Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations

NCT05810740 | Completed Phase 1 Results

• 1 other identifier: W00074CI103_1PF74
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Melanoma; BRAF V600 Mutation; Unresectable Melanoma; Metastatic Melanoma

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (22)

• Time to Reach Cmax (Tmax) for 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

• Terminal Half-life (t1/2) for 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

• First Order Terminal Elimination Rate Constant (λz) 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

• Residual Area (AUC_%Extrap_obs) for 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

• Mean Residence Time (MRT) for 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

Study Arms (2)

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.

Drug: Binimetinib 15 MG; Drug: Binimetinib 45 MG

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.

Drug: Binimetinib 15 MG; Drug: Binimetinib 45 MG

Interventions

Binimetinib 15 MG DRUG

Binimetinib 15 mg tablet

Binimetinib 15 mg then Binimetinib 45 mg; Binimetinib 45 mg then Binimetinib 15 mg

Binimetinib 45 MG DRUG

Binimetinib 45 mg tablet

Binimetinib 15 mg then Binimetinib 45 mg; Binimetinib 45 mg then Binimetinib 15 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Supine systolic BP ≥ 90 mmHg and ≤ 140 mmHg
• Supine diastolic BP ≥ 50 mmHg and ≤ 90 mmHg
• Supine pulse rate (PR) ≥ 45 to ≤ 100 beats per minute (bpm)
• Body temperature between ≥ 35.0°C and ≤ 37.5°C
• 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.

You may not qualify if:

• 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:
• 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
• Inability to determine the QT interval on ECG
• Complete left bundle branch block
• Use of a ventricular-paced pacemaker
• Congenital long QT syndrome
• History of or presence of clinically significant ventricular or atrial tachyarrhythmia
• Clinically significant resting bradycardia (\< 40 bpm)
• History of clinically documented myocardial infarction
• History of angina pectoris

Sponsors & Collaborators

• Pierre Fabre Medicament: lead
• Biotrial: collaborator

Study Sites (1)

Biotrial

Rennes, 35000, France

Location

MeSH Terms

Conditions

Melanoma

Interventions

binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Ana Catarina Pinto, Responsible Medical Officer
• Organization: Pierre Fabre Médicament

ana.catarina.pinto@pierre-fabre.com

5 3450 6059

Study Officials

• Marina Klein, MD

  Biotrial

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2022
• First Posted: April 12, 2023
• Study Start: August 31, 2022
• Primary Completion: December 22, 2022
• Study Completion: January 18, 2023
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)