to chronological order (the order in which they 
signed the ICF).


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Screen-failed participants keep their participant number. New participants must always be 
allotted a new participant number.
The sequences will be randomized as follows:
x
Binimetinib 1 x 45 mg tablet (T) / binimetinib 3 x 15 mg tablet (R)
x
Binimetinib 3 x 15 mg tablet (R) / binimetinib 1x 45 mg tablet (T)
For each participant, the Sponsor will provide one study treatment box, identified by a study 
treatment code and containing 2 blisters (one per period). There will be 2 types of study 
treatment boxes, randomly assigned: 
x
Blister 1 = R + blister 2 = T.
x
Blister 1 = T + blister 2 = R.
The assignment of the treatment kit numbers (101 to 152) to participants will be done in 
ascending order of inclusion, on D1 pre-dose in Period 1 only and will also be used for Period 2
(each kit contains the treatments for Period 1 and Period 2). This activity will be managed by 
a Pharmacy staff member.
The first participant included will receive the first treatment box and so on for the other 
participants. 
Participants withdrawn from the study will retain their participant number. New participants 
must always be assigned a new participant number. The replacement participant will receive 
the replacement treatment (R101 to R152).
For example: for the participant who is assigned the treatment number 105, their replacement 
participant will receive the treatment number R105.
Treatment numbers and replacement treatment numbers are shown in Table 2.
Table 2: Treatment Numbers
Treatment Number
Replacement Treatment Number
101 to 152
R101 to R152
Blinding
Not applicable, as this is an open-label study.
7.3.
Dose administration
The study treatments will be administered only to participants included in this study following 
the procedures set out in the present clinical study protocol.
Treatments will be given orally on D1 in the morning after a 10-hour overnight fast in each 
period. Participants should be instructed to take binimetinib with approximatively 240 mL of 
water. Participants should be instructed to swallow the tablet(s) whole and not to chew or crush 
them.
Participants will be dosed in an upright position; during the next 4 hours, they will remain 
predominantly in a supine position, but will be allowed to walk short distances, such as to the 
toilet.
Follow-up evaluation (EOS visit) will be performed D30 (±3 days) after the last study treatment
administration, or discontinuation.


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7.4.
Dose Modification
None.
7.5.
Supply, Packaging and Labeling of the investigational products
A sufficient quantity, to be defined by Biotrial, of study treatments to perform the study and to 
ensure retention samples requested per FDA Guidance [15] will be supplied as well as an 
acknowledgement of receipt form. The Institut de Recherche Pierre Fabre will provide a 
certificate of analysis and a batch release certificate for those batches of study treatment used 
in the study. As soon as the pharmacist receives delivery of the study treatments, he/she will 
check the contents and immediately return documents to the Investigational Medicinal Products 
Department of the Institut de Recherche Pierre Fabre (IRPF) and/or designee (acknowledgment 
of receipt, and temperature recording graph of the Temptale®) that accompanies the parcel 
containing study treatment, duly completed and signed. Documents included in the parcel will 
be kept in the Investigator's file.
The study treatments will be packed and labeled for clinical use purpose by Institut de 
Recherche Pierre Fabre or designee according to the European Union-Good Manufacturing 
Practice, including its annex 13, and all local regulations.
The study treatments will bear the following information on the labels:
Treatment unit box labeling
-
Sponsor's name and address.
-
Product name.
-
Pharmaceutical form.
-
Dosage.
-
Administration route.
-
Number of units.
-
Batch and/or code number.
-
Protocol number and EudraCT number.
-
Treatment number.
-
Statement "FOR CLINICAL TRIAL USE ONLY."
-
Storage conditions.
-
Expiry date.
Treatment unit blister labeling
-
Name of the Sponsor.
-
Protocol number.
-
Packaging batch number.
-
Treatment number.
-
Expiry date as month/year (EXP: MM/YYYY).
-
Dosage & concentration of the tested product.
-
Period.


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The Investigator, or designee, will only dispense study treatments to participants included in 
this study. The dispensing for each participant will be documented in the participant’s eCRF.
Further details will be provided in the study-specific Pharmacy Manual.
7.6.
Storage of the investigational products
Binimetinib 45 mg tablets will be stored below 25°C. For binimetinib 15 mg tablets there are 
no specific storage instructions. All study treatments will be stored in a secure and locked 
storage area with limited access, with temperature control and monitoring.
Further details will be provided in the study-specific Pharmacy Manual.
The pharmacist at Biotrial will be responsible for the correct storage and handling of the study 
treatments.
Deviations from the storage requirements, including any actions taken, must be documented.
7.7.
Accountability, reconciliation and return of the investigational products
The Investigator must maintain a complete and current dispensing and inventory record. The 
Investigator is accountable for all test articles supplied by the Sponsor. The dispenser uses this 
information to maintain an accurate and complete dispensing and inventory record. The 
designated copies of the completed dispensing and inventory record will be returned to the 
Sponsor.
Regulatory agencies require accounting for the disposition of all investigational drugs received 
by each clinical site. Information on drug disposition required by law consists of the date 
received, date administered, quantity administered, and the participant to whom the drug was 
administered.
Study treatments are shipped to the investigational site as needed. Drug accounting will be 
reviewed by the site monitor during routine monitoring visits. Each time a dose is prepared for 
a participant, the following information should be recorded: the participant’s study number, the 
total dose prepared, the number of tablets used, the number of the lot from which the dose was 
prepared, and the initials of the person preparing the dose. 
At the completion or termination of the study, a final drug accountability review and 
reconciliation must be completed, and any discrepancies must be investigated and their 
resolution documented.
All full, partially full, and empty study treatment containers must be returned by Biotrial to the 
Sponsor or destroyed by Biotrial after the Monitor has performed accountability (this does not 
include retention samples) and after Sponsor approval and with the appropriate form.
Upon completion or termination of the study, a sample of all study supplies will be retained at 
the study site according to applicable regulations. Once the retention period has elapsed, any 
remaining unused drug will be returned to the Sponsor in the original containers, or destroyed, 
as directed in writing by Sponsor.
Retention samples will be collected in compliance with the current FDA guidance [15].
7.8.
Recall
In case of recall of study treatments (decided by the Competent Authorities or the Sponsor), 
the Investigator will be immediately informed by the Sponsor.


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The Investigator, in collaboration with the Sponsor representatives [Study Manager, clinical 
research associate (CRA)] must urgently:
-
Put in quarantine all study treatments concerned by the recall.
-
Stop the administration of the concerned study treatments to the participants.
The Study Manager/CRA organizes the return of the recalled products to the Investigational 
Medicinal Product Management Service of IRPF or designee, according to the Sponsor 
procedures.
7.9.
Study Treatment Retention
A sufficient quantity of Binimetinib 45 mg tablets and MEKTOVI® (binimetinib 15 mg tablets)
will be supplied by Sponsor to perform the study and to ensure retention samples requested per 
FDA Guidance [15]. The Sponsor’s representative will provide a certificate of analysis for the 
batches of IMP used in the study.
7.10.
Treatment Compliance
All doses will be administered in the clinical unit under direct supervision of the Investigator 
or designee. 
After administration of each study treatment, a hand check and a mouth check will be 
performed to verify that the participant has swallowed the dose. All drug administration 
information will be recorded in the eCRF and in the drug accountability form.
The definition of overdoses is provided in Section 9.4.6; the definitions of medication errors, 
abuse and misuse are provided in Appendix 2. Overdoses, medication errors, abuse or misuse 
will be collected as part of study treatment dosing information and/or as a protocol violation, 
as required. 
7.11.
Prior Treatments
Reasonable efforts will be made to determine all relevant treatments [prescription drugs or 
OTC medications (except acetaminophen, i.e., paracetamol) and vitamins, supplements, and 
herbal remedies] received by the participant within 2 weeks before study treatment
administration. Intake of acetaminophen (i.e., paracetamol) by the participant within 1 week 
before study treatment administration should also be determined. The participants’ COVID-19
vaccination status at the time of the screening visit will be determined.
As indicated in Section 6.2, the intake of prescription drugs, OTC medications (except 
acetaminophen, i.e., paracetamol) and vitamins, supplement and herbal remedies within 
2 weeks before dosing and the intake of acetaminophen, i.e., paracetamol, on a daily basis for 
more than 2 consecutive days within 1 week before dosing are prohibited. Any vaccination is 
prohibited within 4 weeks prior to dosing. In addition, participation in any clinical investigation 
within 4 weeks prior to dosing or longer if required by local regulations, or within seven half-
lives of the investigational agent taken (whichever is longer), is prohibited, and participants 
who had taken part in a clinical investigation receiving any form of binimetinib should have 
completed a 3-week washout prior to baseline.
All relevant information must be recorded on the participant's eCRF.
7.12.
Concomitant Treatments
Concomitant treatments are not permitted throughout the study (i.e., until after the PK blood 
sampling and safety evaluations at t72h after the last study treatment administration), except 


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HRT for postmenopausal women. Concomitant medications / therapies will be assessed 
continuously (see Section 2, SoA).
For any participant, if the use of any concomitant treatment becomes necessary (e.g., the 
treatment of an AE) before the end of the PK and safety evaluations at t72h after the last study 
treatment administration, the treatment must be recorded on the eCRF, including the reason for 
treatment, generic name of the drug, dosage, route, and date and time of administration. If a 
treatment is administered, the Sponsor’s medical monitor must be promptly notified in order 
to assess the participant’s eligibility for continuing study participation.


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8. DISCONTINUATION CRITERIA AND RELATED PROCEDURES
8.1.
Withdrawal criteria
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, which corresponds to the EOS visit [i.e., 30 (± 3 days) after the last study 
treatment administration or discontinuation]. See the SoA (Section 2) for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that need to 
be completed.
The EOS visit is not required for participants who did not receive any dose of study treatment.
The participant will be permanently discontinued both from the study treatment and from the 
study at that time.
If a participant withdraws from the study at his/her own request, he/she will be asked to write 
and sign a statement of consent withdrawal.
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records.
8.2.
Stopping rules
For this study, stopping rules will be used and any stopping rules will result in an immediate 
stop to dosing. This could be a final end of dosing or a temporary halt. Restart is possible 
without a substantial amendment if review leads to a conclusion which is fully within 
predefined conditions for the relevant stopping criterion and after agreement of the French 
authorities. Any submitted substantial amendment (If needed to re-start the study) should 
include a rationale for the proposed dosing and for the continuation of the trial and details of 
any adjustments to the protocol including additional safety monitoring, if applicable.
Stopping rules are:
-
At the individual level:
•
A ‘serious’ adverse reaction (i.e., a SAE considered at least possibly related to the 
study treatment administration).
•
A ‘severe’ non-serious adverse reaction (i.e., severe non-serious AE considered as, 
at least, possibly related to the study treatment administration).
•
Any AE assessed as related to study treatment that would lead to undue risk if 
dosing with study drug continued or escalated, in the judgment of the principal 
Investigator.
•
ECG: prolongation of QTcF to > 500 ms or of > 60 ms over baseline, drug--related.
•
6DIHW\ODERUDWRU\WHVWV,QFUHDVHLQ$/7$67[8/1.
•
6DIHW\ ODERUDWRU\ WHVWV ,QFUHDVH LQ $/7$67   [ 8/1 DQG total bilirubin
 2x ULN.


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•
A significant ophthalmologic abnormality related to the tested drug, which 
contra-indicates
a second drug administration according to the principal 
Investigator.
-
At the study level:
•
A ‘serious’ adverse reaction (i.e., a SAE considered at least possibly related to the 
study treatment administration) in one participant.
•
‘Severe’ non-serious adverse reactions (i.e., severe non-serious AEs considered as, 
at least, possibly related to the study treatment administration) in two participants
in the same cohort, independent of within or not within the same system organ class.
•
Any AE assessed as related to study drug that would lead to undue risk if dosing 
with study treatment continued or escalated, in the judgment of the principal 
Investigator.
8.3.
Discontinuation of Study Treatment
Participants may voluntarily discontinue from the study treatment for any reason at any time.
If a participant decides to discontinue from study treatment, the Investigator must make every 
effort (e.g., telephone, email, letter) to determine the primary reason for this decision and record 
this information in the participant’s chart and on the appropriate eCRF pages. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reasons (see Sections 8.4 and 8.5).  
The Investigator should discontinue study treatment for a given participant if, on balance, 
he/she believes that continuation would be detrimental to the participant’s well-being 
(see Section 8.2). 
Participants who discontinue study treatment before completing all two study periods should 
NOT be considered withdrawn from the study and may be considered not evaluable for PK 
(see Section 8.6). They should return for a visit within 30 (± 3) days after the last study 
treatment dose, at which time all of the assessments listed for the EOS visit will be performed. 
The EOS visit eCRF page should be completed, giving the date and reason for not completing 
the study. If participants fail to return for the EOS visit for unknown reasons, every effort (e.g.,
telephone, email, letter) should be made to contact them as specified in Section 8.4.
See the SoA (Section 2) for data to be collected at the time of discontinuation of study treatment 
and follow-up and for any further evaluations that need to be completed. 
8.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
x
The center must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study.


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x
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.
x
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
x
If necessary, the participant will be replaced (see Section 8.6).
Discontinuation of the study as a whole is handled as part of Appendix 1.
8.5.
Withdrawn participant data collection
The principal Investigator and/or other Investigator involved in the study will document on the 
termination page of the eCRF and in the participant’s medical records the primary reason for 
the participant’s withdrawal as follows: 
-
The participant’s withdrawal. See Section 8.1.
-
Lost to follow-up. See Section 8.4.
-
Adverse event: if an AE occurs and is considered by the Investigator liable to threaten the 
health of the participant or if a serious disease occurs and necessitates the prescription of a 
medication incompatible with the pursuit of the study treatment, the Clinical Study 
Manager should immediately be informed by phone or fax or e-mail and a report explaining 
the discontinuation will be forwarded to him/her as soon as possible. Information related 
to the withdrawal due to the AE will be filled out in the eCRF.
-
Protocol deviation (erroneous inclusion): the decision to maintain or not the participant in 
the study will be taken jointly by the Investigator and the Sponsor. 
-
Physician decision.
-
Non-compliance with the study treatment.
-
Other reasons: if none of the above-mentioned reasons are applicable, then the reason will 
be specified (technical problems, study/site terminated by Sponsor …). 
See the SoA (Section 2) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
All withdrawals will be reported to the Sponsor.
For all drop-outs, the EOS visit (if applicable) will be arranged as described in Section 8.3, and 
will document the progress of their condition. In every case, the eCRF must be filled in up to 
the last visit performed.
8.6.
Replacement of participants
Participants will be replaced on a case-by-case basis after discussion between the Sponsor and 
the Investigator.
-
Participants who discontinue study treatment
In case of moderate or severe AE causing the participant to withdraw, a joint decision 
between the Sponsor and the Investigator will be made on the appropriateness of replacing 
the participant or not.


