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Binimetinib Oral Tablet

Marina Klein, MD

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 relative bioavailability of the 45 mg tablet in comparison to three 15 mg tablets intake is therefore required.

The 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 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.

Relative Bioavailability of Binimetinib 3 x 15 mg and 45 mg Formulations

A Randomized, Single-center, Open-label, Single Dose, Two-period, Crossover Study to Investigate the Relative Bioavailability of Binimetinib 3 x15 mg and 45 mg Tablets in Healthy Participants

heart rate (HR), PR interval, QRS duration, QRS axis, QT interval, QTcF

Erythrocytes (red blood cells, RBCs), hematocrit, hemoglobin, platelets; leukocyte count with differential: basophils, eosinophils, lymphocytes, monocytes, neutrophils / absolute neutrophil count; RBC indices: mean corpuscular hemoglobin, mean corpuscular volume, reticulocytes/erythrocytes, ALT, albumin, ALP, AST, bicarbonate, bilirubin (total and indirect), urea, calcium, chloride, CK, creatinine, amylase, lipase, total cholesterol, glucose, lactate dehydrogenase, magnesium, potassium, sodium, total protein, uric acid, blood pregnancy test (hCG), coagulation (aPTT or PT)

Supine and standing systolic BP, diastolic BP and PR, body temperature

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

Biotrial

Pierre Fabre Medicament

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.

Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations

A Randomized, Single-center, Open-label, Single Dose, Two-period, Crossover Pivotal Bioequivalence Study Comparing Binimetinib 3 x 15 mg and 45 mg Tablets in Healthy Participants

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.

AUC is the area under the curve constructed by plotting the concentration of binimetinib and its metabolite against the time for each blood sample.

Area under the plasma concentration-time curve from time of administration to infinity

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

Relative comparison between area under the curve for Test drug vs. area under the curve for Reference drug

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

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

residual area under the curve expressed as area under the concentration-time curve extrapolated from tz to ∞ in % of the total AUC

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

Clinically notable shift from baseline in ECG parameters including heart rate (beats/min), Pulse Rate interval (msec), QRS duration (msec), QRS axis (deg), QT interval (msec) and Fridericia QTc interval (msec)

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.

Potentially Clinically Significant Abnormalities values of Body Temperature (C°)

Clinically notable shift from baseline in blood hematology parameters (hemoglobin, leukocytes, eosinophils, lymphocytes, neutrophils and platelets)

Clinically notable shift from baseline in clinical chemistry parameters (alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, gamma glutamyl transferase (GGT), creatinine, urea, bicarbonate, calcium, chloride, magnesium, potassium, sodium, glucose, cholesterol, urate, albumin, creatine kinase (CK), lactate dehydrogenase, amylase and lipase)

Clinically notable shift from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time)

Mean changes from baseline in the quantitative assessment of blood, glucose, ketones, leukocytes, pH and protein in dipstick urinalysis

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Relative Bioavailability of Binimetinib 3 x 15 mg and 45 mg Formulations	NCT05103891	Melanoma BRAF V600 Mutat... Unresectable Me... Metastatic Mela...	Binimetinib Ora...	18 Years - 65 Years	Pierre Fabre Medicament
Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations	NCT05810740	Melanoma BRAF V600 Mutat... Unresectable Me... Metastatic Mela...	Binimetinib Ora...	18 Years - 65 Years	Pierre Fabre Medicament
Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations	NCT05810740	Melanoma BRAF V600 Mutat... Unresectable Me... Metastatic Mela...	Binimetinib Ora...	18 Years - 65 Years	Pierre Fabre Medicament

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