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CompletedNCT05810740Updated Sep 19, 2024Results posted

Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations

A Phase 1 interventional study of Binimetinib 15 MG and Binimetinib 45 MG in Melanoma, BRAF V600 Mutation and Unresectable Melanoma, sponsored by Pierre Fabre Medicament. Completed at 1 site in France. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-09-19.

Sponsored by Pierre Fabre Medicament · Phase 1, Interventional, and Other

Phase
Phase 1
Study type
Interventional
Enrollment
37
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Melanoma
  • BRAF V600 Mutation
  • Unresectable Melanoma
  • Metastatic Melanoma

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03

In context

Melanoma

3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.

This study's enrollment of 37 is close to the median of 38 across 2,351 interventional studies indexed under Melanoma.

Browse Melanoma studies →

Lead sponsor

Pierre Fabre Medicament is the lead sponsor of 71 studies on the registry; 6 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Inclusion criteria

All the following inclusion criteria had to 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. Male and female between ≥ 18 and ≤ 65 years of age (at the day of signature of consent).

  4. 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.

  5. 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.

  6. Body mass index (BMI) of ≥ 18.5 to \< 30 kg/m2 with body weight ≥ 50 kg and \< 100 kg.

  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)

    1. Supine systolic BP ≥ 90 mmHg and ≤ 140 mmHg
    2. Supine diastolic BP ≥ 50 mmHg and ≤ 90 mmHg
    3. Supine pulse rate (PR) ≥ 45 to ≤ 100 beats per minute (bpm)
    4. Body temperature between ≥ 35.0°C and ≤ 37.5°C
    5. Orthostatic hypotension had 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 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:

    1. Total bilirubin ≤ upper limit of normal (ULN).
    2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) ≤ ULN and alkaline phosphatase (ALP) ≤ 1.1 X ULN.
    3. Serum creatinine within normal range, except on P1D-1 and P2D-1 (≤ 1.1 X ULN).
    4. Serum amylase and lipase ≤ ULN.
    5. Fasting glucose, coagulation panel (prothrombin ratio) within normal range and activated partial thromboplastin time (aPTT) ≤ 1.1 X ULN.

    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.

  9. Able to communicate well with the Investigator and comply with the requirements of the study.
  10. 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).
  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 criteria

Exclusion criteria:

Participants meeting any of the following criteria were not 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 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.
  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:

    1. 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
    2. Inability to determine the QT interval on ECG
    3. Complete left bundle branch block
    4. Use of a ventricular-paced pacemaker
    5. Congenital long QT syndrome
    6. History of or presence of clinically significant ventricular or atrial tachyarrhythmia
    7. Clinically significant resting bradycardia (\< 40 bpm)
    8. History of clinically documented myocardial infarction
    9. History of angina pectoris
    10. History of known structural abnormalities (i.e., cardiomyopathy)
    11. Other clinically significant cardiovascular disease (e.g., congestive heart failure, atherosclerosis, labile hypertension, or uncontrolled hypertension)
    12. 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 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

  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 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:

    1. History of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding
    2. History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, cholecystectomy or bowel resection
    3. History of, or clinical evidence of, pancreatic injury or pancreatitis
    4. Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as ALT, AST, GGT, ALP, or serum bilirubin
    5. Malabsorption syndrome
    6. History of impaired renal function or elevated creatinine values indicating impaired renal function
    7. 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 was not to 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 (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  18. Underwent major surgery ≤ 3 weeks prior to starting study treatment 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 was 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 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
  22. 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

  23. Malignancy with the following exceptions:

    1. Adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing was required prior to study entry)
    2. 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 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
  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 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.
05

Study design

Phase
Phase 1
Primary purpose
Other
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
37 participants (actual)

Study arms

  • Experimental
    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.

    Drug: Binimetinib 15 MG · Drug: Binimetinib 45 MG

  • Experimental
    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 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.

    Drug: Binimetinib 15 MG · Drug: Binimetinib 45 MG

Interventions

  • DrugBinimetinib 15 MG

    Binimetinib 15 mg tablet

  • DrugBinimetinib 45 MG

    Binimetinib 45 mg tablet

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 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

  2. 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

    Time frame: 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

  3. 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.

    Time frame: 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

Secondary outcomes

  1. 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.

