Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations

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.

Eligibility Criteria:
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:

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.