A Relative Bioavailability Study Evaluating Two New Encorafenib Formulations

Study Overview
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Brief Summary
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Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations

Detailed Description
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In order to decrease the size of the current formulated encorafenib capsule and improve the physical stability, 2 new encorafenib tablet formulations have been developed. This study is intended to select the optimal tablet formulation for commercialization based on the tablet pharmacokinetics. A preliminary assessment of the effect of a proton-pump inhibitor on the pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in the formulation selection.

Official Title
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A PHASE 1, RANDOMIZED, OPEN-LABEL STUDY IN HEALTHY PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF TWO NEW ENCORAFENIB FORMULATIONS RELATIVE TO THE CURRENT FORMULATION AND TO EVALUATE THE EFFECT OF A PROTON-PUMP INHIBITOR ON ENCORAFENIB PLASMA PHARMACOKINETICS

Conditions
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Healthy

Intervention / Treatment
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* Drug: Encorafenib capsule formulation (CAP)
* Drug: Encorafenib first formulation
* Drug: Encorafenib second formulation
* Drug: Rabeprazole tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be male or female of non-childbearing potential of 18 years of age or older, inclusive, at the time of signing the informed consent document. Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight >50 kg (110 lb). Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and the protocol. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. Evidence of any active and uncontrolled bacterial or viral infection. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). History of human immunodeficiency virus infection, hepatitis B, or hepatitis C; positive testing for human immunodeficiency virus, Hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C virus antibody. Hepatitis B vaccination is allowed. Positive COVID-19 test at first admission. Other medical or psychiatric conditions, laboratory test abnormalities, other conditions or situations related to COVID-19 pandemic or, in the investigator's judgment, make the participant inappropriate for the study. Use of prescription or non-prescription medications within 7 days prior to the first dose of encorafenib with the exception of moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose. History of known sensitivity to rabeprazole, substituted benzimidazoles or to any component of the rabeprazole formulation. Previous administration with an investigational product (drug or vaccine) within 30 days. Known hypersensitivity to encorafenib or its excipients. A positive urine drug or cotinine test. Screening supine blood pressure ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. Baseline standard 12 lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. Aspartate transaminase or alanine aminotransferase level ≥ 1.5 × upper limit of normal. Total bilirubin level ≥1.5 × upper limit of normal. Estimated glomerular filtration rate <60 ml/min/1.73 m2

Ages Eligible for Study
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Minimum Age: 18 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: Four Period Treatment Sequence: PPI Effect<br>Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days. | Drug: Encorafenib capsule formulation (CAP)<br>* A single encorafenib dose of the CAP formulation<br>Drug: Encorafenib first formulation<br>* first formulation<br>Drug: Encorafenib second formulation<br>* second formulation<br>Drug: Rabeprazole tablet<br>* Proton-pump inhibitor<br>|
| Experimental: Four Period Treatment Sequence: PPI Effect Second Formulation<br>Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days. | Drug: Encorafenib capsule formulation (CAP)<br>* A single encorafenib dose of the CAP formulation<br>Drug: Encorafenib first formulation<br>* first formulation<br>Drug: Encorafenib second formulation<br>* second formulation<br>Drug: Rabeprazole tablet<br>* Proton-pump inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma AUCinf after administration of the first formulation | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma Cmax after administration of the first formulation | Maximum plasma concentration | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUClast after administration of the first formulation | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUCinf of the second formulation | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma Cmax after administration of the second formulation | Maximum plasma concentration | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUClast after administration of the second formulation | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUCinf after administration of the CAP (encorafenib formulated capsule) formulation | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma Cmax after administration of the CAP formulation | Maximum plasma concentration | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUClast after administration of the CAP formulation | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma AUCinf of the first formulation after 5 days of 20 mg daily rabeprazole dosing | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma Cmax of the first formulation after 5 days of 20 mg daily rabeprazole dosing | Maximum plasma concentration | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma AUClast of the first formulation after 5 days of 20 mg daily rabeprazole dosing | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma AUCinf of the second formulation after 5 days of 20 mg daily rabeprazole dosing | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma Cmax of the second formulation after 5 days of 20 mg daily rabeprazole dosing | Maximum plasma concentration | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma AUClast of the second formulation after 5 days of 20 mg daily rabeprazole dosing | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) | Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE is defined as one of the following: is fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs. | Time the participant provides informed consent through and including a minimum of 28 calendar days after the last administration of the study intervention. | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital signs (body temperature, respiratory rate, radial pulse, systolic and diastolic blood pressure) will be obtained with participant in the seated position, after having sat calmly for at least 5 minutes. | Baseline through Period 4 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | ECG abnormalities criteria include a) a postdose QTcF is increased by ≥60 ms from the baseline and is >450 ms; or b) an absolute QTcF value is ≥500 ms for any scheduled ECG | Baseline through Period 4 (period 4 is defined as Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48) | 
| Number of Participants With Laboratory Test Abnormalities | Following parameters will be analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein); urinalysis. | ≤ 28 days pre-dose, screening and discharge Period 1-4 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the first formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma Decay Half-Life (t1/2) after administration of the first formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Apparent Oral Clearance (CL/F) after administration of the first formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Apparent Volume of Distribution (Vz/F) after administration of the first formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the second formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Plasma Decay Half-Life (t1/2) after administration of the second formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Apparent Oral Clearance (CL/F) after administration of the second formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Apparent Volume of Distribution (Vz/F) after administration of the second formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma Decay Half-Life (t1/2) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Apparent Oral Clearance (CL/F) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Apparent Volume of Distribution (Vz/F) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Time to Reach Maximum Observed Plasma Concentration Plasma after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Plasma Decay Half-Life (t1/2) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Apparent Oral Clearance (CL/F) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Apparent Volume of Distribution (Vz/F) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the CAP formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3) | 
| Plasma Decay Half-Life (t1/2) after administration of the CAP formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3) | 
| Apparent Oral Clearance (CL/F) after administration of the CAP formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3) | 
| Apparent Volume of Distribution (Vz/F) after administration of the CAP formulation |  | Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Encorafenib, Rabeprazole, Healthy adult participants