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The Investigator and the Sponsor will decide whether participants who withdraw from the 
study for any reason other than safety will be replaced.
-
Participants who vomit within 4 hours after dosing
In case of vomiting, PK sampling post-vomiting should not be done.
-
Participants who require concomitant medication
Administration of concomitant medication could lead to the replacement of the participant. 
Decisions regarding replacement of participants requiring concomitant medication have to 
be discussed with the Sponsor on a case-by-case basis.
-
Participants for whom one or more of the planned PK samples could not be collected / 
tested
Replacements will be decided case-by-case by the Sponsor who will be informed as soon 
as possible (at the latest within 24 hours), in order to confirm the replacement.
Replacement of participants will only be done if fewer than 36 participants are evaluable for 
PK.
If replacement of participants is necessary, the replacement participants will be randomized to 
the same treatment sequence as the participants they are replacing.


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9. PROCEDURES
9.1.
Investigational schedule
The schedule of assessments is described in Section 2 (SoA). 
When several procedures are scheduled at the same theoretical time, the 12-lead ECG will be 
obtained first, followed by vital signs. The time windows allowed for the post-dose study 
procedures are provided in Appendix 5.
For pre-dose assessments, the time window will be 45 minutes. When no doses are planned, 
no time window is required.
The PK blood samples will be collected at the scheduled time within the windows noted in 
Section 9.3.1.
Rechecking of any parameter is to be limited to one time except when the measurement has 
not been obtained in accurate conditions.
9.2.
Total volume of blood collected
Table 3 summarizes the number and volume of blood samples collected during the study:
Table 3: Volume of blood
Type
Sample (mL)
Number of 
samples
Volume 
(mL)
Hepatitis B surface antigen, hepatitis C 
antibody and HIV
3.5
1
3.5
Hematology
3
8
24
Clinical chemistry (including when 
applicable screening FSH and estradiol in 
serum)
3.5
8
28
Coagulation
2.7
8
21.6
PK blood samples
4
36
144
Pregnancy test in serum (when applicable)
3.5
4
14
Total volume (mL)
235.1 mL
Less than 450 mL of blood (which correspond to a blood donation) will be collected during the 
study within the 2 months of the study.
9.3.
Pharmacokinetic Evaluation
9.3.1. Pharmacokinetic Assessment Methods and Timing
Blood samples of approximately 4 mL will be collected for plasma determinations of 
binimetinib and its metabolite AR00426032.
Serial blood samples (n=18 by period) will be collected over 72 hours: at pre-dose within 
15 min before treatment administration (0h), then t+0.5h (± 1 min), 0.75h (± 1 min), 1h 
(± 3 min), 1.25h (± 3 min), 1.5h (± 3 min), 2h (± 5 min), 3h (± 5 min), 4h (± 5 min), 5h 
(± 5 min), 6h (± 5 min), 8h (± 5 min), 10 (± 5 min), 12 h (± 5 min), 24h (± 15 min), 36h 
(± 30 min), 48h (± 120 min) and 72h (± 120 min) post-dose. 


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Each blood sample will be drawn by direct venepuncture or via an intravenous catheter into 
K2EDTA tubes. If an indwelling catheter is used for blood collection, approximately 1 mL will 
be drawn and discarded before sampling. Care must be taken to collect blood slowly without 
causing hemolysis.
When a sampling time is close to meal time, the sample will be collected before the meal. 
The exact actual date and time of dose should be recorded in the eCRF.
The exact actual date and time of each sample collection should be recorded in the eCRF and 
used for the PK calculations.
If vomiting occurs within the 4 hours post dose, the exact time of the first vomiting episode 
must be recorded in the eCRF.
Complete information regarding blood sample collection and processing, handling and 
shipment will be provided in the study-specific Laboratory Manual. The primary and back-up 
aliquots will be stored at -70°C until shipment.
9.3.2. Sample shipment and storage
The samples will be shipped in a container filled with enough dry ice to ensure that the samples 
are kept frozen.
Study samples will be shipped to the bioanalytical laboratory on dry ice, as separate shipments 
for the primary and back-up samples.
9.3.3. Bioanalytical method
Plasma concentrations of binimetinib and its metabolite AR00426032 will be evaluated in the 
same run, using a validated method, which includes solid phase extraction plasma sample 
preparation and liquid chromatography coupled to tandem mass spectrometry.
9.3.4. Pharmacokinetic Criteria
The PK parameters will be determined using Phoenix® WinNonlin® version 8.1 or higher 
(Certara USA, Inc., Princeton, NJ).
The following plasma PK parameters will be calculated for binimetinib, by standard non-
compartmental methods for those participants with sufficient plasma concentration data:
-
Cmax: maximum observed plasma concentration.
-
Tmax: time to reach maximum observed plasma concentration.
-
Tlast: time of last observed plasma concentration.
-
AUClast: Area under the plasma concentration-time curve from time of administration to the 
last observed plasma concentration.
-
AUCinf: Area under the plasma concentration-time curve from time of administration to 
infinity.
-
Oz: apparent terminal elimination rate constant.
-
t1/2: terminal elimination half-life calculated as follows: t1/2 = Ln(2)/Oz.
-
MRT: mean residence time.
-
CL/F: apparent total body clearance.


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Vz/F: apparent volume of distribution.
-
AUC_%Extrap_obs: residual area expressed in percentage.
Additionally, the following PK parameters will be derived by non-compartmental analysis 
from the plasma AR00426032 concentration-time profiles: Cmax, Tmax, AUClast, AUCinf, Oz, t1/2,
MRT, Tlast.
The metabolite-parent ratio based on AUCinf (MRAUC), accounting for differences in 
molecular weights will be calculated.
The list of parameters may be adjusted, if needed, during the analysis. 
9.4.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 2.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or study procedures, or that 
caused the participant to discontinue the study (see Section 8).
The records of AEs must describe the nature (diagnosis, signs and symptoms), severity,
date/time of onset, date/time of end, outcome and actions taken with study treatment, and 
relationship to study treatment (in the Investigator's opinion). It must be specified whether the 
event is serious or not and if yes, at least one seriousness criterion must be specified. The 
severity of AEs will be evaluated using the National Cancer Institute - Common Terminology 
Criteria for Adverse Events version 5.0 (NCI-CTCAE V5.0 [15]).
9.4.1. Time Period and Frequency for Collecting AE/SAE Information
All AEs, including SAEs, will be collected for each participant from the signing of the ICF 
until the EOS visit [30 (± 3) days after the last study treatment administration or 
discontinuation] at the time points specified in the SoA (Section 2).
Medical occurrences that begin before obtaining informed consent will be recorded on the 
Medical History/Current Medical Conditions section of the eCRF, not the AE section.
All SAEs will be recorded and reported to the Sponsor or designee immediately (i.e., without 
delay) and under no circumstance should this exceed 24 hours, as indicated in Section 9.4.2.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation for the participant or after the end of the study. However, if the Investigator learns 
of any SAE, including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be related to the study treatment or study participation, 
the Investigator must promptly notify the Sponsor, but not report the event in the eCRF.
9.4.2. Method of Detecting, Recording and Reporting AEs and SAEs
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, whatever the relationship to the study treatment or study procedures, 
or that caused the participant to discontinue the study treatment.


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
(participant’s spontaneous reporting) and non-leading verbal questioning of the participant is 
the preferred method to inquire about AE occurrences.
The methods of recording, evaluating, and assessing causality of AE and SAE are the 
following.
AE and SAE Recording
x
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
x
For a recurrent AE that resolves and subsequently recurs, each recurrence must be recorded 
as a separate AE.
x
For a continuous AE (i.e., unresolved between participant assessments), any change in 
severity (improvement or worsening) or seriousness must be recorded with the indication 
of the start and (if applicable) the end of the change within the same AE eCRF form.
x
The Investigator will then record all relevant AE/SAE information in the eCRF.
x
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE eCRF page/SAE form.
x
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor.
x
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Severity
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study, and grade them using NCI-CTCAE V5.0 [16].
For any term that is not specifically listed in the NCI-CTCAE scale, severity should be assigned 
a grade of 1 through 5 using the following NCI-CTCAE guidelines:
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
-
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.
-
Grade 3: Severe or medically
significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
An event is defined as ‘serious’ when it meets at least 1 of the predefined seriousness criteria 
as described in the definition of an SAE (see Appendix 2), NOT when it is rated as severe.


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Assessment of Causality
The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE.
x
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
x
The Investigator will use clinical judgment to determine the relationship.
x
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.
x
The Investigator will also consult the Investigator’s Brochure [1] and/or Product 
Information [12], for marketed products, in his/her assessment.
x
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
x
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Pierre Fabre Corporate Vigilances Division. 
However, it is very important that the Investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to Pierre Fabre Corporate 
Vigilances Division.
x
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Details regarding the grading of the causal relationship of an AE/SAE with study medication 
are provided in Appendix 2.
Procedures for completing and transmitting SAE notification form are provided below:
SAE Reporting to Pierre Fabre via Paper SAE form
x
E-mail transmission of the SAE form immediately and within 24 hours (with all the 
available information about the event) is the preferred method to transmit this information 
to the Pierre Fabre Corporate Vigilances Division.
x
Contacts for SAE reporting: HQ.pharmacovigilance@pierre-fabre.com
AEs must be documented as soon and as completely as possible on the “Adverse Events” pages 
in the eCRF. Follow-up information must be entered as soon as available.
AEs that occur during the study should be treated by established standards of care that will 
protect the life and health of the participants. If such treatment constitutes a deviation from the 
protocol, the participants should be withdrawn from the study and the reason must be 
documented in the eCRF.
9.4.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs (as defined in Appendix 2), will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 8.4). 


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Follow-up of AEs and SAEs
x
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
x
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
x
New or updated information will be recorded using a new SAE form.
x
The Investigator will submit any updated SAE data to the Sponsor’s Corporate Vigilances 
Division within 24 hours of receipt of the information.
9.4.4. Regulatory Reporting of Serious Adverse Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. Thus, all SAEs, regardless of study 
treatment or relationship to study treatment and occurring once the ICF has been signed, must 
be reported by the Investigator to the Sponsor as soon as he/she is informed of the event (no 
later than within 24 hours).
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Independent Ethics Committee (IEC), and Investigators.
The Sponsor will inform the French Regulatory Authority (ANSM), the IEC and the relevant 
Regional Health Agency (ARS) without delay of any new safety medical fact (See definition 
in Appendix 2) and if necessary, of the appropriate measures taken for ensuring the safety of 
the participants. The Sponsor will inform the ANSM of any new safety medical facts at the 
following address: vig-essaiscliniques@ansm.sante.fr.
All suspected unexpected serious adverse reactions (SUSARs), SAEs, and serious adverse drug 
reactions (SADRs) will be submitted to ANSM without delay at the following address:
declarationsusars@ansm.sante.fr.
For all studies, Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then
file it along with the Investigator’s Brochure.
9.4.5. Pregnancy
Only female partners of male participants are concerned in this section, as only 
post-menopausal female participants will be included in this study.
Details of all pregnancies in the female partners of male participants will be collected on the 
Pregnancy form after the start of study treatment and until the 30 days after the last study 
treatment administration.


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Pregnancies discovered in the period after the signature of the ICF but before any study 
treatment exposure are not to be reported to the Sponsor unless associated to a seriousness 
criterion (e.g., SAE study-protocol related procedure). 
If a female partner of a male participant becomes pregnant, the participant must inform the 
Investigator, and both should receive counseling as to the continuation of the pregnancy.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of
learning of the pregnancy using the Pregnancy form and should follow the procedures outlined 
below:
x The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the participant is in the study, during or after 
exposure to study treatment. This applies only to male participants who receive study 
treatment.
x The Investigator will record pregnancy occurrence on the Pregnancy form and submit it to 
the Sponsor within 24 hours of learning of pregnancy.
x After obtaining the necessary signed ICF to collect pregnancy data from the pregnant female 
partner of a male study participant directly (required within 72 hours), additional pregnancy 
information will be submitted to the Sponsor on a new Pregnancy form. 
x The pregnant female will be followed until the completion/termination of the pregnancy. 
Information on the status of the mother and the neonate will be forwarded to the Sponsor 
using the Pregnancy form. The outcome of the pregnancy and the impact on the baby’s
health will be followed as long as it is needed. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.
x A spontaneous abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such.
x Any post-study pregnancy-related SAE considered related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 9.4.2. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he/she may learn of an SAE through spontaneous reporting.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
Pregnancy Reporting to Pierre Fabre via paper Pregnancy form
x
E-mail transmission of the pregnancy form, within 24 hours, is the preferred method to 
transmit this information to the Pierre Fabre Corporate Vigilances Division.
x
Contacts for pregnancy reporting: HQ.pharmacovigilance@pierre-fabre.com.
9.4.6. Overdose
For this study, any dose of binimetinib greater than 45 mg within a 24-hour time period will be 
considered an overdose. The Sponsor does not recommend specific treatment for an overdose 
(see Investigator’s Brochure [1]).


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In the event of an overdose, the Investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
binimetinib can no longer be detected systemically (at least 3 days). In the absence of 
seriousness criteria, the overdoses, and associated AEs if any, are reported only on the AE 
form of the eCRF. If the definition of seriousness criteria is met, the SAE reporting form 
must be also completed and transmitted to the Sponsor.
3. Document the quantity of the excess dose as well as the duration of the overdose in the AE 
form of the eCRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4.7. Medication errors
In the absence of seriousness criteria, medication errors, and associated AEs if any, are reported 
only on the AE form of the eCRF.
If the definition of seriousness criteria is met, the SAE Notification form must also be completed 
and transmitted to the Sponsor.
x
E-mail transmission of the SAE form immediately and within 24 hours (with all the 
available information about the event) is the preferred method to transmit this information 
to the Pierre Fabre Corporate Vigilances Division.
x
Contacts for SAE reporting: HQ.pharmacovigilance@pierre-fabre.com
9.5.
Safety Assessment
Rechecking of any parameter is to be limited to one time except when the measurement has 
not been obtained in accurate conditions.
9.5.1. Physical Examination
The timing of the complete physical examinations, body weight and height and BMI is 
provided in Section 2 (SoA). BMI is calculated from the participants’ height and weight.
The physical examinations will be performed by the Investigator or his/her representatives.
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological, musculoskeletal 
in addition to head, eyes, ears, nose, throat, neck and lymph nodes systems. Height and weight 
will also be measured and recorded. The physical examination will NOT include pelvic, rectal 
or breast examinations.
Further examination of other body systems may be performed in case of evocative symptoms 
at the Investigator’s discretion.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
Any abnormality identified at baseline should be recorded as medical history.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be recorded 
in the participant’s notes. New or worsened clinically significant abnormalities should be 
recorded as AEs on the AE eCRF.