    Time frame: 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

  2. 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

    Time frame: 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

  3. 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

    Time frame: 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

  4. 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.

    Time frame: 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

  5. Mean Residence Time (MRT) for Binimetinib

    Mean residence time (MRT) is defined as the average time for binimetinib to reside in the body

    Time frame: 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

  6. 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

    Time frame: 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

  7. 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

    Time frame: 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

  8. Maximum Observed Plasma Concentration (Cmax) for AR00426032

    Cmax is referred as the maximum observed concentration of AR00426032 in blood plasma determined by bioanalysis

    Time frame: 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

  9. Time to Reach Cmax (Tmax) for AR00426032

    The timepoint at which the maximum concentration of AR00426032 is determined by bioanalysis in the blood plasma

    Time frame: 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

  10. 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

    Time frame: 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

  11. 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

    Time frame: 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

  12. Mean Residence Time (MRT) for AR00426032

    Mean residence time (MRT) is defined as the average time for AR00426032 to reside in the body

    Time frame: 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

  13. 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.)

    Time frame: 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)

  14. 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)

    Time frame: 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

  15. Clinically Significant Changes From Baseline of Coagulation Parameters

    Clinically significant shifts from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time)

    Time frame: 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

  16. 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

    Time frame: Urinalysis samples were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS

  17. 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

    Time frame: 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

  18. 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.

    Time frame: 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

  19. 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)

    Time frame: 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

  20. 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

    Time frame: A complete physical examination was performed at screening, on Day -1 of each period, at H24 post-dose of each period, and at EOS

  21. 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

    Time frame: A visual examination was performed at Screening at at EOS.

  22. 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

    Time frame: An opthalmologic examination was performed at Screening at at EOS.

07

Results

Posted Sep 19, 2024

Participant flow

Treatment Period 1 (5 Days)
Participant flow — Treatment Period 1 (5 Days)
MilestoneBinimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mg
Started1918
Completed1918
Not completed00
Washout (7 Days)
Participant flow — Washout (7 Days)
MilestoneBinimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mg
Started1918
Completed1918
Not completed00
Treatment Period 2 (5 Days)
Participant flow — Treatment Period 2 (5 Days)
MilestoneBinimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mg
Started1918
Completed1918
Not completed00

Outcome measures

PrimaryArea 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.

Time frame:
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
Reported as:
Geometric mean · h*ng/mL
Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib
h*ng/mLReference FormulationTest Formulation
Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib1786 ± 23.221723 ± 24.13
Statistical analysis
  • Reference Formulation vs Test Formulation · Ls-mean ratio, percent: 96.43 · 90% CI 92.57 to 100.46
PrimaryAUC 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

Time frame:
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
Reported as:
Geometric mean · h*ng/mL
AUC From Time of Administration to Infinity (AUCinf) for Binimetinib
h*ng/mLReference FormulationTest Formulation
AUC From Time of Administration to Infinity (AUCinf) for Binimetinib1834 ± 23.091784 ± 23.85
Statistical analysis
  • Reference Formulation vs Test Formulation · Geometric mean ratio: 97.19 · 90% CI 93.47 to 101.06
PrimaryMaximum 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.

Time frame:
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
Reported as:
Geometric mean · ng/mL
Maximum Observed Plasma Concentration (Cmax) for Binimetinib
ng/mLReference FormulationTest Formulation
Maximum Observed Plasma Concentration (Cmax) for Binimetinib388.0 ± 46.3362.2 ± 41.1
Statistical analysis
  • Reference Formulation vs Test Formulation · Geometric mean ratio: 94.02 · 90% CI 87.25 to 101.33
SecondaryTime 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.

Time frame:
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
Reported as:
Median · h
Time to Reach Cmax (Tmax) for Binimetinib
hReference FormulationTest Formulation
Time to Reach Cmax (Tmax) for Binimetinib1.0000 (0.500 to 3.000)0.7500 (0.500 to 2.000)
SecondaryTerminal 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

Time frame:
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
Reported as:
Geometric mean · h
Terminal Half-life (t1/2) for Binimetinib
hReference FormulationTest Formulation
Terminal Half-life (t1/2) for Binimetinib13.002 ± 26.19413.901 ± 24.696
SecondaryFirst 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

Time frame:
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
Reported as:
Geometric mean · /h
First Order Terminal Elimination Rate Constant (λz) of Binimetinib
/hReference FormulationTest Formulation
First Order Terminal Elimination Rate Constant (λz) of Binimetinib0.05331 ± 26.193810.04986 ± 24.69575
SecondaryResidual 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.

Time frame:
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
Reported as:
Geometric mean · % of the total AUC
Residual Area (AUC_%Extrap_obs) for Binimetinib
% of the total AUCReference FormulationTest Formulation
Residual Area (AUC_%Extrap_obs) for Binimetinib2.2836 ± 53.78622.8499 ± 64.4826
SecondaryMean Residence Time (MRT) for Binimetinib

Mean residence time (MRT) is defined as the average time for binimetinib to reside in the body

Time frame:
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
Reported as:
Geometric mean · h
Mean Residence Time (MRT) for Binimetinib
hReference FormulationTest Formulation
Mean Residence Time (MRT) for Binimetinib11.67 ± 22.6612.588 ± 27.196
SecondaryArea 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

Time frame:
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
Reported as:
Geometric mean · h*ng/mL
Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032
h*ng/mLReference FormulationTest Formulation
Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032223.9 ± 29.4213.5 ± 32.0
SecondaryAUC 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

Time frame:
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
Reported as:
Geometric mean · h*ng/mL
AUC From Time of Administration to Infinity (AUCinf) for AR00426032
h*ng/mLReference FormulationTest Formulation
AUC From Time of Administration to Infinity (AUCinf) for AR00426032296.8 ± 18.7287.5 ± 23.3
SecondaryMaximum Observed Plasma Concentration (Cmax) for AR00426032

Cmax is referred as the maximum observed concentration of AR00426032 in blood plasma determined by bioanalysis

Time frame:
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
Reported as:
Geometric mean · ng/mL
Maximum Observed Plasma Concentration (Cmax) for AR00426032
ng/mLReference FormulationTest Formulation
Maximum Observed Plasma Concentration (Cmax) for AR0042603241.62 ± 41.1937.88 ± 44.25
SecondaryTime to Reach Cmax (Tmax) for AR00426032

The timepoint at which the maximum concentration of AR00426032 is determined by bioanalysis in the blood plasma

Time frame:
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
Reported as:
Median · h
Time to Reach Cmax (Tmax) for AR00426032
hReference FormulationTest Formulation
Time to Reach Cmax (Tmax) for AR004260321.1250 (0.750 to 5.000)1.000 (0.750 to 3.000)
SecondaryTerminal 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

Time frame:
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
Reported as:
Geometric mean · h
Terminal Half-life (t1/2) for AR00426032
hReference FormulationTest Formulation
Terminal Half-life (t1/2) for AR0042603213.924 ± 24.95513.843 ± 19.281
SecondaryFirst 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

Time frame:
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
Reported as:
Geometric mean · /h
First Order Terminal Elimination Rate Constant (λz) of AR00426032
/hReference FormulationTest Formulation
First Order Terminal Elimination Rate Constant (λz) of AR004260320.04978 ± 24.954960.05007 ± 19.28093
SecondaryMean Residence Time (MRT) for AR00426032

Mean residence time (MRT) is defined as the average time for AR00426032 to reside in the body

Time frame:
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
Reported as:
Geometric mean · h
Mean Residence Time (MRT) for AR00426032
hReference FormulationTest Formulation
Mean Residence Time (MRT) for AR0042603214.900 ± 23.15014.952 ± 22.934
SecondaryClinically 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.)

Time frame:
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)
Reported as:
Count of participants · Participants
Clinically Significant Changes From Baseline of Blood Hematology Parameters
ParticipantsReference FormulationTest Formulation
Clinically Significant Changes From Baseline of Blood Hematology Parameters00
SecondaryClinically 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)

Time frame:
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
Reported as:
Count of participants · Participants
Clinically Significant Changes From Baseline of Clinical Chemistry Parameters
ParticipantsReference FormulationTest Formulation
Clinically Significant Changes From Baseline of Clinical Chemistry Parameters00
SecondaryClinically Significant Changes From Baseline of Coagulation Parameters

Clinically significant shifts from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time)

