Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Melanoma, BRAF V600 Mutation, Unresectable Melanoma, Metastatic Melanoma

Intervention / Treatment
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* Drug: Binimetinib Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy participant. Female participants must be postmenopausal or sterilized. Body mass index (BMI) of ≥ 18.5 to < 30 kg/m2, with body weight ≥ 50 kg and < 100 kg. Vital signs within defined ranges or if out of normal ranges, considered as not clinically significant by the Investigator. Participants must have safety laboratory values within the normal ranges or if out of normal ranges considered as not clinically significant by the Investigator. Exclusion Criteria: Pregnant or currently breastfeeding women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. 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. 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 may jeopardize the participant in case of participation in the study. History of autonomic dysfunction or Gilbert syndrome. 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]. Neuromuscular disorders that were associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). Smoker or use of tobacco products or products containing nicotine in the last 4 weeks prior to first dosing of study treatment. Malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior to study entry). Primary malignancy which had been completely resected and was in complete remission for ≥ 5 years. History of retinal degenerative disease. Any vaccination within 4 weeks prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Binimetinib 15 mg / Binimetinib 45 mg<br>2 periods | Drug: Binimetinib Oral Tablet<br>* Two-period Crossover study<br>|
| Experimental: Binimetinib 45 mg / Binimetinib 15 mg<br>2 periods | Drug: Binimetinib Oral Tablet<br>* Two-period Crossover study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC) from time of administration to last observed plasma concentration (AUClast) for binimetinib and AR00426032 (binimetinib metabolite) | AUC is the area under the curve constructed by plotting the concentration of binimetinib and its metabolite against the time for each blood sample. | 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 and AR00426032 (binimetinib metabolite) | 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 and AR00426032 (binimetinib metabolite) | Cmax is referred as the maximum observed concentration of binimetinib and 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 | 
| AUC Test (T) / Reference (R) ratios for binimetinib | Relative comparison between area under the curve for Test drug vs. area under the curve for Reference drug | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach Cmax (Tmax) for binimetinib and AR00426032 (binimetinib metabolite) | The timepoint at which the maximum concentration of binimetinib or 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, λz) for binimetinib and AR00426032 (binimetinib metabolite) | 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. | 
| Residual area (AUC_%Extrap_obs) for binimetinib and AR00426032 (binimetinib metabolite) | residual area under the curve expressed as area under the concentration-time curve extrapolated from tz to ∞ in % 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. | 
| Mean residence time (MRT) for binimetinib and AR00426032 (binimetinib metabolite) | mean residence time (MRT) is defined as the average time for binimetinib and 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. | 
| Potentially Clinically Significant Abnormalities values in 12-lead Electrocardiograms (ECG) | 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) | Through study completion, an average of 2 months | 
| Potentially Clinically Significant Abnormalities values of Blood Pressure | 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. | Through study completion, an average of 2 months | 
| Potentially Clinically Significant Abnormalities values of Body Temperature | Potentially Clinically Significant Abnormalities values of Body Temperature (C°) | Through study completion, an average of 2 months | 
| Notable Change From Baseline of Blood Hematology Parameters | Clinically notable shift from baseline in blood hematology parameters (hemoglobin, leukocytes, eosinophils, lymphocytes, neutrophils and platelets) | Through study completion, an average of 2 months | 
| Notable Change From Baseline of Clinical Chemistry parameters | 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) | Through study completion, an average of 2 months | 
| Notable Change From Baseline of Coagulation parameters | Clinically notable shift from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time) | Through study completion, an average of 2 months | 
| Notable Change From Baseline of Urinalysis parameters | Mean changes from baseline in the quantitative assessment of blood, glucose, ketones, leukocytes, pH and protein in dipstick urinalysis | Through study completion, an average of 2 months | 
| 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 | Through study completion, an average of 2 months |