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9.5.2. Visual and Ophthalmological Examinations
9.5.2.1.
Visual Assessment
Visual assessment (general inspection of the eyes, examination of motility and alignment, any 
visual disturbances such as blurred vision or loss of vision) will be performed on site by the 
Investigator.
The timing of the assessments is summarized in Section 2 (SoA).
9.5.2.2.
Ophthalmologic Examination
The full ophthalmologic examination will be performed by an ophthalmologist and will include 
best corrected visual acuity for distance testing, optical coherence tomography and/or 
fluorescein angiography, slit lamp examination, IOP and fundoscopy with attention to retinal 
abnormalities.
The timing of the assessments is summarized in Section 2 (SoA).
9.5.3. Vital Signs
9.5.3.1.
Parameters
Measured parameters: Supine and standing systolic BP, diastolic BP and PR, body temperature.
9.5.3.2.
Method of Assessment
Qualified staff members will perform BP measurements. If possible, BP measurements will be 
taken from the same arm (opposite the arm that is used for blood sample collection) by an 
automated BP monitor using the oscillometric method (e.g., Dinamap®). If there is a clinically 
important change in BP from the previous recording, 1 additional measurement will be taken 
to confirm the change.
BP and PR will be measured using an automatic device for each participant, after at least 
5 minutes at rest in the supine position and after standing for 5 minutes. Body temperature will 
be measured using an appropriate thermometer.
The timing of the assessments is summarized in Section 2 (SoA).
9.5.4. Standard 12-lead ECG
9.5.4.1.
Parameters
-
Measured parameters: heart rate (HR), PR interval, QRS duration, QRS axis, QT interval.
-
Derived parameters: one correction of the QT interval will be investigated: QTcF.
-
Observations and comments on the quality of the trace if needed, on normality or 
abnormality. 
9.5.4.2.
Method of Assessment
The timing of the assessments is summarized in Section 2 (SoA).
The measurements will consist of triplicate 12-lead digital ECGs (conducted within 
approximately 5 to 10 minutes total time). ECGs should be performed before blood collection 
at equivalent nominal time points.


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Participants must rest in the supine position for at least 5 minutes before the ECG recording is 
started. The ECG may be recorded during the period of rest required before the measurements 
of supine blood pressure and pulse rate. A qualified physician will review the ECGs promptly 
and any clinically important finding will be recorded in the appropriate section of the eCRF. 
The Investigator is responsible for providing the interpretation of all ECGs.
9.5.5. Laboratory safety parameters
9.5.5.1.
Blood Safety Analysis
The following parameters will be determined:
-
Hematology: 
Erythrocytes (red blood cells, RBCs), hematocrit, hemoglobin, platelets; leukocyte count with 
differential: basophils, eosinophils, lymphocytes, monocytes, neutrophils / absolute neutrophil 
count; RBC indices: mean corpuscular hemoglobin,
mean corpuscular volume,
reticulocytes/erythrocytes.
-
Clinical chemistry: 
ALT, albumin, ALP, AST, GGT, bicarbonate, bilirubin (total and indirect), urea, calcium, 
chloride, CK, creatinine, amylase, lipase, total cholesterol, glucose, lactate dehydrogenase,
magnesium, potassium, sodium, total protein, uric acid.
A blood pregnancy test (hCG) will be performed at the screening visit, D-1 of each period and 
at the EOS visit.
For postmenopausal female participants, serum FSH and estradiol will be performed at 
screening to confirm postmenopausal status (except, if the participant is treated with HRT).
-
Coagulation: 
aPTT and prothrombin ratio.
9.5.5.2.
Urinalysis parameters
Dipstick determination of pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrites
and leukocyte esterase will be performed. In case of positive results for white blood cells, red 
blood cells and/or nitrites, urine will be sent to the laboratory for microscopy and culture. If 
there is an explanation for the positive dipstick results (e.g., menses), this will have to be 
discussed with the Sponsor and should be recorded, and there might be no need to perform 
microscopy and culture.
9.5.5.3.
Method of Assessment
Samples of blood will be collected in fasted conditions at the visits summarized in Section 2
(SoA).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
All abnormal laboratory tests with values considered clinically significant during participation 
in the study or within 30 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor.


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If such values do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, and the Sponsor notified.
Samples of urine will be collected at the visits summarized in Section 2 (SoA).
9.5.5.4.
Laboratory Safety Determinations
Laboratory tests will be performed by Centre Eugène Marquis, Laboratoire de Biologie, 
Avenue Bataille Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
9.5.6. COVID-19 tests
COVID-19 antigenic tests will be performed at the time points indicated in Section 2 (SoA). A
COVID-19 polymerase chain reaction (PCR) test will be performed on P1D-1, if required.
9.6.
Demographic and Baseline Characteristics
9.6.1. Demography and Other Participant Information
The following information will be collected at the time points indicated in Section 2 (SoA):
x
Informed consent (before any procedures specified in this protocol are performed).
x
Verification of inclusion and exclusion criteria (see Sections 6.1 and 6.2, respectively).
x
Demography (sex, age at screening, year of birth and ethnicity).
x
Medical history.
x
Alcohol history.
x
Smoking history.
x
Prior medications / therapies / procedures.
x
COVID-19 vaccination status.
x
Concomitant medications / therapies.
9.6.2. Standard Cardiac Echocardiography
A standard cardiac echocardiogram will be performed for orientation regarding cardiac 
function and will only assess LVEF by Simpson and presence/absence of potential 
abnormalities. In case of abnormal findings, those findings will be reported on the safety report 
completed by the cardiologist during the analysis. 
The principal Investigator or designated site physician will review and sign all echocardiogram 
reports. 
Results must be summarized in writing and classified as normal; abnormal, clinically relevant; 
or abnormal, not clinically relevant. Once signed, the original echocardiogram report will be 
retained with the participant’s source documents.
The timing of the assessment is summarized in Section 2 (SoA).
9.6.3. Serology, Drug Screen, Alcohol Breath Test, Urine Cotinine Test, and 
Hormonology
Blood tests will be carried out to test for the presence of HBs Ag, HCV Ab and HIV.
Urinary screening will be carried out to test for benzodiazepines, cocaine, cannabinoids, 
morphine, amphetamines, methamphetamines and ecstasy.
Alcohol breath tests will be performed.
Urine cotinine tests will be performed (considered positive only if > 200 ng/mL due to possible 
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Serum FSH and estradiol tests will be performed for postmenopausal women (except if treated 
with HRT).
The timing of the assessments is summarized in Section 2 (SoA).


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10. DATA MANAGEMENT AND STATISTICS
10.1.
Data entry and management
10.1.1. Data collection
EDC via eCRFs will be used for this study. For each participant who signed an ICF, an eCRF 
must be completed and signed electronically by the Investigator or co-investigator. This also 
applies to screen failures and those participants who fail to complete the study. If a participant
withdraws from the study, the reason must be noted on the eCRF. Case report forms are to be 
completed on an ongoing basis.
Study data will be collected by the Investigator or dedicated study personnel. Data will be 
collected on source documents and entered by the study personnel into the eCRFs in a timely 
manner.
External data (including at least PK concentrations, ECGs, and safety laboratory results), as 
described in the Data Management Plan, will not be captured on the eCRF. However, for ECGs 
and safety laboratory results, the clinical significance (significant or not significant) of the 
results will be entered in the eCRF.
Validated results from bioanalysis of treatment concentrations in plasma will be transmitted by 
the bioanalytical center to the subcontractor in charge of PK analysis. The study treatment 
concentrations and final PK parameters will be uploaded in the final database from an 
electronic data file respectively provided by the bioanalytical laboratory and the subcontractor.
All the documents must be archived for a minimum of 25 years or according to the Sponsor’s 
procedures, whichever is longer.
10.1.2. Data coding
Biotrial will ensure coding for AEs, prior and concomitant medications and medical history in 
compliance with the Medical Dictionary for Regulatory Activities (MedDRA) and the World 
Health Organization (WHO) Drug Global Dictionary, using the most recent versions of 
MedDRA and WHODrug Global Dictionary. The data coding will be validated by a Physician.
10.1.3. Data validation
Biotrial will prepare the data validation document.
Biotrial will be responsible for data entry and their validation (according to the Sponsor’s
requirements).
Biotrial will organize a data review meeting before database lock.
The scope of data cleaning and the data to be locked will be described in the study-specific 
Data Management Plan (or in any other specific plan).
For the database lock at study end, all data will be entirely validated and locked and access for 
users will be modified to read-only to prevent any further changes to the data.
10.2.
Statistical considerations
10.2.1. Sample size
The primary objective of this study is to demonstrate bioequivalence between the test 45 mg-
binimetinib tablet and the reference 3 x 15 mg binimetinib commercial tablets, based on 
PK endpoints Cmax, AUCinf and AUClast.


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The null hypothesis is that the true ratio of the geometric mean of the test treatment to the 
geometric mean of the reference treatment, P(Test)/ P(Reference), for the Cmax, AUClast, and 
AUCinf is either <0.80 or >1.25.
The alternate hypothesis is that the true ratio of the geometric mean of the test treatment to the 
geometric mean of the reference treatment for the Cmax, AUCinf and AUClast, is either t0.80 or 
d1.25.
For each PK parameter designated as a primary endpoint, a two one-sided t-test (TOST) [17]
procedure with D=0.05 for each one-sided test will be used to test this set of hypotheses. 
Bioequivalence will be declared if the 90% CI for the true ratio of test to reference geometric 
means falls entirely within the range of 0.80 to 1.25 for all primary parameters (i.e the null 
hypothesis must be rejected), in accordance with the EMA guideline on the investigation of 
bioequivalence [14].
Based on these criteria, assuming intra participant CV (CVintra) of Cmax to be around 25% as 
observed on the pilot study [7] and a “test/Reference” mean ratio of 1.05; thirty-six participants 
are needed to achieve a power of 90% at an alpha of 0.05.
Up to 40 participants will be included into the study to complete the study with at least 36 
evaluable participants.
10.2.2. Statistical methods
The Statistical Analysis Plan (SAP), including the PK analysis plan, will be prepared by the 
Sponsor or delegates and finalized prior to the first visit of the first participant. The SAP will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. Any major modifications related to 
the primary endpoint definition or analysis will also be described in a protocol amendment.
The statistical analyses will be performed by the Biostatistics Unit of Biotrial Biometrics using 
SAS® software version 9.4 or higher (SAS Institute Inc., Cary, NC, USA).
PK data will be analyzed by Biotrial using Phoenix® WinNonlin® version 8.1 or higher (Certara 
USA, Inc., Princeton, NJ) and SAS® software version 9.4 or higher (SAS Institute Inc., Cary,
NC, USA).
Descriptive statistics will be supplied according to the nature of the criteria:
-
Quantitative variables: sample size, arithmetic mean, standard deviation (SD), standard 
error of the mean (SEM), minimum, median and maximum, and quartiles if necessary (with 
geometric mean, arithmetic and geometric coefficients of variation, and quartiles for PK 
parameters).
-
Qualitative variables: sample size, absolute and relative frequencies per class.


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All listings will be presented by participant (except for PK listings, by formulation and 
participant). 
No interim analysis is planned.
Further details of the statistical analysis will be described in the SAP and agreed upon by the 
Sponsor.
10.2.3. Description of data sets
10.2.3.1. Definition of data sets
The Enrolled set will be defined as all participants who signed the ICF for the study.
The Screened set will be defined as all enrolled participants having successfully completed the 
screening period.
The Randomized set will be defined as all randomized participants.
The Safety set will be defined as all included participants having taken at least one dose of 
study treatment, including those who did not complete the study.
The Pharmacokinetic set will be defined as all of the participants who have taken one dose of 
study treatment in the two periods without any event (including no vomiting within 4 hours 
after dosing) and/or important protocol deviation affecting PK evaluation, with complete PK 
profiles in these two periods, i.e., sufficient PK concentration data to support the calculation of 
primary PK criteria.
The analysis sets will be validated during the data review meeting.
10.2.3.2. Description of the sets
A summary table with the description of the number of screened participants, the number of 
randomized participants, the number of participants who completed the study, the number of 
participants who discontinued classified by reason of withdrawal, and the number of 
participants in each analysis set will be performed by sequence and overall. Corresponding 
individual listings will be prepared.
Listings with analysis sets, EOS status and visit dates will also be generated. A specific listing 
with discontinued participants will be prepared, as well as a listing of participants excluded 
from analysis sets. 
10.2.4. Demographic and baseline characteristics
The following analysis will be performed on the Randomized set.
The participants’ demographic characteristics and baseline characteristics will be summarized 
by sequence and overall and listed. 
Tables by sequence and overall with the number of participants having at least one medical or 
surgical history and a corresponding listing will be prepared.
Tables by sequence and overall with number of participants having at least one previous 
treatment will be prepared. The same table will be prepared for concomitant treatments.
Details of drug dosing and meals will be listed.


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10.2.5. Protocol deviations
A summary table of important protocol deviations by sequence and overall and the 
corresponding listing will be prepared.
10.2.6. Pharmacokinetic analysis
The analysis will be performed on the Pharmacokinetic Set.
Relevant PK parameters will be calculated for binimetinib and AR00426032 (see 
Section 9.3.4) by standard non-compartmental methods for those participants with sufficient 
plasma concentration data.
Plasma concentration and PK parameters
Plasma concentrations (binimetinib and AR00426032) will be summarized over time by 
formulation and corresponding listings will be prepared. 
Concentration-time profile plots will be prepared on linear and log-linear coordinates for each 
participant with both formulations on the same graph, as well as arithmetic mean (±SD) with 
both formulations on the same graph.
Binimetinib and AR00426032 PK parameters will be summarized by formulation and 
corresponding listings will be prepared.
For binimetinib only:
x
Scatter plots and box whisker plots will be generated for the comparison of Cmax,
AUClast and AUCinf.
x
To demonstrate the bioequivalence between the two formulations, primary PK 
parameters (AUClast, AUCinf and Cmax) will be analyzed separately using linear mixed 
effects model with log-transformed PK parameter as the dependent variable, sequence, 
period and formulation as fixed effects and participant with sequence as random effect.
Point estimates and 90% CIs will be provided for the ratio of Test to Reference (3 x 15 
mg formulation as Reference and 45 mg formulation as Test). Bioequivalence will be 
declared if the 90% CI for the ratio of Test to Reference geometric means is within the 
range of 0.80 to 1.25 for all primary endpoints.
x
Tmax will be analyzed using non-parametric tests.
10.2.7. Safety analysis
10.2.7.1. Criteria
-
AEs.
-
Vital signs/temperature.
-
Standard 12-lead ECG.
-
Hematology, blood chemistry, coagulation, urinalysis.
-
Complete physical examination, weight.
-
Visual examination.
-
Ophthalmologic examination.
-
COVID-19 tests.


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10.2.7.2. Statistical methodology
Descriptive analysis of safety parameters will be performed on the Safety set.
AEs will be considered treatment-emergent if they start or worsen during the on-treatment 
period.
TEAEs will be summarized by system organ class and preferred term in tables with:
-
The number of participants with at least one TEAE and the number of TEAEs for each 
formulation.
Analyses taking into account severity and drug relationship to treatment will be also carried 
out. All AEs will be listed.
The description will be performed by formulation and measurement time (when applicable) for 
measurements during the two treatment periods, and overall for measurements performed at 
screening and EOS visits.
For vital signs and ECG parameters, potentially clinically significant abnormalities (PCSA)
will be specified in the SAP and participants with PCSA values will be summarized.
The presence of orthostatic hypotension and abnormal HR increase will be derived and the 
number and percentage of participants with at least one orthostatic hypotension/ abnormal HR 
increase will be presented by formulation and measurement time, as well as a corresponding 
listing. 
Visual and ophthalmologic abnormalities and dermatological abnormalities will be described, 
and corresponding listings will be generated.
Laboratory data (hematology, biochemistry, coagulation and urinalysis) will be described. For 
laboratory tests covered by the NCI-CTCAE (version 5.0 [16]), laboratory data will be graded 
accordingly, Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 (death) will not be used.
For laboratory tests where grades are not defined by NCI-CTCAE, results will be graded by 
the low/normal/high classifications based on laboratory normal ranges.
All laboratory parameters will be listed.


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11. REFERENCES
1. Binimetinib Investigator’s Brochure, Edition No. 18 dated 13 MAY 2022.
2. ARRAY-162-111. 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. Array Biopharma Inc. 2013.
3. CMEK162A2102. A Phase 1, single-center, open-label study to investigate the absorption, 
distribution, metabolism and excretion (ADME) of MEK162 (binimetinib) following a 
single oral dose of 45 mg [14C]MEK162 (binimetinib) in healthy male subjects. Novartis. 
2014.
4. ARRAY-162-104. A single-dose relative bioavailability and food effect study of ARRY-
438162 (binimetinib) tablets and capsules in healthy volunteers. Array Biopharma Inc. 
2008.
5. CMEK162A2101J. A randomized, single-center, open-label, two-sequence, two-period 
cross-over study to investigate the relative bioavailability of MEK162 Novartis CSF and 
Array CSF following a single oral dose given as 3 x 15 mg tablets in healthy subjects. 
Novartis. 2013.
6. CMEK162A2110. A randomized, single-center, open-label, two-period, crossover study to 
investigate the relative bioavailability of MEK162 liquid formulation and film-coated 
tablets following a single oral dose of 45 mg in healthy subjects. Novartis. 2014.
7. W00074CI101. A randomized, single-center, open-label, single dose, two-period, 
crossover study to investigate the relative bioavailability of binimetinib 3 x15 mg and 45 
mg tablets in healthy participants. Pierre Fabre Médicament. 2022.
8. CMEK162A2103. A randomized, single-center, open-label, 3-period, crossover study to 
investigate the effect of food on the pharmacokinetics of oral MEK162 (binimetinib) in 
healthy subjects. Novartis. 2014.
9. CMEK162A2105. An open-label, single-arm, 3-period, fixed-sequence, crossover study to 
investigate the effect of oral MEK162 (binimetinib) on the pharmacokinetics of oral 
midazolam in healthy volunteers. Novartis. 2014.
10. ARRAY-162-105. An open-label, 2-arm, parallel-group, fixed-sequence study to 
investigate the influence of a proton pump inhibitor (rabeprazole) on binimetinib or 
encorafenib pharmacokinetics in healthy adult subjects. Array Biopharma Inc. 2017.
11. Flaherty KT, Robert C, Hersey P, et al (2012) Improved Survival with MEK Inhibition in 
BRAF-Mutated Melanoma. N Engl J Med; 367:107-14.
12. MEKTOVI 
summary 
of 
product 
characteristics. 
https://www.ema.europa.eu/en/documents/product-information/mektovi-epar-product-
information_fr.pdf. Accessed on 30 MAY 2022.
13. 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.


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14. EMA. Guideline on the Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 
1/ Corr **. 20 Jan 2010.
15. Guidance for Industry; Handling and Retention of BA and BE samples; U.S. Department 
of Health and Human Services; Food and Drug Administration Center for Drug Evaluation 
and Research (CDER); May 2004.
16. National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE 
version 
5.0), 
Nov 
2017. 
Available 
at:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf.
17. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach 
for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 
Dec;15(6):657-80. doi: 10.1007/BF01068419. PMID: 3450848.


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12. APPENDICES
Appendix 1: Regulatory and legal considerations
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS
Monitoring
The Investigator will allow the representative of the Sponsor and the study Monitor:
-
To check and to verify the site, the facilities and the material used for the study.
-
To meet all members of the team involved in the study.
-
To consult all the documents relevant to the study.
-
To check that the eCRFs have been correctly completed.
-
To have direct access to source documents for comparison of data therein with 
the data in the eCRFs.
-
To check that AEs have been documented.
-
To verify that the study is carried out in compliance with the protocol.
This study will be monitored at regular intervals, by mutual agreement of the Investigator and 
Monitor.
All information dealt with during these visits will be treated as strictly confidential.
The Investigator will provide the Sponsor with the following:
-
Study status updates at regular intervals.
-
Adequately completed eCRFs.
Audit - Inspection
The Investigator will be informed that an audit will be carried out, at the request of the Sponsor, 
before, during or after the study.
The Investigator will be informed that the Regulatory Authorities may also carry out an 
inspection. In this case, the Investigator must inform the Sponsor as soon as he receives the 
notification of inspection.
The Investigator must allow the representatives of the Regulatory Authorities and persons 
responsible for the audit to:
-
Inspect the site, facilities and material used for the study.
-
Meet all members of his team involved in the study.
-
Have direct access to study data and source documents.
-
Consult all the documents relevant to the study.
QUALITY CONTROL AND QUALITY ASSURANCE
Written procedures describing data flow, data entry or electronic capture, data cleaning and 
processing, and required quality control must be utilized.
Trained site personnel must conduct data entry, or data must be transferred electronically from 
the device into the EDC system.


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The entered/electronically transferred data will be systematically checked by the clinical 
research organization (Biotrial) staff, either by using error messages printed from validation 
programs or by manual checks carried out based on database listings. Data checks for data 
consistency and plausibility must be defined and implemented in the EDC system. Queries are 
raised and resolved electronically within the EDC system.
After the completion of the data cleaning and data review process and full resolution of the 
data queries, the database will be locked. Any changes to the database after that time may only 
be made by joint written agreement between the Sponsor and the Investigator.
The Investigator must guarantee the confidentiality of the study data in the medical files by 
implementing security measures to prevent unauthorized access to the data and to the computer 
system.
STUDY SUSPENSION, TERMINATION, AND COMPLETION
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason.
If the Investigator suspends or terminates the study, the Investigator will promptly inform the 
Sponsor and the regulatory authorities and provide them with a detailed written explanation. 
The Investigator will also return all test articles, test article containers, and other study
materials to the Sponsor.
Upon study completion, the Investigator will provide the Sponsor and IEC with final reports 
and summaries as required by regulations.


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ETHICS AND REGULATORY ASPECTS
Current texts
The study will be carried out in accordance with:
-
The most recent recommendations of the World Medical Association (WMA).
-
The International Council on Harmonization (ICH) recommendations: Good 
Clinical Practice (GCP) [E6 (R2)], (CPMP/ICH/135/95), 2016.
-
Decree of 26th April 2006 (n°2006-477) relative to biomedical research and French 
law n°2002-303 of 4th March 2002 regarding participant's rights.
-
French law n°78-17 of 6th January 1978 relative to Data processing, Data files and 
individual liberties, modified by law n°2016-41 of 26 JAN 2016, ruling n°2016-
800 of 16 JUN 2016 and updated by deliberation n°2016-262.
-
European directive 2005/28/CE dated 8 April 2005 (GCP) translated in French law 
by the Decision of 24 Nov 2006 setting the GCP for biomedical research on drugs
for human use.
-
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.
-
Guidance for Industry; Handling and Retention of BA and BE samples; U.S. 
Department of Health and Human Services; Food and Drug Administration Center 
for Drug Evaluation and Research (CDER); May 2004.
Participant Information and Consent
An unconditional prerequisite for a participant’s participation in the trial is his/her written 
informed consent. The volunteer’s written informed consent to participate in the trial must be 
given before any trial-related activities are carried out. Nevertheless, if necessary and after 
agreement of the Sponsor, any measures identical to those planned in the protocol for the 
participants’ screening that have already been performed within the timelines given by the 
protocol for the screening exams could be used for the protocol in order to minimize the 
constraints on the participants.
Participants will be verbally informed by an Investigator of all pertinent aspects of the trial: the 
nature of the study, its aim, its possible risks and restrictions, its duration and the fee that they 
will receive. The protocol will be explained during a meeting prior to the study and each 
participant must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time. At this meeting, an information sheet will be given to 
each participant. The language used in doing so must be chosen so that the information can be 
fully and readily understood by lay persons. 
The participant should carefully read before signing and dating the informed consent form. 
He/She can ask all necessary questions to the Investigator. After having obtained answers to 
his/her satisfaction and being given sufficient time to think about their decision (up to a few 
days), the participant can then decide whether or not to take part in the study. The informed 
consent form must be signed and personally dated by both the participant and the Investigator. 
A copy of the signed document should be given to the participant.
On request by the Sponsor, a copy of the signed information sheets and informed consent forms
will be retained in a sealed envelope by the Investigator and delivered to the Sponsor at the end 
of the study for archiving. Under no circumstances will this envelope be opened by the Sponsor. 


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It may only be examined at the request of Regulatory Authorities. A copy will be kept by the 
Investigator for 25 years or according to the Sponsor’s procedures, whichever is longer (the 
third copy is given to the participant).
The completed “participant screen log” will be signed by the Investigator to attest that consent 
has been obtained from all participants.
Whenever important new information becomes available that may be relevant to the 
participant’s consent, the written participant information sheet and any other written 
information provided to participants will be revised by the Sponsor and be submitted again to 
the IEC for review and favorable opinion/authorization. The agreed, revised information will 
be provided to each participant in the trial for signing and dating. The Investigator will explain 
the changes from the previous version.
Submission to the authorities
Ethics Committee (CPP)
It is the responsibility of the Sponsor to seek and obtain the favorable opinion of the CPP 
(Comité de Protection des Personnes, i.e., Independent Ethics Committee). This activity is 
delegated to Biotrial.
The present clinical trial will not be initiated until this favorable opinion is obtained.
ANSM authorization
It is the responsibility of the Sponsor to seek and obtain the ANSM (French Drug Agency) 
authorization for conducting the present clinical trial. This activity can be delegated to Biotrial.
The present clinical trial will not be initiated until the ANSM authorization is received.
Protocol Amendments
Any significant change (substantial modification) in the study requires a protocol amendment 
for authorization or for information. Concerning a protocol amendment sent to ANSM and/or 
IEC for authorization, an Investigator must not make any changes to the study without 
regulatory authorities and Sponsor approval except when necessary to eliminate apparent 
immediate hazards to the participants. A protocol change intended to eliminate an apparent 
immediate hazard to participants may be implemented immediately, but the change must then 
be documented in an amendment, reported to the regulatory authorities/IEC within 5 working 
days, and submitted in the required time frame. All protocol amendments must be reviewed 
and approved following the same process as the original protocol.
Regulatory requirements
In compliance with French law, approval as a site for clinical research without direct individual 
therapeutic benefit was granted to Jean-Marc Gandon by the Minister for Health to Biotrial 
Rennes center (site n°05001M).


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DATA PROCESSING AND ARCHIVING OF DOCUMENTS AND DATA RELATIVE 
TO THE RESARCH
After the study, the Investigator will keep all information relevant to the study for 25 years, or 
according to the Sponsor’s procedures, whichever is longer.
CONFIDENTIALITY AND AGREEMENTS
Confidentiality
Before starting the study, the Investigator must confirm receipt of adequate documentation 
from the Sponsor so as to be able to decide whether or not to perform the study.
All documents and information given to the Investigator by the Sponsor with respect to the 
study are strictly confidential.
The Investigator and his colleagues agree to use them only with the framework of this study, 
in order to carry out the protocol. This agreement is binding as long as the confidential 
information has not been disclosed to the public by the Sponsor.
The Investigator may use the technical protocol to obtain the informed consent of study 
participants. It must not be disclosed to other parties without the written authorization of the 
Sponsor.
The Investigator keeps a confidential participant identification list for the study. The 
Investigator must maintain source documents for each participant in the study.
Data on participants collected in eCRFs during the study will be documented in an anonymous 
fashion. All information in the eCRFs must be traceable to these source documents.
REPORT AND PUBLICATION
Report:
The results of the study will be reported in a Clinical Study Report. This report will be prepared 
by Biotrial according to existing Standard Operating Procedures (ICH Biotrial or Sponsor own 
format).
In compliance with the regulations, the final report will be produced within one year of 
completing the study and in agreement with the work order.
The final report will be provided to all Investigators having included participants in the study.
The clinical study report will be provided as Word and PDF files. Also, SAS transfer files of 
the data will be provided electronically. All data will be presented CTD-compliant.
Publication:
The Investigator will only use the information in the context of the study. The information 
cannot be used without the Sponsor’s authorization. Hence, all or part of the information should 
only be divulged, submitted for publication or claimed for industrial proprietary act with the 
written consent of the Sponsor.


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Appendix 2: Adverse event and serious adverse event definitions
Definitions
AE Definition
x
An AE is any untoward medical occurrence from signature of informed consent in a patient or 
clinical study participant, temporally associated with the use of study intervention, whether or not 
considered related to the study treatment.
x
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment.
Events Meeting the AE Definition
x
Any abnormal laboratory test results (e.g., hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that 
worsen from informed consent signature, considered clinically significant in the medical and 
scientific judgment of the Investigator (i.e., not related to progression of underlying disease).
x
Any new or worsening of the AE that is assessed by the Investigator as related to the disease 
progression must be reported as an AE.
x
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or severity of the condition.
x
New conditions detected or diagnosed after informed consent signature even though it may have 
been present before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
x
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. The event of an overdose itself meets the definition of an Adverse Event 
and should be reported as an AE/SAE.
Events NOT Meeting the AE Definition
x
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
x
Adverse Drug Reactions
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. A causal relationship between a medicinal product and an AE is at least a 
reasonable possibility. An adverse reaction, in contrast to an AE, is characterized by the fact 
that a causal relationship between a medicinal product and an occurrence is suspected.
Serious Adverse Events or Serious Adverse Drug Reactions
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.


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A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, 
if it were more severe.
x
Requires inpatient hospitalization or prolongation of existing hospitalization
x
In general, hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
x
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE.
Any hospitalization, or prolongation of hospitalization due to the circumstances listed below will not 
be notified as a SAE to the Sponsor by the Investigator:
-
planned (as per protocol) medical/surgical procedure including 24 hours hospitalization after 
the first treatment administration, 
-
preparation for routine health assessment/procedure (e.g., routine colonoscopy), 
-
planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
-
administrative or social reasons (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances)
c.
Results in persistent disability/incapacity
x
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
x
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
d.
Is a congenital anomaly/birth defect
e.
Other situations:
x
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious.
x
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.
Suspected Unexpected Serious Adverse Reaction
A SUSAR is an unexpected SAE having a reasonable possibility of a causal relationship with 
the study drug.