Time frame:
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
Reported as:
Count of participants · Participants
Clinically Significant Changes From Baseline of Coagulation Parameters
ParticipantsReference FormulationTest Formulation
Clinically Significant Changes From Baseline of Coagulation Parameters00
SecondaryClinically 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

Time frame:
Urinalysis samples were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS
Reported as:
Count of participants · Participants
Clinically Significant Changes From Baseline of Urinalysis Parameters
ParticipantsReference FormulationTest Formulation
Clinically Significant Changes From Baseline of Urinalysis Parameters00
SecondaryClinically 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

Time frame:
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
Reported as:
Count of participants · Participants
Clinically Significant Abnormalities Values of Vital Sign Parameters
ParticipantsReference FormulationTest Formulation
Clinically Significant Abnormalities Values of Vital Sign Parameters00
SecondaryClinically 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.

Time frame:
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
Reported as:
Count of participants · Participants
Clinically Significant Orthostatic Hypotension
ParticipantsReference FormulationTest Formulation
Clinically Significant Orthostatic Hypotension01
SecondaryClinically 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)

Time frame:
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
Reported as:
Count of participants · Participants
Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG)
ParticipantsReference FormulationTest Formulation
Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG)00
SecondaryClinically 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

Time frame:
A complete physical examination was performed at screening, on Day -1 of each period, at H24 post-dose of each period, and at EOS
Reported as:
Count of participants · Participants
Clinically Significant Physical Examination Abnormalities
ParticipantsReference FormulationTest Formulation
Clinically Significant Physical Examination Abnormalities00
SecondaryAbnormal 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

Time frame:
A visual examination was performed at Screening at at EOS.
Reported as:
Count of participants · Participants
Abnormal Changes From Baseline in Visual Examinations
ParticipantsReference FormulationTest Formulation
Abnormal Changes From Baseline in Visual Examinations00
SecondaryAbnormal 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

Time frame:
An opthalmologic examination was performed at Screening at at EOS.
Reported as:
Count of participants · Participants
Abnormal Changes From Baseline in Ophthalmologic Examinations
ParticipantsReference FormulationTest Formulation
Abnormal Changes From Baseline in Ophthalmologic Examinations10

Adverse events

Collected over 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.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Reference Formulation0/36 (0%)0/36 (0%)5/36 (13.9%)
Test Formulation0/37 (0%)0/37 (0%)4/37 (10.8%)
Most frequent other events
Showing 10 of 11
Most frequent other events
EventReference FormulationTest Formulation
Covid-19Infections and infestations1/361/37
Tooth abscessInfections and infestations1/360/37
Viral infectionInfections and infestations1/360/37
Vision blurredEye disorders1/360/37
Anal pruritusGastrointestinal disorders1/360/37
Frequent bowel movementsGastrointestinal disorders1/360/37
ToothacheGastrointestinal disorders1/360/37
Ocular discomfortEye disorders0/361/37
Retinal vascular disorderEye disorders0/361/37
Abdominal painGastrointestinal disorders0/361/37

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
<=18 years000
Between 18 and 65 years181836
>=65 years101
Age, Continuous
Age, Continuous(years)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
Mean40.7 ± 14.0543.9 ± 13.3542.3 ± 13.62
Sex: Female, Male
Sex: Female, Male(Participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
Female314
Male161733
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
Hispanic or Latino000
Not Hispanic or Latino191837
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
France191837
Alcohol history
Alcohol history(Participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
Never9110
Current101727
Smoking history
Smoking history(Participants)Binimetinib 15 mg Then Binimetinib 45 mgBinimetinib 45 mg Then Binimetinib 15 mgTotal
Never111223
Former8614
08

Study locations

1 site
  • Biotrial
    Rennes, 35000, France
09

References and documents

Study documents

  • Study protocol · Oct 26, 2022
  • Statistical analysis plan · Aug 25, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — 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.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 19, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05810740
Lead sponsor
Pierre Fabre Medicament
Collaborators
Biotrial
Responsible party
Sponsor
First posted
Apr 12, 2023
Start date
Aug 31, 2022
Primary completion
Dec 22, 2022
Completion
Jan 18, 2023
Results posted
Sep 19, 2024
Last update
Sep 19, 2024

Study contacts

Marina Klein, MD
principal investigator · Biotrial

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Sep 2023. You cannot join it, but the record below documents what was studied.

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