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| Name | Class |
|---|---|
| Biotrial | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Binimetinib 15 mg then Binimetinib 45 mg | Experimental | 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. |
|
| Binimetinib 45 mg then Binimetinib 15 mg | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Binimetinib 15 MG | Drug | Binimetinib 15 mg tablet |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration. | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| AUC From Time of Administration to Infinity (AUCinf) for Binimetinib | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Maximum Observed Plasma Concentration (Cmax) for Binimetinib | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight. | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Cmax (Tmax) for Binimetinib | Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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Inclusion criteria:
All the following inclusion criteria had to be met for a participant to be eligible to be included in this study:
Provide a signed and dated ICF.
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.
Male and female between ≥ 18 and ≤ 65 years of age (at the day of signature of consent).
Female participants had to be postmenopausal or sterilized. Note: due to preclinical data of teratogenicity and lack of data on human pregnancies with binimetinib, women of childbearing potential were excluded from this study.
Women were considered postmenopausal and not of childbearing potential if they 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 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 was not included. In the case of oophorectomy alone, the reproductive status of the woman was to be confirmed by a follow-up hormone level assessment to consider her of non-childbearing potential.
Men with a female partner of childbearing potential were 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 was recommended: condom for the male participant and an intrauterine device with spermicide or oral or implanted hormonal contraception for the female partner.
Body mass index (BMI) of ≥ 18.5 to < 30 kg/m2 with body weight ≥ 50 kg and < 100 kg.
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)
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.
Participants had to 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:
NB: It was to be noted that for the parameters acceptable at ≤ 1.1 X ULN, if more than one parameter exceeded ULN, the participant was excluded.
Able to communicate well with the Investigator and comply with the requirements of the study.
Participants had to be willing to comply with dietary and fluid restrictions (from D-7 to 72 hours after the last study treatment administration, see Section 9.4.7.3).
Willing to remain in the clinical research unit as required by the protocol.
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 criteria:
Participants meeting any of the following criteria were not eligible to be included in this study:
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.
Pregnant or currently breastfeeding women, where pregnancy was 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.
A past medical history of clinically significant ECG abnormalities or a family history (grandparents, parents, and siblings) of prolonged QT interval syndrome.
Impaired cardiovascular function.
Note: including any one of the following:
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 were of clinical significance and could have had an impact on the safety of the participant or the study as determined by the Investigator iv. Any cardiac conduction abnormalities
History of fainting spells or orthostatic hypotension episodes
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which might jeopardize the participant in case of participation in the study
Note: The Investigator was to be guided by evidence of any of the following:
History of autonomic dysfunction or Gilbert syndrome
History of immunocompromised status, including a positive human immunodeficiency virus (HIV) infection (enzyme-linked immunosorbent assay and western blot) test result
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
Significant illness within the 2 weeks prior to dosing
History of clinically significant drug allergy
History of atopic allergy (asthma, urticaria, and eczematous dermatitis)
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
Participants taking acetaminophen (i.e., paracetamol) on a daily basis for more than 2 consecutive days within 1 week prior to dosing was not to be enrolled
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]
Subfoveal choroidal thickness outside of 40μm - 475μm range
Neuromuscular disorders that were associated with elevated creatine kinase (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
Underwent major surgery ≤ 3 weeks prior to starting study treatment or who had not recovered from side effects of such a procedure
Known history or ongoing alcohol abuse within 4 weeks prior to dosing of study treatment Note: alcohol consumption was prohibited 1 week prior to dosing
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
Smoker or use of tobacco products or products containing nicotine in the 4 weeks prior to first dosing of study treatment Note: smokers were defined as any participant who reported the use of a product containing nicotine during the preceding 30 days or had a positive urine cotinine test > 200 ng/mL
Medical, psychiatric, cognitive, or other conditions that could have compromised the participant's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
Malignancy with the following exceptions:
History of retinal degenerative disease
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 was longer) Note: participants who had taken part in a clinical investigation receiving any form of binimetinib had to have completed a 3-week washout prior to baseline
Donation or loss of 400 mL or more of blood within 4 weeks prior to dosing
Inability to swallow
Any vaccination within 4 weeks prior to dosing
Participant was 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 could order a re-test of any parameter evaluated during the initial screening visit if he/she needed to evaluate the evolution of said parameter(s) or to confirm the value observed Rechecking of any parameter was to be limited to one time except when the measurement had not been obtained in accurate conditions.