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New Safety Medical Fact
According to:
-
French law n°2012-300 of 12 MAR 2015 and decree n°2016-1537 of 16 NOV 2016
(modified by decree n°2017-884 of 09 MAY 2017) relative to research on human persons, 
articles R1123-46 to R1123-62.
A new safety medical fact is any new safety data which could lead to a new evaluation of the 
benefit/risk balance of the research or the study treatment or which could be sufficient to 
consider changes to the administration of the study treatment, the conduct of the research, the 
documents relating to the research, or to stop or amend the protocol or similar studies. Biotrial 
and the Sponsor will follow the instructions for ensuring the safety of the participants and for 
the submission/reporting of the new safety medical fact to the French health authorities that are 
defined in the Safety Management Plan.
Other Reportable Information: Certain information, although not considered an SAE, must 
be recorded, reported, and followed up as indicated for an SAE. This includes: 
-
Overdose of an investigational product as specified in this protocol (see Section 9.4.6) with 
or without an AE.
-
Medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product, with or without an AE.
Medication Error, Misuse and Abuse
Medication error refers to an unintentional error in dispensing or administration of the study 
treatment not in accordance with the protocol.
Misuse is defined as any situation where the study treatment is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse is defined as the persistent or sporadic intentional excessive use of the study treatment,
which is accompanied by harmful physical or psychological effects. 
Causal relationship with trial medication
The relationship of an AE to the investigational product is a clinical decision by the Investigator 
based on all available information at the time of the completion of the eCRF and is graded as 
follows:
1.
No reasonable possibility: a reaction for which sufficient information exists to indicate 
that the etiology is unrelated to the study treatment; the participant did not receive the study 
medication or the temporal sequence of the AE onset relative to administration of the study 
medication is not reasonable or the event is clearly related to other factors such as the 
participant’s clinical state, therapeutic intervention or concomitant therapy.
2.
Reasonable possibility: a reaction that follows a reasonable temporal sequence from 
administration of the drug or in which the drug level has been established in body fluids or 
tissues, that follows a known or expected response pattern to the suspected drug, and that 
is confirmed by improvement on stopping or reducing the dosage of the drug, and 
reappearance of the reaction on repeated exposure (re-challenge).


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Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study treatment, additional evaluation should be considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female participant with 1 of the following:
x
Documented hysterectomy.
x
Documented bilateral salpingectomy.
x
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the
above (e.g., mullerian agenesis, androgen insensitivity), the Investigator’s discretion should be 
applied to determine study entry.
Note: documentation can come from the site personnel: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female:
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement.
-
Females on HRT and whose menopausal status is in doubt will not be included.
Contraceptive guidance:
The contraceptive measures to be used by the participants in this study are described in the 
inclusion criteria (see Section 6.1).
Collection of pregnancy information:
The collection of pregnancy information is described in Section 9.4.5.


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Appendix 4: Vital Signs and Electrocardiogram (ECG) normal ranges
Normal ranges applicable for vital signs:
Parameter
Normal ranges
Systolic Blood Pressure
[90-140] mmHg
Diastolic Blood Pressure
[50-90] mmHg
Pulse Rate
[45-100] beats/min
Orthostatic hypotension: decrease in systolic BP > 20 mmHg or diastolic BP > 10 mmHg
when changing from the supine to the standing position.
Note: Clinical signs and symptoms of postural hypotension (dizziness, syncope, etc.,)
should be also evaluated, regardless of vital signs.
Body temperature
[35.0-37.5] ºC
Normal ranges applicable for ECG:
Parameter
Normal ranges
QRS Duration, Aggregate
110 msec
PR Interval, Aggregate
220 msec
ECG Mean Heart Rate
[45-100] beats/min
QTcF Interval, Aggregate
450 msec (males)
470 msec (females)


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Appendix 5: Time windows for performing safety and pharmacokinetic (PK)
assessments
Procedure
Time Point
Time Window
Safety laboratory assessments 
(hematology, clinical chemistry, 
coagulation, urinalysis)
Inferior or equal to H2
± 15 min
]H2-H6]
± 30 min
]H6-H24]
± 60 min
Superior to H24
± 120 min
12-lead ECG
[5-10[ min
± 2 min
[10-15] min
± 5 min
]15-30] min
± 10 min
]30 min-H2]
± 15 min
]H2-H6]
±30 min
]H6-H24]
± 60 min
Superior to H24
± 120 min
PK blood collection 
[H0.5-H0.75]
±1 min
[H1-H1.5]
±3 min
[H2-H12]
±5 min
H24
± 15 min
H36
± 30 min
[H48-H72]
± 120 min
Vital Signs
Inferior or equal to H2
± 15 min
]H2-H6]
± 30 min
]H6-H24]
± 60 min
Superior to H24
± 120 min

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
This document contains confidential information that should only be disclosed to those persons responsible 
for the study. This information must not be disclosed to any third party without prior written authorisation 
from the Sponsor.
Study protocol code
W00074CI103 
Biotrial code
1PF74
Study title
A randomized, single-center, open-label, single 
dose, two-period, crossover pivotal bioequivalence 
study comparing binimetinib 3x15 mg and 45 mg 
tablets in healthy participants
Study 
investigational 
medicinal 
product
binimetinib (MEKTOVI®)
Development phase
Phase I
Sponsor
Pierre Fabre Médicament represented by the 
Institut de Recherche Pierre Fabre
Les Cauquillous
81500 Lavaur
FRANCE
Version of the statistical analysis plan
Final Version 1.0
Date of the statistical analysis plan
25AUG2022


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SIGNATURE PAGE
TITLE
RESPONSIBILITY
NAME & OFFICE
SIGNATURE/DATE
Biostatistics 
Project 
Leader 
Author
Morgane GILLES
BIOTRIAL 
BIOMETRICS
7-9 
rue 
Jean-Louis 
Bertrand
CS 34246
35042 Rennes Cedex
Pharmaco-
kineticist 
Approver
Julien PAGES
BIOTRIAL
7-9 
rue 
Jean-Louis 
Bertrand
CS 34246
35042 Rennes Cedex
FRANCE
Sponsor's 
Head of 
statistics
Approver
David JEGOU
Pierre Fabre Médicament 
represented by the Institut 
de Recherche Pierre Fabre
Les Cauquillous
81500 Lavaur
FRANCE
Sponsor's  
Head of 
Oncology 
Innovation
Unit
Reviewer
Eric CHETAILLE
Pierre Fabre Médicament 
represented by the Institut 
de Recherche Pierre Fabre
Les Cauquillous
81500 Lavaur
FRANCE
Sponsor's
Pharmaco-
kineticist
Reviewer
Laurence BARTHE
Pierre Fabre Médicament 
represented by the Institut 
de Recherche Pierre Fabre
Les Cauquillous
81500 Lavaur
FRANCE



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TITLE
RESPONSIBILITY
NAME & OFFICE
SIGNATURE/DATE
Sponsor's 
Head of 
Pharmaco-
kinetics 
Approver
Eric DIDIER
Pierre Fabre Médicament 
represented by the Institut 
de Recherche Pierre Fabre
Les Cauquillous
81500 Lavaur
FRANCE


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REVISION HISTORY
Date
Version 
number
Reason for change
Authored by
30JUN2022
D0.1
Initiation
M.GILLES
28JUL2022
D0.2
Implementation of sponsor’s comments
M.GILLES
22AUG2022
D0.3
Implementation of sponsor’s comments
M.GILLES
25AUG2022
V1.0
Implementation of sponsor’s comments
M.GILLES


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TABLE OF CONTENTS
1. 
Introduction.................................................................................................................. 10 
2. 
Study objectives............................................................................................................. 10 
2.1. 
Primary objective....................................................................................................... 10 
2.2. 
Secondary objectives ................................................................................................. 10 
3. 
Study methodology ....................................................................................................... 10 
3.1. 
Protocol overview...................................................................................................... 10 
3.2. 
Planned analyses........................................................................................................ 11 
4. 
Sample Size................................................................................................................... 11 
5. 
Changes to the planned analysis from protocol.......................................................... 11 
6. 
Statistical considerations.............................................................................................. 11 
7. 
Description of study participants ................................................................................. 13 
7.1. 
Definition of analysis sets.......................................................................................... 13 
7.2. 
Participant disposition ............................................................................................... 13 
7.3. 
Protocol deviations .................................................................................................... 14 
8. 
Demographic data and baseline characteristics.......................................................... 14 
8.1. 
Demographic data...................................................................................................... 14 
8.2. 
Other baseline characteristics .................................................................................... 14 
8.3. 
Medical and surgical history and procedures ............................................................ 15 
8.4. 
Prior and concomitant medications ........................................................................... 15 
8.5. 
Compliance................................................................................................................ 15 
9. 
Pharmacokinetic data................................................................................................... 15 
9.1. 
Generalities................................................................................................................ 16 
9.2. 
Plasma concentrations and pharmacokinetic parameters .......................................... 18 
9.2.1. 
Plasma parameters.............................................................................................. 18 
9.2.2. 
Plasma pharmacokinetic analysis....................................................................... 19 
10. 
Pharmacodynamics data .............................................................................................. 20 
11. 
Safety data..................................................................................................................... 20 
11.1. Adverse events........................................................................................................... 20 
11.2. Clinical laboratory data ............................................................................................. 22 
11.3. Other safety parameters............................................................................................. 24 
11.3.1.    Vital signs data………………............................................................................ 24 
11.3.2. 
Electrocardiogram data……………… .............................................................. 24 


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11.3.3. 
Physical examination ……………………......................................................... 25 
11.3.4. 
Visual and ophthalmologic examinations .......................................................... 25 
11.3.4.1.    Visual assessment .................................................................................................... 25 
11.3.4.2.    Ophthalmologic examination................................................................................... 25 
11.3.5. 
Substance use and physical activity ................................................................... 26 
11.3.6. 
COVID-19 tests.................................................................................................. 26 
11.3.7. 
Pregnancy test .................................................................................................... 26 
12. 
Procedures and data formats ....................................................................................... 26 
13. 
Reporting conventions.................................................................................................. 26 
14. 
References..................................................................................................................... 27 
15. 
Appendices.................................................................................................................... 28 
15.1. Appendix 1 - Schedule of activities of the study....................................................... 28 
15.2. Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA) 32 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABBREVIATION
DEFINITION
ADPP
ADaM Pharmacokinetic Parameters dataset
AE
Adverse Event
ALP
ALkaline Phosphatase
ALT
ALanine aminoTransferase
AST
ASpartate Aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
Area Under the Curve
AUC_%Extrap_obs
Residual area expressed in percentage
AUClast
Area Under the Curve from time zero to last quantifiable plasma 
concentration
AUCinf
Area Under the Curve from time zero to infinity
BLQ
Below the Limit of Quantification
BMI
Body Mass Index
CI
Confidence Interval
CK
Creatine Kinase
CL/F
Apparent total body clearance
Clast
Last observed quantifiable plasma concentration
Cmax
Maximum observed plasma concentration
COVID-19
Coronavirus disease 2019
CRF
Case Report Form
CSR
Clinical Study Report
CV
Coefficient of Variation
eCRF
electronic Case Report Form
ECG
ElectroCardioGram
EMA
European Medicines Agency
EOS
End Of Study
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone 
GGT
Gamma Glutamyl Transferase
GMR
Geometric Mean Ratio
HBsAg
Hepatitis B surface Antigen
hCG
human Chorionic Gonadotropin


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ABBREVIATION
DEFINITION
HGB
Hemoglobin
HIV
Human Immunodeficiency Virus
i.e.
id est
ICH
International Conference on Harmonisation
IMP
Investigational Medicinal Product (synonymous with “study drug”)
Ȝz
First order terminal elimination rate constant
LLN
Lower Limit of Normal range
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic Ratio
MRT
Mean Residence Time
MW
Molecular Weight
NA
Not Applicable
NC
Not Calculated
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for 
Adverse Events
ND
Not Determined
PCR
Polymerase Chain Reaction
PCSA
Potentially Clinically Significant Abnormalities
PK
PharmacoKinetics
PT
Preferred Term
QRS
QRS interval duration
QT
Time interval for ventricular depolarisation and repolarisation
QTc
Corrected QT interval
QTcF
QT interval corrected using Fridericia’s formula
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS®
Statistical Analysis System®
SD
Standard Deviation
SEM
Standard Error of the Mean
SOC
System Organ Class
SOP
Standard Operating Procedure
t1/2
Terminal elimination half-life
Tlast
Time to reach last observed quantifiable plasma concentration
Tmax
Time to reach maximum observed plasma concentration


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ABBREVIATION
DEFINITION
TEAE
Treatment-Emergent Adverse Event
TOST
Two One-Sided Test
ULN
Upper Limit of Normal range
ULQ
Upper Limit of Quantification
Vz/F
Apparent volume of distribution
WHO
World Health Organisation


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1. Introduction
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analysing 
study data and outlines the statistical programming specifications, tables, figures and listings. 
It describes the safety and pharmacokinetics (PK) variables and analysis sets, anticipated data 
transformations and manipulations, and other details of the analyses not provided in the study 
protocol.
The analyses described are based upon the final clinical study protocol V1.2 dated 22 June 2022
and will be prepared in accordance with the International Conference on Harmonisation (ICH) 
E9.
The statistical analyses will be performed by the Biostatistics unit of BIOTRIAL 
BIOMETRICS in agreement with the sponsor.
The SAP will be validated and signed before the first visit of the first participant.
2. Study objectives
2.1. Primary objective
The primary objective is to demonstrate the bioequivalence of binimetinib 1 x 45 mg tablet Test 
formulation in comparison to 3 x 15 mg tablet Reference formulation in healthy participants 
under fasted conditions.
2.2. Secondary objectives
The secondary objectives are:
-
to measure secondary PK parameters of binimetinib and PK parameters of the 
metabolite (AR00426032)
-
to evaluate the safety and tolerability of binimetinib as a 1 x 45 mg Test tablet in 
comparison to 3 x 15 mg Reference tablets in healthy participants.
3. Study methodology
3.1. Protocol overview
This will be a randomized, single-center, open-label, two-sequence, two-period, crossover 
phase I study to demonstrate the bioequivalence of binimetinib 3 x 15 mg and 1 x 45 mg tablets 
in healthy participants. The Reference (R) formulation will be the currently commercially 
available tablet containing 15 mg of binimetinib as active substance, administered as three 
tablets for a total of 45 mg binimetinib. The Test (T) formulation will be the tablet containing 
45 mg of binimetinib as active substance in one tablet. 
Participants will be randomized to one of 2 treatment sequences (RT or TR) containing 2 
treatment periods, with at least a 7-day washout between each dose.
The study will consist of:
-
a screening period between 21 and 2 days before the first study treatment 
administration on Period (P) 1 Day (D) 1,
-
2 treatment periods of 5 days each (including one ambulatory visit at D4 per period),
-
a washout of at least 7 days between P1D1 and P2D1,


