A Relative Bioavailability Study Evaluating Two New Encorafenib Formulations

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Encorafenib capsule formulation (CAP)
Drug: Encorafenib first formulation
Drug: Encorafenib second formulation
Drug: Rabeprazole tablet

Registration Number: NCT05446142

Lead Sponsor: Pfizer

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Four Period Treatment Sequence: PPI Effect Second Formulation	Encorafenib first formulation	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.
Four Period Treatment Sequence: PPI Effect	Encorafenib capsule formulation (CAP)	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.
Four Period Treatment Sequence: PPI Effect	Encorafenib first formulation	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.
Four Period Treatment Sequence: PPI Effect	Encorafenib second formulation	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.
Four Period Treatment Sequence: PPI Effect	Rabeprazole tablet	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.
Four Period Treatment Sequence: PPI Effect Second Formulation	Encorafenib capsule formulation (CAP)	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.
Four Period Treatment Sequence: PPI Effect Second Formulation	Encorafenib second formulation	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.
Four Period Treatment Sequence: PPI Effect Second Formulation	Rabeprazole tablet	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.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	AUCinf for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by AUClast + (Clast/kel), where AUClast was the area under the plasma concentration-time profile from time zero to last quantifiable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was first-order elimination rate constant.
Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	AUClast for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated using Linear/Log trapezoidal method.
Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	Cmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data.

Secondary Outcome Measures

Name	Time	Method
Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	t½ for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	CL/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/AUCinf after oral dose.
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality	Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline)	Haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards. The assessment did not take into account whether each participants's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. The baseline measurement for safety laboratory tests for all periods was the predose measurement on Day -1 of Period 1. Only those categories in which at least 1 participant had data were reported.
Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	Vz/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/(AUCinf \* kel) after oral dose.
Number of Participants Meeting Vital Signs Categorical Criteria	Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline)	Supine blood pressure (BP) and pulse rate (PR) were measured at times specified. For Periods 1 to 3, the baseline measurement was the predose measurement on Day -1 of each period. For Period 4, the baseline measurement was the predose measurement on Day -1 of Period 3. The reported categories included: systolic blood pressure (SBP)\>=90mmHg; change from baseline (CFB) in SBP\>=30mmHg; diastolic blood pressure (DBP)\<50mmHg; CFB in DBP\>=20mmHg; PR\<40 beats per minute (bpm) or PR\>120bpm. Only those categories in which at least 1 participant had data were provided.
Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole	Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose	Tmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data as time of first occurrence.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline)	An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occurred during follow-up within the lag time of up to 28 days after the last encorafenib dose were counted as treatment emergent and attributed to the last treatment taken. Events that occurred during the washout period (up to 28 days from the last treatment) between study periods were counted as treatment emergent and attributed to the previous treatment taken.
Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities	Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline)	Absolute values and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by protocol pre-defined categorization criterion. QTcF were derived using Fridericia's heart rate correction formula. For each period, triplicate ECGs were conducted predose on Day 1; all other ECG measurements were single ECGs. The baseline ECG value was the average of the triplicate ECG measurements collected before dose administration on Day 1. Changes from baseline were defined as the change between the postdose ECG measurement and the derived baseline ECG.