A Relative Bioavailability Study Evaluating Two New Encorafenib Formulations (ERBA)

• ClinicalTrials.gov Identifier: NCT05446142
• Recruitment Status: Completed
• First Posted: July 6, 2022
• Results First Posted: February 23, 2024
• Last Update Posted: February 23, 2024
• Sponsor: Pfizer
• Collaborators: Ono Pharmaceutical Co. Ltd; Pierre Fabre Laboratories
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Encorafenib capsule formulation (CAP); Drug: Encorafenib first formulation; Drug: Encorafenib second formulation; Drug: Rabeprazole tablet	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: July 1, 2022
• Actual Primary Completion Date: September 30, 2022
• Actual Study Completion Date: September 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Four Period Treatment Sequence: PPI Effect; 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); A single encorafenib dose of the CAP formulation; Drug: Encorafenib first formulation; first formulation; Drug: Encorafenib second formulation; second formulation; Drug: Rabeprazole tablet; Proton-pump inhibitor
Experimental: Four Period Treatment Sequence: PPI Effect 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.	Drug: Encorafenib capsule formulation (CAP); A single encorafenib dose of the CAP formulation; Drug: Encorafenib first formulation; first formulation; Drug: Encorafenib second formulation; second formulation; Drug: Rabeprazole tablet; Proton-pump inhibitor

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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.
2. Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole [ Time Frame: 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.
3. 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 [ Time Frame: 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.

Secondary Outcome Measures :

1. Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole [ Time Frame: 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.
2. Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole [ Time Frame: 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.
3. Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole [ Time Frame: 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.
4. Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole [ Time Frame: 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.
5. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: 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.
6. Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality [ Time Frame: 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.
7. Number of Participants Meeting Vital Signs Categorical Criteria [ Time Frame: 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.
8. Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Connecticut

New Haven Clinical Research Unit

New Haven, Connecticut, United States, 06511

Sponsors and Collaborators

Pfizer

Ono Pharmaceutical Co. Ltd

Pierre Fabre Laboratories

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] June 27, 2022

Statistical Analysis Plan  [PDF] July 4, 2022

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT05446142
• Other Study ID Numbers: C4221024
• First Posted: July 6, 2022
• Results First Posted: February 23, 2024
• Last Update Posted: February 23, 2024
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

Encorafenib; Rabeprazole; Healthy adult participants

Additional relevant MeSH terms:

Rabeprazole; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action