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an End of Study (EOS) visit to be performed 30 (± 3) days after the last study 
treatment administration or discontinuation.
Study treatments will be given by the oral route in fasted condition.
In each treatment period, following the 48h post-dose procedures, the participants will be 
discharged and will return for an ambulatory visit on D4, and then return for the next treatment 
period or an EOS visit.
The schedule of activities is available in section 15.1.
3.2. Planned analyses
Final analyses will be performed when all participants complete the study and after the database 
lock.
4. Sample Size
The primary objective of this study is to demonstrate bioequivalence between the Test 1 x 
45 mg binimetinib tablet and the Reference 3 x 15 mg binimetinib commercial tablets, based 
on PK endpoints Cmax, AUCinf and AUClast.
The null hypothesis is that the true ratio of the geometric mean of the Test treatment to the 
geometric mean of the Reference treatment, μ(T)/μ(R), for the Cmax, AUCinf and AUClast is 
either <0.80 or >1.25. The alternate hypothesis is that the true ratio of the geometric mean of 
the Test treatment to the geometric mean of the Reference treatment for the Cmax, AUCinf and 
AUClast, is 0.80 and 1.25. For each PK parameter designated as a primary endpoint, a two 
one-sided t-test (TOST) [1] procedure with Į=0.05 for each one-sided test will be used to test 
this set of hypotheses. 
Bioequivalence will be declared if the 90% confidence interval (CI) for the true ratio of test to 
reference geometric means falls entirely within the range of 0.80 to 1.25 for all primary 
parameters (i.e the null hypothesis must be rejected), in accordance with the European 
Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines on the 
investigation of bioequivalence [2][3].
Based on these criteria, assuming intra participant coefficient of variation (CVintra) of Cmax to 
be around 25% as observed on the pilot study [4] and a “Test/Reference” mean ratio of 1.05; 
thirty-six participants are needed to achieve a power of 90% at an alpha of 0.05.
Up to 40 participants will be included into the study to complete the study with at least 36 
evaluable participants.
5. Changes to the planned analysis from protocol 
Not applicable.
6. Statistical considerations
Demography and safety data will be analysed using SAS£ software version 9.4 or higher (SAS 
institute Inc. Cary NC USA).
Pharmacokinetic (PK) data will be analysed using Phoenix£ WinNonlin£ version 8.1 or higher 
(Certara USA, Inc., Princeton, NJ) and SAS£ software version 9.4 or higher (SAS Institute Inc. 
Cary NC USA).
Descriptive statistics will be supplied according to the nature of the criteria:


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Quantitative variable: number of participants, arithmetic mean, standard deviation (SD), 
standard error of the mean (SEM), minimum, median and maximum, and quartiles if 
necessary [with geometric mean, arithmetic and geometric CV, and quartiles for PK 
analyses]. 
-
Qualitative variable: number of participants, absolute and relative frequencies per class.
-
Percentages will be provided with one decimal place.
Unless specified otherwise, the calculation of percentages will be based on the number of 
observed values. Therefore, counts of missing values will be included in the denominator and
displayed as a separate category if any.
For the values measured outside of the treatment periods, data will be organised overall and, 
for description at baseline, by sequence:
-
Test/Reference
-
Reference/Test
With the following footnote: " Reference: binimetinib 3 x 15 mg tablet; Test: binimetinib 1 x 
45 mg tablet.".
For the values obtained during the treatment periods, data will be organised by formulation
group:
-
binimetinib 1 x 45 mg tablet,
-
binimetinib 3 x 15 mg tablet.
All safety listings will be sorted by participant, sequence and measurement time if applicable.
All pharmacokinetics listings will be sorted by treatment group, participant and measurement 
time.
All listings containing an evaluation date will display the study day defined as the day relative 
to the first administration of study drug:
-
If evaluation precedes first drug administration then: 
(date of evaluation) - (date of first study drug administration)
-
Study day -1 will be defined as the day prior to the first administration date.
-
If evaluation is on or after the first drug administration then: 
-
(date of evaluation) – (date of first study drug administration) + 1 
-
Study day 1 will be defined as the day of the first administration date.
-
There will be no study day 0.
Handling of missing, retest values and unscheduled visits
No management of missing values or values below/above a limit of detection/quantification 
will be performed, except for pharmacokinetic values (see section 9.1). In clinical laboratory 
data, “<LOQ” or “>ULQ” is reported in the qualitative variable. When converting the 
qualitative variable to the quantitative variable, “<LOQ” or “>ULQ” will be automatically 
treated as missing.
For all parameters and for participants with retest values, the last non-missing value will be 
used for the measurement time before the first IMP administration within each period (provided 
it was measured before IMP administration within each period) and the first non-missing value 
will be used for the measurement time after the first IMP administration within each period.


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Unscheduled visits will not be analysed but presented in listings only.
Handling of incomplete dates
No management of incomplete dates will be performed. The incomplete dates will be labelled 
as such in the listings.
Baseline definition
For all parameters, baseline will be defined as the last available assessment prior to the first 
IMP administration within each period, including additional assessments (where applicable). 
Assessments that occurred on the same day as first dose, when time of assessment is not 
available, will be as assumed to be prior to first dose. 
Duration
Duration (in days, hh:mm) will be calculated by the difference between the start and stop date 
and time (e.g. duration of AE (days, hh:mm) = end of AE date and time - AE onset date and 
time).
Duration (in days) will be calculated by the difference between the start and stop date + 1 (e.g. 
duration of a medication (days) = end of medication date - onset of medication date + 1).
Type I error rate
Unless stated otherwise, statistical tests will be two-sided and will be carried out at the 5% level 
of significance.
7. Description of study participants
7.1. Definition of analysis sets
The following analysis sets will be defined:
Enrolled set: all participants who signed the ICF for the study.
Screened set: all enrolled participants having successfully completed the screening period.
Randomized set: all randomized participants.
Safety set: all included participants having taken at least one dose of study treatment, including 
those who did not complete the study.
Pharmacokinetic set: all of the participants who have taken one dose of study treatment in the 
two periods without any event (including no vomiting within 4 hours after dosing) and/or 
important protocol deviation affecting PK evaluation, with complete PK profiles in these two 
periods, i.e. sufficient PK concentration data to support the calculation of primary PK criteria
(see section 9.1).
The analysis sets will be precisely defined and validated during the data review meeting and 
prior to database lock..
The safety and pharmacokinetic sets will be analysed using participants as treated. The 
randomized set will be analysed using participants as randomized.
7.2. Participant disposition
A summary table with the description of the number of screened participants, the number of 
randomized participants, the number of participants who completed the study and the number 


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of participants who discontinued the study, classified by main reason of withdrawal, will be 
prepared by sequence and overall for the participants in the screened set. Corresponding 
individual listings will be provided.
A summary table with the description of the number and percentage of participants in each 
analysis set (Randomized set, Safety set and Pharmacokinetic Set) will be prepared by sequence 
and overall. A specific listing of participants excluded from safety and/or pharmacokinetic 
analyses will be provided with the reason(s) for exclusion.
A summary table with the number and percentage of participants at each period will be prepared 
by treatment group and overall on the participants in the randomized set.
Listings with end of study status and study visit dates will also be generated.
In addition, due to possible impact of COVID-19 pandemic on participants’ disposition, the 
following disposition table will be presented for all randomized patients by sequence:
-
number (%) of participants infected (i.e. at least one AE related to COVID-19 and/or 
positive Polymerase Chain Reaction test result).
-
number (%) of discontinued participants due to COVID-19 and reasons of discontinuation,
-
number (%) of participants impacted (with at least one important protocol deviation due to 
COVID-19 or for whom the conduct of the study has been impacted (missed visit, remote 
visit, unscheduled visit, etc.)),
-
number (%) of participants with important protocol deviations due to COVID-19.
7.3. Protocol deviations
A summary table by sequence and overall with the number and percentage of participants 
presenting all protocol deviations judged important during the data review meeting will be 
prepared for the participants in the randomized set. All important protocol deviations will be 
listed and important protocol deviations due to COVID-19 will be flagged if applicable.
8. Demographic data and baseline characteristics
The analyses of the demographic and baseline characteristics will be performed on the 
randomized set.
8.1. Demographic data
The participants’ demographic characteristics will be summarised by sequence and overall, and 
listed:
-
age at screening (years) – continuous,
-
sex, 
-
ethnicity, 
-
height at screening (cm)
-
weight at screening (kg)
-
Body Mass Index (BMI) recorded at screening (kg/m²)
8.2. Other baseline characteristics
All parameters recorded before dosing (COVID-19 vaccination status, smoking and alcohol
history) will be summarised by sequence and overall, and listed.


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Positive results as well as all individual data for urine drug screen (benzodiazepines, cocaine, 
cannabinoids, morphine, amphetamines, methamphetamines and ecstasy), alcohol breath test 
and urine cotinine test performed at screening and on Day -1 of each period (see section 15.1)
will be listed.
Positive results as well as all individual data for serology (Hepatitis B surface antigen, hepatitis 
C antibody and HIV) will be listed.
For postmenopausal female participants, serum follicle-stimulating hormone (FSH) and 
estradiol will only be listed.
8.3. Medical and surgical history and procedures
Information on medical and surgical history recorded at the screening visit and procedures will 
be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 
24.0.
A table with the number and percentage of participants having at least one previous/ongoing 
medical history or one surgical history will be generated by sequence and overall, by System 
Organ Class (SOC) and Preferred Term (PT). Previous/ongoing medical history will be listed 
as well as prior surgeries and concomitant surgeries.
8.4. Prior and concomitant medications
Information on prior and concomitant medications will be coded according to the WHO Drug 
Dictionary version of March 2022 (B3 with primary ATC selection).
A prior medication will be defined as a medication stopped prior to the date and time of the first 
administration of IMP. Prior medications are recorded in the “Concomitant medication” eCRF 
page and identified by the “Taken prior to treatment start” variable.
A concomitant medication will be defined as a medication that is taken by participants any time 
during the treatment period (on or after the date and time of first IMP administration for each 
participant). If the date value does not allow allocation of a medication to the prior or 
concomitant category (missing or incomplete start or end date), this medication will be 
considered concomitant.
A table with the number and percentage of participants having taken at least one previous 
medication and a table with the number and percentage of participants having taken at least one 
concomitant medication will be generated by sequence and overall (overall and by medication 
class [2nd level of Anatomical Therapeutic Chemical (ATC)] and medication drug name). Prior
and concomitant medications will be listed separately. 
8.5. Compliance
A listing with IMP administration dates and times will be generated. Time of meals intake will 
also be listed. 
9. Pharmacokinetic data
Plasma concentrations of binimetinib and corresponding non-compartmental derived PK 
parameters [AUC from time of administration to last observed plasma concentration (AUClast), 
AUCinf, Cmax, Tmax and AUC Test (T)/Reference (R) ratios] will be used as primary endpoints 
to evaluate the bioequivalence of binimetinib 1 x 45 mg tablet formulation in comparison to the 
commercialized 3 x 15 mg tablet formulation in healthy participants under fasted conditions.


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The pharmacokinetic statistical analysis will be performed on the PK set.
9.1. Generalities
Reasons for exclusion:
Before concentration data are communicated by the bioanalytical laboratory, the following 
rules will lead to exclude a participant from the PK set:
-
Any participant who discontinued with study treatment (no administration in the second 
period),
-
Any participant having experienced vomiting or diarrhoea within 4 hours after dosing,
-
Any participant having taken prohibited concomitant treatment or medication affecting PK 
throughout the study,
-
Any participant for whom a washout of at least 7 days between each dose was not respected,
-
Any participant who did not remain fasted for at least 10 hours before dosing,
-
The following deviations will be discussed case by case:
- Any deviation related to PK sample technical handling or storage,
- Any participant with insufficient PK samples to support the calculation of primary PK 
criteria.
In the following cases (exceptions), the decision to exclude a participant from the statistical 
analysis (i.e. participant kept in the PK set but flagged and only listed, concentrations and 
parameters will not be used for statistical analysis) could be done after concentration data are 
communicated by the bioanalytical laboratory:
1) Any participant with lack of any measurable concentrations or only very low plasma 
concentrations for reference formulation (i.e. its AUC is less than 5% of reference 
formulation geometric mean AUC, calculated without inclusion of data from the outlying 
participant),
2) Any participant with non-zero baseline concentrations > 5% of Cmax.
The following rules for PK parameter calculation after each administration will be used:
Actual sampling times will be used for deriving PK parameters.
-
For plasma concentrations and PK parameters:
-
All BLQ values will be substituted according to the rules described in the following 
table and by type of analysis:


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Substitution value if BLQ occurs:
Type of analysis
Before 
Tmax
After Tmax & between 2 
quantifiable 
concentrations
After 
Tmax
& 
NOT 
between 2 quantifiable 
concentrations
PK non-compartmental 
analysis
0
Missing
Missing
Descriptive statistics
0
0
0
Plotting of individual 
data
0
Missing
Missing
Listing of individual 
data
BLQ
BLQ
BLQ
-
Some conditions for plasma PK parameters have to be fulfilled:
1) the percentage of the extrapolated AUC (AUC_%Extrap_obs) should not exceed 
20% of the AUCinf of each individual profile,
2) the elimination rate constant should be determined over a time interval equal to at 
least 2 x t1/2,
3) WKHGHWHUPLQDWLRQRIȜz should use only those data points judged to describe the 
terminal log-linear decline resulting in an adjusted coefficient of determination 
value R² (RsqadjDQGDPLQLPXPRIGDWDSRLQWVZLOOEHXVHGLQFDOFXODWLQJ
Ȝz excluding Cmax.
If these conditions are not fulfilled, the following unreliable PK parameters will be 
flagged in the listings and will be excluded from the analysis:
1) if the time interval used for the determination of the elimination rate constant is 
inferior to 2 x t1/2 and/or not with a minimum of 3 data points and/or if the Rsqadj <
0.8: Ȝz, t1/2, AUCinf, CL/F, Vz/F, MRT and MRAUC.
2) if AUC_%Extrap_obs> 20%: AUCinf, CL/F, Vz/F, MRT and MRAUC.
No graphic representation will be done if all values are BLQ.
The following rules for mean plasma concentration calculation will be used:
-
If at least 3 of the values are evaluable (either BLQ values replaced by zero or numeric 
values): statistics will be calculated with the replaced and numeric values.
-
If less than 3 values are evaluable: only the minimum and maximum will be presented 
and the other statistics will be considered as "Not Applicable" (NA).
-
If at least one value is BLQ (replaced by 0), the geometric mean and its CV% will be 
presented as "Not Calculated" (NC).
For summary statistics for PK parameters:
-
If at least 3 values are analysable and not missing: statistics will be calculated with the 
available values.


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-
If less than 3 values are analysable: only the minimum and maximum of the available 
numeric values will be presented. All other statistics will not be calculated and will be 
presented as "Not Determined" (ND).
All BLQ concentrations and missing data will be labelled as such in the concentration data 
listings.
9.2. Plasma concentrations and pharmacokinetic parameters
9.2.1. Plasma parameters
Blood samples will be drawn in each treatment period (see section 15.1) at pre-dose and at 
H0.5, H0.75, H1, H1.25, H1.5, H2, H3, H4, H5, H6, H8, H10, H12, H24, H36, H48 and H72 
post-dose of each period.
Relevant plasma pharmacokinetic (PK) parameters of binimetinib and its metabolite 
AR00426032 will be calculated by standard non-compartmental methods for the participants
with sufficient plasma concentration data (a PK profile with at least 3 quantifiable 
concentrations). The rules defined in the previous section (9.1) will be used.
The different areas under the concentration-time curve (AUC) will be calculated using the 
linear-log trapezoidal method: the linear trapezoidal method for increasing or equal 
concentrations and the logarithmic trapezoidal method for decreasing concentrations.
The following plasma pharmacokinetic parameters will be calculated for binimetinib and 
AR00426032:
Parameters (unit)
Definition
Cmax (ng/mL)
Maximum observed plasma concentration
Tmax (h)
Time to reach maximum observed plasma concentration
Tlast (h)
Time to reach last observed quantifiable plasma concentration
AUClast (ng/mL.h)
Area under the plasma concentration-time curve from time zero 
to the last quantifiable plasma concentration
AUCinf (ng/mL.h)
Area under the plasma concentration-time curve from time zero 
to infinity, calculated as follows: 
AUCinf = ܣܷܥ௟௔௦௧+
஼೗ೌೞ೟
஛೥,
where Clast is the last observed quantifiable concentration
Ȝz (/h)
First order terminal elimination rate constant
t1/2 (h)
Terminal elimination half-life, calculated as follows: t1/2 = lQȜz
MRT (h)
Mean Residence Time, calculated as follows:
MRT = 
஺௎ெ஼೔೙೑
஺௎஼೔೙೑
where AUMCinf is the area under the first moment curve from 
zero to infinity.
The following plasma pharmacokinetic parameters will be calculated only for binimetinib:
Parameters (unit)
Definition
AUC_%Extrap_obs (%)
Residual area expressed in percentage


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Parameters (unit)
Definition
CL/F (L/h)
Apparent total body clearance, calculated as follows: 
CL/F = Dose / AUCinf
Vz/F (L)
Apparent volume of distribution, calculated as follows:
9]) &/)Ȝz
MRAUC
Metabolite-parent ratio based on AUCinf accounting for 
differences in molecular weights (MW), calculated as follows:
MRAUC =
஺௎஼೔೙೑ ಲೃబబరమలబయమ ெௐಲೃబబరమలబయమ 
Τ
஺௎஼೔೙೑ ್೔೙೔೘೐೟೔೙೔್ெௐ್೔೙೔೘೐೟೔೙೔್
Τ
9.2.2. Plasma pharmacokinetic analysis
Listings with plasma concentrations (including PK blood sampling dates, times and elapsed 
times) and PK parameters will be provided by formulation group and participant. These listings 
will be generated for all participants with an available PK profile (complete or incomplete), 
including those who are excluded from the pharmacokinetic set. Participants excluded will be 
flagged.
Plasma concentrations and PK parameters of binimetinib and AR00426032 including 
descriptive statistics will be presented in tables separately for each formulation group. 
Individual plasma concentration versus time profiles of binimetinib and AR00426032 will be 
presented graphically on linear and log/linear coordinates for each participant with all 
formulations received by the participant on the same graph.
The graph of arithmetic mean ± SD over time will be provided for plasma concentration of 
binimetinib and AR00426032 on linear and log/linear coordinates with all formulation groups 
on the same graph as well as for each formulation group with both analytes on the same graph. 
Individual plasma concentration-time profiles (spaghetti plots) of binimetinib and AR00426032 
will also be presented for each formulation group on linear and log/linear coordinates.
For binimetinib only:
Scatter plots will be generated for the comparison of the Cmax, AUClast and AUCinf (if 
applicable) parameters of binimetinib between the formulation groups.
Box whisker plots will be generated for the comparison of Cmax, AUClast and AUCinf (if 
applicable) parameters of binimetinib between the formulation groups.
To demonstrate the bioequivalence between the two formulations, primary PK parameters 
(Cmax, AUClast and AUCinf) will be analyzed separately using linear mixed effects model with 
log-transformed PK parameter (variable PARAMCD) as the dependent variable, sequence
(TRTSEQPN), period (APERIOD) and formulation (TRTAN) as fixed effects and participant 
within sequence (USUBJID(TRTSEQPN)) as random effect. Point estimates and 90% CIs will 
be provided for the ratio of Test to Reference (3 x 15 mg formulation as Reference and 1 x 45 
mg formulation as Test). In accordance with EMA and FDA guidelines, bioequivalence will be 
declared if the 90% CI for the ratio of Test to Reference geometric means is within the range 
of 80.00% to 125.00% (0.80 to 1.25) for all primary endpoints.
Estimated geometric mean ratios (GMRs) and 90% CIs will also be displayed in a figure.
The following SAS code will be used:
proc mixed data=ADPP method=REML;
by PARAMCD;


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class TRTSEQPN APERIOD TRTAN USUBJID;
model ln(AVAL) = TRTSEQPN APERIOD TRTAN / solution ddfm=kr;
random USUBJID(TRTSEQPN);
lsmeans TRTAN / cl alpha=0.10;
estimate ‘Test versus Reference’ TRTAN -1 1 / cl alpha=0.10 e;
run;
The Wilcoxon signed-rank test will be used to test for the difference in Tmax of binimetinib 
between the 2 formulations.
Differences in Tmax of binimetinib between the 2 formulations will be explored by computing 
the Hodges-Lehmann shift estimate and the corresponding 90% CI. The difference between the 
2 formulations [di=(xi, yi)] for each participant and for binimetinib is calculated and sorted, 
WKHQWKHDYHUDJHYDOXHRIWKHGLIIHUHQFHRIHDFKRUGHUHGSDLUGMGLZLWKLMLVFRPSXWHGDQG
the median difference is estimated, then the confidence interval for the mean difference is 
estimated based on the Wilcoxon signed-rank distribution.
10. Pharmacodynamics data
Not applicable.
11. Safety data
The safety analyses will be performed on the safety set.
11.1. Adverse events
Adverse events, including pre-treatment events, will be recorded from the time of consent 
through until the EOS visit.
A treatment-emergent adverse event (TEAE) is an adverse event that starts or worsens during 
the on-treatment period. All analyses described in section 11.1 will be based on TEAEs if not 
otherwise specified.
The following treatment periods will then be considered:
Period
Start date/time
End date/time
Before any 
treatment
Date/time of inform consent
Date/time of first IMP 
administration of period 1 - 1
minute
Treatment 
1
Date/time of first IMP administration 
of period 1
Date/time of first IMP 
administration of period 2 - 1
minute
Treatment 
2
Date/time of first IMP administration 
of period 2
Date of end of study
Adverse events will be summarized by worst grade according to the National Cancer Institute 
- Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE V5.0 [5]) per 
participant and coded using MedDRA Version 24.0.


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A summary table will present the number and percentage of participants with a TEAE overall 
and by formulation, including: 
-
TEAEs;
-
TEAEs, grade >=3;
-
Related TEAEs;
-
Related TEAEs, grade >=3;
-
TEAEs leading to any dose reduction;
-
Related TEAEs leading to any dose reduction;
-
TEAEs leading to permanent treatment discontinuation;
-
Related TEAEs leading to permanent treatment discontinuation;
-
Serious TEAEs;
-
Related serious TEAEs;
-
TEAEs leading to death;
-
Related TEAEs leading to death.
Treatment-emergent adverse events will be summarised in tables as follows [overall and by 
SOC and PT]:
-
Number and percentage of participants with at least one TEAE and number of 
occurrences of a TEAE by formulation and overall,
-
By worst NCI-CTCAE grade, with the number and percentage of participants with 
at least one TEAE and number of occurrences of a TEAE by formulation and overall,
-
By causality to study treatment, with the number and percentage of participants with 
at least one TEAE and number of occurrences of a TEAE by formulation and overall.
If there are only a few treatment-emergent DGYHUVHHYHQWV10), only a listing will be generated.
Additionally, AEs related to COVID-19 will be summarised by formulation and overall and 
listed separately. If there are only a few adverse events related to COVID-19 RQO\D
listing will be generated.
All adverse events reported in the electronic Case Report Form (eCRF) will be listed with the 
SOC, the PT and the investigator's verbatim. All TEAEs will also be listed with the SOC and 
the PT. An additional listing will be provided for TEAEs leading to death and other serious and 
significant TEAEs (SAEs or TEAEs leading to study withdrawal). If more than 10 of these 
TEAEs are observed, a summary table with the number and percentage of participants with at 
least one TEAE and number of occurrences of a TEAE by formulation and overall will be 
provided, as well as three distinct listings (for TEAEs leading to death, TEAEs leading to study 
withdrawal and SAE).
Note:
i.
The occurrence of an adverse event is defined by the appearance of a new single 
event, the reappearance of a previously recovered event or the worsening of a 
continuous event in severity or seriousness (relative to its previous status).
ii.
In the descriptive tables, the number of participants with at least one adverse 
event/TEAE for a given PT will also correspond to the number of adverse 
events/TEAEs whatever the number of occurrences during the studied period. 
iii.
In case of a change of severity or causality for an event during the same treatment 
period, the severity will be the highest recorded intensity and the causality will be the 
highest likelihood recorded.
iv.
SOCs will be sorted by descending order of frequency for the overall, PTs will be 
sorted by descending order of frequency for the overall within each SOC.


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11.2. Clinical laboratory data
The following clinical laboratory parameters will be measured (see section 15.1):
-
at screening,
-
on Day -1 of each period;
-
at H24 and H48 post-dose of each period;
-
at EOS.
Haematology parameters will be listed and grouped as follows:
-
Red blood cells: erythrocytes (10^12/L), ery. mean corpuscular hemoglobin (pg), ery. mean 
corpuscular volume (MCV) (fL), hematocrit (ratio), hemoglobin (HGB) (g/L) and 
reticulocytes/erythrocytes (%).
-
White blood cells: leukocytes (10^9/L), basophils (10^9/L), basophils/leukocytes (%), 
eosinophils 
(10^9/L),
eosinophils/leukocytes 
(%),
lymphocytes 
(10^9/L), 
lymphocytes/leukocytes (%), monocytes (10^9/L), monocytes/leukocytes (%), neutrophils 
(10^9/L) and neutrophils/leukocytes (%).
-
Other parameters: platelets (10^9/L).
Blood chemistry parameters will be listed and grouped as follows:
-
Liver function: alanine aminotransferase (ALT) (IU/L), alkaline phosphatase (ALP) (IU/L), 
aspartate aminotransferase (AST) (IU/L), bilirubin (μmol/L), gamma glutamyl transferase 
(GGT) (IU/L) and indirect bilirubin (μmol/L).
-
Renal chemistry: creatinine (μmol/L) and urea (mmol/L).
-
Electrolytes: bicarbonate (mmol/L), calcium (mmol/L), chloride (mmol/L), magnesium 
(mmol/L), potassium (mmol/L) and sodium (mmol/L).
-
Metabolism parameters: glucose (mmol/L), cholesterol (mmol/L) and urate (μmol/L).
-
Other proteins: albumin (g/L), creatine kinase (CK) (IU/L), lactate dehydrogenase (IU/L) 
and protein (g/L).
-
Digestive enzymes: amylase (IU/L) and lipase (IU/L).
Coagulation parameters will be listed and grouped as follows:
-
Coagulation parameters: activated partial thromboplastin time (sec) and prothrombin time 
(sec).
Urinalysis parameters will be listed and grouped as follows:
-
Planned urinalysis parameters: dipstick determination of pH, erythrocytes, glucose, ketones, 
leukocytes and protein.
-
Direct microscopy (in case of abnormal urinalysis parameters and in the listing only).
For haematology, blood chemistry and coagulation, raw data and changes from baseline will be 
described by formulation group at baseline and for each post-baseline measurement. 
For urinalysis, raw data (planned parameters) will be described by summary statistics or 
frequency tables by formulation group at baseline and for each post-baseline measurement.
For haematology, blood chemistry, coagulation and urinalysis, values higher or lower than the 
laboratory reference range (H, L) or abnormal values for urinalysis will be listed.
For haematology, blood chemistry and coagulation, for laboratory tests covered by the NCI-
CTCAE [5] laboratory data will be graded accordingly. Grade 0 will be assigned for all non-


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missing values not graded as 1 or higher. Grade 5 (death) will not be used. The parameters to 
be analyzed according to NCI-CTCAE criteria are the following:
-
Haematology:
-
Red blood cells: HGB;
-
White blood cells: leukocytes, eosinophils, lymphocytes and neutrophils;
-
Other parameters: platelets.
-
Blood chemistry:
-
Liver function: ALT, ALP, AST, bilirubin and GGT.
-
Renal chemistry: creatinine;
-
Electrolytes: bicarbonate, calcium*, magnesium, potassium and sodium;
-
Metabolism parameters: glucose and cholesterol;
-
Other proteins: albumin, CK and lactate dehydrogenase;
-
Digestive enzymes: amylase and lipase.
-
Coagulation: activated partial thromboplastin time.
* For calcium, NCI-CTCAE grading is based on corrected calcium, calculated from albumin and 
calcium as follows based on International System of Units (SI): corrected calcium (mmol/L) = measured 
total calcium (mmol/L) + 0.02 x (40 - serum albumin (g/L)).
Shift tables with the number of participants having values in each NCI-CTCAE grade according 
to the baseline position will be prepared by formulation group for each post-baseline 
measurement. A similar table will be provided with low/normal/high classification for 
laboratory tests not covered by the NCI-CTCAE, which are the following:
-
Haematology:
-
Red blood cells: erythrocytes, ery. mean corpuscular HGB, ery. MCV, haematocrit and 
reticulocytes/erythrocytes;
-
White blood cells: basophils and monocytes; 
-
Blood chemistry:
-
Liver function: indirect bilirubin;
-
Renal chemistry: urea;
-
Electrolytes: calcium and chloride;
-
Metabolism parameters: urate;
-
Other proteins: protein;
Values (raw data and changes from baseline at each measurement time) will be listed and data 
out of normal ranges will be flagged with clinical significance information.
Urinalysis values will be listed, including direct microscopy, if any.