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| Name | Affiliation | Role |
|---|---|---|
| Marina Klein, MD | Biotrial | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Biotrial | Rennes | 35000 | France |
Pierre Fabre will provide access to individual de-identified data and related study documents [e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)] upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.
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| ID | Title | Description |
|---|---|---|
| FG000 | Binimetinib 15 mg Then Binimetinib 45 mg | 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. |
| FG001 | Binimetinib 45 mg Then Binimetinib 15 mg | 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 five-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 on day 1 of a second five-day period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 (5 Days) |
| |||||||||||||
| Washout (7 Days) |
| |||||||||||||
| Treatment Period 2 (5 Days) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Binimetinib 15 mg Then Binimetinib 45 mg | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration. | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
|
Adverse events (AEs) were recorded from the time of consent until the end of the follow-up period (up to 30 days after Treatment period 2) and over a total period of 47 days.
AEs were summarized by worst grade according to the NCI-CTCAE V5.0 per participant.
The analysis population was the safety set that consisted of the healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants discontinued treatment before the second treatment period and therefore did not receive the reference formulation binimetinib 15 mg.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Reference Formulation | Binimetinib 3x15 mg | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Covid-19 | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ana Catarina Pinto, Responsible Medical Officer | Pierre Fabre Médicament | 5 3450 6059 | ana.catarina.pinto@pierre-fabre.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 26, 2022 | Sep 6, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 25, 2022 | Sep 6, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C581313 | binimetinib |
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| Binimetinib 45 MG | Drug | Binimetinib 45 mg tablet |
|
| Terminal Half-life (t1/2) for Binimetinib | The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| First Order Terminal Elimination Rate Constant (λz) of Binimetinib | The first Order Terminal Elimination Rate Constant (λz) of Binimetinib corresponds to the rate at which a drug is removed from the human system | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Residual Area (AUC_%Extrap_obs) for Binimetinib | The residual area under the curve is expressed as a percentage of the total AUC extrapolated from tz to ∞, based on the area under the concentration-time curve. | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Mean Residence Time (MRT) for Binimetinib | Mean residence time (MRT) is defined as the average time for binimetinib to reside in the body | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration of AR00426032, a metabolite of binimetinib | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| AUC From Time of Administration to Infinity (AUCinf) for AR00426032 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity of AR00426032, a metabolite of binimetinib | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Maximum Observed Plasma Concentration (Cmax) for AR00426032 | Cmax is referred as the maximum observed concentration of AR00426032 in blood plasma determined by bioanalysis | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Time to Reach Cmax (Tmax) for AR00426032 | The timepoint at which the maximum concentration of AR00426032 is determined by bioanalysis in the blood plasma | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Terminal Half-life (t1/2) for AR00426032 | The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| First Order Terminal Elimination Rate Constant (λz) of AR00426032 | The first Order Terminal Elimination Rate Constant (λz) of AR00426032 corresponds to the rate at which a drug is removed from the human system | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Mean Residence Time (MRT) for AR00426032 | Mean residence time (MRT) is defined as the average time for AR00426032 to reside in the body | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
| Clinically Significant Changes From Baseline of Blood Hematology Parameters | Clinically significant shift from baseline in blood hematology parameters (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.) | Blood samples for hematology parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at end of study (EOS) |
| Clinically Significant Changes From Baseline of Clinical Chemistry Parameters | Clinically significant shift from baseline in clinical chemistry parameters (alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, gamma glutamyl transferase (GGT), indirect bilirubin, creatinine, urea, bicarbonate, calcium, chloride, magnesium, potassium, sodium, glucose, cholesterol, urate, albumin, creatine kinase (CK), lactate dehydrogenase, protein, amylase, and lipase) | Blood samples for clinical chemistry parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
| Clinically Significant Changes From Baseline of Coagulation Parameters | Clinically significant shifts from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time) | Blood samples for coagulation parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
| Clinically Significant Changes From Baseline of Urinalysis Parameters | Clinically significant changes from baseline in the quantitative assessment of pH, bilirubin, erythrocytes, glucose, ketones, leukocyte esterase, nitrite, protein, and urobilinogen | Urinalysis samples were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