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11.3. Other safety parameters
11.3.1. Vital signs data
Supine and standing systolic and diastolic blood pressure (mmHg), pulse rate (beats/min) and 
body temperature (C°) be measured (see section 15.1):
-
at screening,
-
on Day -1 of each period,
-
at Day 1 pre-dose, H24 and H72 post-dose of each period,
-
at EOS.
The presence of orthostatic hypotension and the presence of abnormal HR increase will be 
derived as follows for a pair of values (supine and standing) corresponding to the same 
examination:
-
Orthostatic hypotension: standing SBP - VXSLQH6%3-20 mmHg or 
standing DBP - VXSLQH'%3-10 mmHg,
-
Abnormal PR increase: standing PR - supine PR EHDWVPLQ
Raw data and changes from baseline (for supine position only) will be described by treatment 
group at baseline and for each post-baseline measurement. Missing data will define a separate 
category. 
A summary table with the number and percentage of participants with PCSA values (defined 
in section 15.2) will be generated by formulation and measurement time.
A specific listing of participants with PCSA values will be generated.
The number and percentage of participants with at least one orthostatic hypotension will be 
presented by formulation and measurement time. 
The number and percentage of participants with at least one abnormal HR increase will be 
presented by formulation and measurement time. 
Values (raw data and changes from baseline (for supine position only) at each measurement 
time) will be listed and PCSA values will be flagged with clinical significance information. 
A listing of participants having at least one orthostatic hypotension or at least one abnormal HR 
increase will be provided.
11.3.2. Electrocardiogram data
Standard 12-lead ECG parameters (including heart rate (beats/min), PR interval (msec), QRS 
duration (msec), QRS axis (deg), QT interval (msec) and Fridericia QTc interval (msec)) and 
ECG abnormalities will be recorded in triplicate (see section 15.1):
-
at screening,
-
on Day -1 of each period,
-
at Day 1 pre-dose and H24 post-dose of each period,
-
at EOS.
The mean of the triplicate ECGs will serve as analysable data.
Only interpretable ECGs will be analysed.
Raw data and changes from baseline (except for QRS axis in degrees and ECG abnormalities) 
will be described by formulation at baseline and for the each post-baseline measurement.


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Shift tables with the number of participants having values lower than the lower PCSA limit 
(Low), normal and higher than the upper PCSA limit (High) (defined in section 15.2) according 
to the baseline position will be prepared by formulation group for each post-baseline 
measurement.
A specific listing of participants with PCSA values will be generated.
Values [raw data/ECG abnormalities and changes from baseline (except for QRS axis in 
degrees) at each measurement time] will be listed and data out of the PCSA ranges will be 
flagged with clinical significance information. 
11.3.3. Physical examination
A complete physical examination, including at minima assessments of the cardiovascular, 
respiratory, gastrointestinal, dermatological and neurological, musculoskeletal in addition to 
head, eyes, ears, nose, throat, neck and lymph nodes systems will be performed (see section 
15.1):
-
at screening,
-
on Day -1 of each period,
-
at H24 post-dose of each period,
-
at EOS.
Height will be measured at screening and weight at screening, on Day -1 and at EOS (see section 
15.1). BMI will be calculated from the participants' height and weight according to the 
following formula: weight (kg)/(height(m))².
For weight and BMI, raw data will be described overall and by measurement time.
Abnormal results as well as all individual data will be listed.
11.3.4. Visual and ophthalmologic examinations
11.3.4.1. Visual assessment
A general inspection of the eyes, examination of motility and alignment, any visual disturbances 
such as blurred vision or loss of vision will be performed (see section 15.1):
-
at screening,
-
on Day -1 of each period,
-
at H24 and H72 post-dose of each period,
-
at EOS.
Abnormal results as well as all individual data will be listed.
11.3.4.2. Ophthalmologic examination
Best corrected visual acuity for distance testing, optical coherence tomography and/or 
fluorescein angiography, slit lamp examination, IOP and dilated fundoscopy with attention to 
retinal abnormalities will be performed (see section 15.1):
-
at screening,
-
at EOS.
Abnormal results as well as all individual data will be listed.


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11.3.5. Substance use and physical activity
Tobacco, xanthine, alcohol, grapefruit and recreational drugs consumption as well as physical 
activity are recorded on Day -1 and Day 4 of each period (see section 15.1).
Substance use and activity as well as all individual data will be listed. 
11.3.6. COVID-19 tests
COVID-19 antigenic test will be performed (see section 15.1):
-
at screening,
-
on Day -1 of each period,
-
at EOS.
COVID-19 polymerase chain reaction (PCR) test is to be performed on Day -1 of each period
if required.
Positive results as well as all individual data will be listed.
11.3.7. Pregnancy test
For all female participants, a blood pregnancy test (hCG) will be performed (see section 15.1):
-
at screening,
-
on Day -1 of each period,
-
at EOS.
Positive results as well as all individual data will be listed.
12. Procedures and data formats
Biotrial standard operating procedures (SOP) will be followed, and in particular on SOP GL-
6.3.6: Programming of the statistical analysis, results editing and quality control.
Derived data produced for the generation of TFLs will follow CDISC ADaM standard (ADaM 
Model v. 2.1 / ADaM IG v. 1.1 or later version).
13. Reporting conventions
All tables, figures and listings to be developed, as well as the shells for each TFL, are described 
in a separate document. They will be prepared using SAS£ software as rtf files and the rtf files 
will be compiled as PDF files (one PDF file by main section).
Orientation=Portrait
Orientation=Landscape
Page margins
Top=2.5
cm; Bottom=4.3
cm; 
Left=2.8 cm; Right=1.5 cm
Top=2.8
cm; 
Bottom=1.5
cm; 
Inside=2.8 cm; Outside=2 cm
Gutter
0 cm, left
0 cm
Header
1.5 cm
1.5 cm
Footer
3.3 cm
1.5 cm
Table and Figure Page Set Up Requirements:
-
Font Type = Time New Roman
-
Font Size = 10 pt (at a maximum, can be reduced to 9 or 8)


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-
Paper Size = A4 (21 cm x 29.7 cm)
-
Graphs: Portable Network Graphics (PNG) format
Listings Page Set Up Requirements:
-
Font Type = Courier New
-
Font Size = 6 pt (at a minimum)
-
Paper Size = A4 (21 cm x 29.7 cm)
Summary statistics will be presented as follows. 
Parameter (Unit)
Statistics
/ Category
Group X
(N=xx)
Quantitative Variable (unit)
n
xx
Geometric Mean&
xx.x
Mean+ ± SD
xx.x ± xx.xx
SEM&
xx.xx
CV%&
xx.x
Geometric CV%&
xx.x
Median
Q1 ; Q3&
xx.x
xx.x ; xx.x
Min ; Max
xx ; xx
Qualitative Variable
Class 1
xx (xx.x %)
Class 2
xx (xx.x %)
…
…
+ For PK parameters only, “Arithmetic Mean” term will be specified in order to distinguish with the 
geometric mean.
& For PK parameters only.
14. References
1.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the 
power approach for assessing the equivalence of average bioavailability. J 
Pharmacokinet Biopharm. 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419. PMID: 
3450848.
2.
EMA. 
Guideline 
on 
the 
Investigation 
of 
Bioequivalence. 
CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **. 20 Jan 2010.
3.
Guidance for Industry; Statistical Approaches to Establishing Bioequivalence; 
U.S. Department of Health and Human Services; Food and Drug Administration Center 
for Drug Evaluation and Research (CDER); January 2001.
4.
W00074CI101. A randomized, single-center, open-label, single dose, two-
period, crossover study to investigate the relative bioavailability of binimetinib 3 x15 
mg and 45 mg tablets in healthy participants. Pierre Fabre Médicament. 2022.
5.
National Cancer Institute, Common Terminology Criteria for Adverse Events 
(CTCAE 
version 
5.0), 
November
2017. 
Available 
at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5
_Quick_Reference_8.5x11.pdf
.


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15. Appendices 
15.1. Appendix 1 - Schedule of activities of the study
Treatment Phase
Epoch
Screening
Treatment Period 1
Washout
Treatment Period 2
Follow-up
Procedure/Assessment
Screening
Run-in
Period 1
Washout 
perioda
Run-in
Period 2
End of Studyb
D-21 to 
D-2
D-1
D1
D2
D3
D4
At least 
7 days
D-1
D1
D2
D3
D4
30 (±3) days 
after last dosing
Relative time (h)
Screening 
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h
t72h
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h t72h
Ambulatory visits
X
X
X
X
Stay in center
<----------------------------------------------------------------->
<------------------------------------------------------------>
Discharge
X
X
Informed consent 
X
Sequence randomization
X
Inclusion 
and 
exclusion 
criteria
X
X
X c
Demographyd
X
Medical history
X
Alcohol history
X
Smoking history
X
Drug / alcohol / tobacco / 
substance usagee
X
X
X
Prior medications / therapies 
/ procedures
X
X
COVID-19 
vaccination 
status
X
Height
X


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Treatment Phase
Epoch
Screening
Treatment Period 1
Washout
Treatment Period 2
Follow-up
Procedure/Assessment
Screening
Run-in
Period 1
Washout 
perioda
Run-in
Period 2
End of Studyb
D-21 to 
D-2
D-1
D1
D2
D3
D4
At least 
7 days
D-1
D1
D2
D3
D4
30 (±3) days 
after last dosing
Relative time (h)
Screening 
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h
t72h
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h t72h
Weight
X
X
X
X
Complete 
physical 
examination
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
Visual examinationg
X
X
X
X
X
X
X
X
Ophthalmologic 
examinationh
X
X
Standard 12-Lead ECGi
X
X
X
X
X
X
X
X
Standard cardiac 
echocardiographyj
X
Hepatitis B surface antigen, 
hepatitis C antibody and HIV
X
COVID-19 testk
X
X
X
X
FSH and estradioll
X
Pregnancy testm
X
X
X
X
Hematologyn
X
X
X
X
X
X
X
X
Clinical chemistryo
X
X
X
X
X
X
X
X
Coagulationp
X
X
X
X
X
X
X
X
Urinalysisq
X
X
X
X
X
X
X
X
PK blood samplesr
<------------------------------------------------------------>
<-------------------------------------------------------->
Concomitant 
medications/therapies
X
Assess continuously


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Treatment Phase
Epoch
Screening
Treatment Period 1
Washout
Treatment Period 2
Follow-up
Procedure/Assessment
Screening
Run-in
Period 1
Washout 
perioda
Run-in
Period 2
End of Studyb
D-21 to 
D-2
D-1
D1
D2
D3
D4
At least 
7 days
D-1
D1
D2
D3
D4
30 (±3) days 
after last dosing
Relative time (h)
Screening 
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h
t72h
Pre-
dose
Dosing
t0h
t3h
t4h t12h t24h t36h t48h t72h
Adverse eventss
X
Assess continuously
Study 
treatment  
administration
X
X
Meals: B=Breakfast, 
Lu=Lunch, Di=Dinnert
Lu, Di
Lu
Di
B
Di
B
Lu, Di
Lu
Di
B
Di
B
At least 7 days between P1D1 and P2D1.
The end-of-study (EOS) visit [30 (± 3 days) after the last study treatment administration or discontinuation] must be done for all the included participants, except participants who did not receive 
any dose of study treatment, for whom the EOS visit is not required. 
For P2D-1: exclusion criteria and only inclusion criteria 7 (vital sign) and 8 (safety lab) will be checked. Clinical relevance of abnormal value could be discussed for the participant’s participation 
in the second period of the trial. However, and among the exclusion criteria PR interval >220ms is acceptable, if not clinically significant (NCS).
Sex, age at screening, year of birth and ethnicity.
Urine drug screen, alcohol breath test and urine cotinine test.
Supine and standing systolic and diastolic BP and PR (after at least 5 minutes at rest in the supine position and after standing for 5 minutes), and body temperature. 
Visual assessment (general inspection of the eyes, examination of motility and alignment, any visual disturbances such as blurred vision or loss of vision) to be performed on site by the Investigator.
Full ophthalmologic examination by ophthalmologist to be performed at screening (within 1 week before randomization: D-9 to D-2) and EOS (within 1 week before EOS) and in case of emergency, 
including best corrected visual acuity for distance testing, optical coherence tomography and/or fluorescein angiography, slit lamp examination, intraocular pressure and fundoscopy with attention 
to retinal abnormalities.
ECGs are to be performed in triplicate (conducted within approximately 5 to 10 minutes total time). ECGs should be performed before blood collection at equivalent nominal time points.
Within 1 week before randomization (D-9 to D-2).
COVID-19 antigenic test is to be performed at screening and D-1 of each treatment period and at the EOS visit. COVID-19 polymerase chain reaction (PCR) test is to be performed on P1D-1, if 
required.
For postmenopausal female participants, serum FSH and estradiol to be performed at screening to confirm postmenopausal status (except if the participant is treated with HRT).
For all female participants, serum pregnancy tests are to be performed at screening, D-1 of each period and at the EOS visit.
Erythrocytes (red blood cells, RBC), hematocrit, hemoglobin, platelets; leukocyte count with differential: basophils, eosinophils, lymphocytes, monocytes, neutrophils/absolute neutrophil count; 
RBC indices: mean corpuscular hemoglobin, mean corpuscular volume, reticulocytes/erythrocytes.


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ALT, albumin, ALP, AST, GGT, bicarbonate, bilirubin (total and indirect), urea, calcium, chloride, CK, creatinine, amylase, lipase, total cholesterol, glucose, lactate dehydrogenase, magnesium, 
potassium, sodium, total protein, uric acid.
aPTT and prothrombin ratio.
Urinalysis (dipstick: pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrites and leukocyte esterase) will be performed. In case of positive results for white blood cells, red blood cells 
and/or nitrites, urine will be sent to the laboratory for microscopy and culture. If there is an explanation for the positive dipstick results (e.g., menses), this will have to be discussed with the Sponsor 
and should be recorded, and there might be no need to perform microscopy and culture)
Serial PK blood samples will be collected at pre-dose within 15 min before treatment administration (0h), and t+0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12h post-dose, as well as at 24, 36, 48 
and 72h post-dose. 1 min, 3 min and 5 min time windows will be authorized up to 0.75 h, up to 1.5 h and up to 12 h, respectively. 15 min, 30 min and 120 min time windows will be authorized at 
24h, 36h and 48h-72h, respectively. 
All AEs are collected from when the participant first provides informed consent until the EOS visit [30 (± 3) days after the last study treatment administration or discontinuation]. 
In addition, a snack will be provided in the afternoon of D1 and lunch will be provided on D2. 


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15.2. Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA)
PARAMETER
LOWER PCSA VALUE
UPPER PCSA VALUE
Vital signs
Supine HR
d 45 beats/min and change from 
baseline d -20 beats/min
t
100 beats/min and change from 
baseline t 20 beats/min
Supine SBP
d 90 mmHg and change from 
baseline d -20 mmHg
t 140 mmHg and change from baseline 
t 20 mmHg
Supine DBP
d 50 mmHg and change from 
baseline d -10 mmHg
t 90 mmHg and change from baseline t
10 mmHg
Standard 12-lead ECG parameters
HR
d 45 beats/min and change from 
baseline d -20 beats/min
t
100 beats/min and change from 
baseline t 20 beats/min
PR
t 220 msec 
QRS
t 120 msec
QTc
!PVHFDQGPVHF+LJK
> 500 msec (High+)
change from baseline > 30 msec and 
FKDQJHIURPEDVHOLQHPVHF+LJK
change from baseline > 60 msec (High+)


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