| Clinically Significant Abnormalities Values of Vital Sign Parameters | Number of participants with at least one clinically significant vital signs abnormality. The following clinical signs were measured: supine and standing systolic and diastolic blood pressure (mmHg), pulse rate (beats/min) body temperature (°C), body weight, and BMI | Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS |
| Clinically Significant Orthostatic Hypotension | The number and percentage of participants with at least one orthostatic hypotension defined as standing systolic blood pressure (SBP) - supine SBP ≤ -20 mmHg or standing diastolic blood pressure (DBP) - supine DBP ≤ -10 mmHg considered clinically significant. | Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS |
| Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG) | Number of participant with at least one clinically significant electrocardiogram abnormality. The following standard 12-lead ECG parameters were recorded: heart rate (beats/min), PR interval (msec), QRS duration (msec), QRS axis (deg), QT interval (msec) and Fridericia QTc interval (msec) | ECG abnormalities were recorded in triplicate at screening, on Day -1 of each period, at Day 1 pre-dose and H24 post-dose of each period, and at EOS |
| Clinically Significant Physical Examination Abnormalities | Number of participants with at least one clinically significant physical examination abnormality. A complete physical examination, including at minima assessments of the cardiovascular, dermatological, ear/nose/throat, eyes, gastrointestinal, general health/overall appearance, head, lymph, musculoskeletal, neck, neurological, and respiratory systems was performed | A complete physical examination was performed at screening, on Day -1 of each period, at H24 post-dose of each period, and at EOS |
| Abnormal Changes From Baseline in Visual Examinations | Visual assessment was performed at screening, on Day -1 of each period, at H24 and H72 post-dose of each period, and at EOS | A visual examination was performed at Screening at at EOS. |
| Abnormal Changes From Baseline in Ophthalmologic Examinations | Abnormal changes from baseline in ophthalmologic examinations including 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 | An opthalmologic examination was performed at Screening at at EOS. |
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| NOT COMPLETED |
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| BG001 | Binimetinib 45 mg Then Binimetinib 15 mg | 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 five-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 on day 1 of a second five-day period. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Alcohol history | Count of Participants | Participants |
|
| Smoking history | Count of Participants | Participants |
|
Binimetinib 3x15 mg |
| OG001 | Test Formulation | Binimetinib 1x45 mg |
|
|
|
| Primary | AUC From Time of Administration to Infinity (AUCinf) for Binimetinib | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Primary | Maximum Observed Plasma Concentration (Cmax) for Binimetinib | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight. | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Time to Reach Cmax (Tmax) for Binimetinib | Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Median | Full Range | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Terminal Half-life (t1/2) for Binimetinib | The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | First Order Terminal Elimination Rate Constant (λz) of Binimetinib | The first Order Terminal Elimination Rate Constant (λz) of Binimetinib corresponds to the rate at which a drug is removed from the human system | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | /h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Residual Area (AUC_%Extrap_obs) for Binimetinib | The residual area under the curve is expressed as a percentage of the total AUC extrapolated from tz to ∞, based on the area under the concentration-time curve. | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | % of the total AUC | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Mean Residence Time (MRT) for Binimetinib | Mean residence time (MRT) is defined as the average time for binimetinib to reside in the body | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration of AR00426032, a metabolite of binimetinib | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | AUC From Time of Administration to Infinity (AUCinf) for AR00426032 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity of AR00426032, a metabolite of binimetinib | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) for AR00426032 | Cmax is referred as the maximum observed concentration of AR00426032 in blood plasma determined by bioanalysis | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Time to Reach Cmax (Tmax) for AR00426032 | The timepoint at which the maximum concentration of AR00426032 is determined by bioanalysis in the blood plasma | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Median | Full Range | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Terminal Half-life (t1/2) for AR00426032 | The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | First Order Terminal Elimination Rate Constant (λz) of AR00426032 | The first Order Terminal Elimination Rate Constant (λz) of AR00426032 corresponds to the rate at which a drug is removed from the human system | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | /h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Mean Residence Time (MRT) for AR00426032 | Mean residence time (MRT) is defined as the average time for AR00426032 to reside in the body | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose |
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| Secondary | Clinically Significant Changes From Baseline of Blood Hematology Parameters | Clinically significant shift from baseline in blood hematology parameters (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.) | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Blood samples for hematology parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at end of study (EOS) |
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| Secondary | Clinically Significant Changes From Baseline of Clinical Chemistry Parameters | Clinically significant shift from baseline in clinical chemistry parameters (alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, gamma glutamyl transferase (GGT), indirect bilirubin, creatinine, urea, bicarbonate, calcium, chloride, magnesium, potassium, sodium, glucose, cholesterol, urate, albumin, creatine kinase (CK), lactate dehydrogenase, protein, amylase, and lipase) | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Blood samples for clinical chemistry parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Changes From Baseline of Coagulation Parameters | Clinically significant shifts from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time) | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Blood samples for coagulation parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Changes From Baseline of Urinalysis Parameters | Clinically significant changes from baseline in the quantitative assessment of pH, bilirubin, erythrocytes, glucose, ketones, leukocyte esterase, nitrite, protein, and urobilinogen | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Urinalysis samples were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Abnormalities Values of Vital Sign Parameters | Number of participants with at least one clinically significant vital signs abnormality. The following clinical signs were measured: supine and standing systolic and diastolic blood pressure (mmHg), pulse rate (beats/min) body temperature (°C), body weight, and BMI | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Orthostatic Hypotension | The number and percentage of participants with at least one orthostatic hypotension defined as standing systolic blood pressure (SBP) - supine SBP ≤ -20 mmHg or standing diastolic blood pressure (DBP) - supine DBP ≤ -10 mmHg considered clinically significant. | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG) | Number of participant with at least one clinically significant electrocardiogram abnormality. The following standard 12-lead ECG parameters were recorded: heart rate (beats/min), PR interval (msec), QRS duration (msec), QRS axis (deg), QT interval (msec) and Fridericia QTc interval (msec) | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | ECG abnormalities were recorded in triplicate at screening, on Day -1 of each period, at Day 1 pre-dose and H24 post-dose of each period, and at EOS |
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| Secondary | Clinically Significant Physical Examination Abnormalities | Number of participants with at least one clinically significant physical examination abnormality. A complete physical examination, including at minima assessments of the cardiovascular, dermatological, ear/nose/throat, eyes, gastrointestinal, general health/overall appearance, head, lymph, musculoskeletal, neck, neurological, and respiratory systems was performed | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | A complete physical examination was performed at screening, on Day -1 of each period, at H24 post-dose of each period, and at EOS |
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| Secondary | Abnormal Changes From Baseline in Visual Examinations | Visual assessment was performed at screening, on Day -1 of each period, at H24 and H72 post-dose of each period, and at EOS | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | A visual examination was performed at Screening at at EOS. |
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| Secondary | Abnormal Changes From Baseline in Ophthalmologic Examinations | Abnormal changes from baseline in ophthalmologic examinations including 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 | The analysis population was the pharmacokinetic set that consisted of 36 healthy participants who had taken one dose of study treatment in the two periods. One participant of the 37 randomised participants was excluded from the pharmacokinetic set due to treatment discontinuation before the second treatment period. | Posted | Count of Participants | Participants | An opthalmologic examination was performed at Screening at at EOS. |
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| 36 |
| 0 |
| 36 |
| 5 |
| 36 |
| EG001 | Test Formulation | Binimetinib 1x45 mg | 0 | 37 | 0 | 37 | 4 | 37 |
| Tooth abscess | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Viral infection | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Ocular discomfort | Eye disorders | MedDRA (25.0) | Systematic Assessment |
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| Retinal vascular disorder | Eye disorders | MedDRA (25.0) | Systematic Assessment |
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| Vision blurred | Eye disorders | MedDRA (25.0) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Anal pruritus | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Frequent bowel movements | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Toothache | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Orthostatic hypotension | Vascular disorders | MedDRA (25.0) | Systematic Assessment |
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Not provided
Not provided
| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |