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| Name | Class |
|---|---|
| Ono Pharmaceutical Co., Ltd. | INDUSTRY |
| Pierre Fabre Laboratories | INDUSTRY |
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Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Four Period Treatment Sequence: PPI Effect | Experimental | 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 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Encorafenib capsule formulation (CAP) | Drug | A single encorafenib dose of the CAP formulation |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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. | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| 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 | 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. | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| Measure | Description | Time Frame |
|---|---|---|
| Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| New Haven Clinical Research Unit | New Haven | Connecticut | 06511 | United States |
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| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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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.
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A total of 18 participants were enrolled and randomized into 1 of the 6 treatment sequences.
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| ID | Title | Description |
|---|---|---|
| FG000 | Encorafenib 75 mg eMCC=>75 mg eMCCL=>75 mg CAP=>75 mg eMCC+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCC on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| FG001 | Encorafenib 75 mg eMCC=>75 mg CAP=>75 mg eMCCL=>75 mg eMCCL+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCCL on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| FG002 | Encorafenib 75 mg eMCCL=>75 mg CAP=>75 mg eMCC=>75 mg eMCC+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCC on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| FG003 | Encorafenib 75 mg eMCCL=>75 m eMCC=>75 mg CAP=>75 mg eMCCL+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCCL on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| FG004 | Encorafenib 75 mg CAP=>75 mg eMCC=>75 mg eMCCL=>75 mg eMCC+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCC on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| FG005 | Encorafenib 75 mg CAP=>75 mg eMCCL=>75 mg eMCC=>75 mg eMCCL+20 mg Rabeprazole | Period 1: Participants received a single oral dose of encorafenib 75 mg as CAP under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 2: Participants received a single oral dose of encorafenib 75 mg as eMCCL under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 3: Participants received a single oral dose of encorafenib 75 mg as eMCC under fasted condition, followed by serial PK sampling from Day 1 to Day 3, and a washout of at least 5 days between successive encorafenib dose. Period 4: Participants received rabeprazole 20 mg daily from Day -5 to -1, and a single oral dose of encorafenib 75 mg eMCCL on Day 1 under fasted condition, followed by serial PK sampling from Day 1 to Day 3. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
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| Period 2 |
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| Period 3 |
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| Period 4 |
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Baseline analysis population included all enrolled participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | All participants enrolled in this study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
Baseline up to Day 28 after the last encorafenib dose. The total duration of the study was approximately 60 days from baseline.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 75 mg Encorafenib eMCC, Fasted | Participants received a single ora l dose of encorafenib 75 mg eMCC under fasted condition. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo | Ear and labyrinth disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 27, 2022 | Jul 24, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 4, 2022 | Jul 24, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000601108 | encorafenib |
| D004304 | Dosage Forms |
| D064750 | Rabeprazole |
| ID | Term |
|---|---|
| D004364 | Pharmaceutical Preparations |
| D013678 | Technology, Pharmaceutical |
| D008919 | Investigative Techniques |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
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| Encorafenib first formulation | Drug | first formulation |
|
| Encorafenib second formulation | Drug | second formulation |
|
| Rabeprazole tablet | Drug | Proton-pump inhibitor |
|
| Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 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. | Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline) |
| Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | 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. | Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline) |
| Number of Participants Meeting Vital Signs Categorical Criteria | 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. | 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) |
| Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | 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. | 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) |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| Years |
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| Age, Customized | Number | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
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| Race/Ethnicity, Customized | Number | Participants |
|
| OG000 | 75 mg Encorafenib eMCC, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCC under fasted condition. |
| OG001 | 75mg Encorafenib eMCCL, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCCL under fasted condition. |
| OG002 | 75mg Encorafenib CAP, Fasted | Participants received a single oral dose of encorafenib 75 mg CAP under fasted condition. |
| OG003 | 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCC (fasted) following 5 days of rabeprazole 20 mg daily. |
| OG004 | 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCCL (fasted) following 5 days of rabeprazole 20 mg daily. |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
|
| Primary | 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 | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
|
| Secondary | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Median | Full Range | hr | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
| Secondary | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Mean | Standard Deviation | hour | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
| Secondary | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/hr | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
| Secondary | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 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. | The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose |
|
|
|
| Secondary | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 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. | All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received. | Posted | Count of Participants | Participants | Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline) |
|
|
|
| Secondary | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | 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. | All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received. Specifically, number of participants analyzed in the table is the total number of participants with at least one observation of the given laboratory test while on study treatment or during lag time. | Posted | Count of Participants | Participants | Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline) |
|
|
|
| Secondary | Number of Participants Meeting Vital Signs Categorical Criteria | 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. | All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received. | Posted | Count of Participants | Participants | 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) |
|
|
|
| Secondary | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | 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. | All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received. | Posted | Count of Participants | Participants | 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) |
|
|
|
| 0 |
| 18 |
| 0 |
| 18 |
| 11 |
| 18 |
| EG001 | 75 mg Encorafenib eMCCL, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCCL under fasted condition. | 0 | 18 | 0 | 18 | 11 | 18 |
| EG002 | 75 mg Encorafenib CAP, Fasted | Participants received a single oral dose of encorafenib 75 mg CAP under fasted condition. | 0 | 17 | 0 | 17 | 8 | 17 |
| EG003 | 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCC (fasted) following 5 days of rabeprazole 20 mg daily. | 0 | 8 | 0 | 8 | 1 | 8 |
| EG004 | 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Participants received a single oral dose of encorafenib 75 mg eMCCL (fasted) following 5 days of rabeprazole 20 mg daily. | 0 | 9 | 0 | 9 | 5 | 9 |
| Eye pain | Eye disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Change of bowel habit | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Paraesthesia oral | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Facial pain | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Feeling hot | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Vessel puncture site bruise | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Vessel puncture site pain | General disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Skin abrasion | Injury, poisoning and procedural complications | MedDRA version 25.0 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Dysaesthesia | Nervous system disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Dermatitis allergic | Skin and subcutaneous tissue disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Pseudofolliculitis | Skin and subcutaneous tissue disorders | MedDRA version 25.0 | Non-systematic Assessment |
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| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA version 25.0 | Non-systematic Assessment |
|
Not provided
Not provided
Not provided
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Natural log transformed encorafenib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 90.35 | 2-Sided | 90 | 79.17 | 103.12 | Other |
| Natural log transformed encorafenib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to eMCC with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to eMCC with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 79.66 | 2-Sided | 90 | 58.70 | 108.08 | Other |
| Natural log transformed encorafenib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to eMCCL with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to eMCCL with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 80.78 | 2-Sided | 90 | 64.82 | 100.68 | Other |
| Natural log transformed encorafenib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 94.67 | 2-Sided | 90 | 89.73 | 99.88 | Other |
| Natural log transformed encorafenib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to eMCC with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to eMCC with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 95.76 | 2-Sided | 90 | 84.10 | 109.04 | Other |
| Natural log transformed encorafenib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to eMCCL with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to eMCCL with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages. | Reference/Test Ratio | 88.31 | 2-Sided | 90 | 82.36 | 94.70 | Other |
| Participants with AEs (Treatment related) |
|
| Participants with SAEs (All Causalities) |
|
| Participants with severe (including fatal) adverse events (All Causalities) |
|
| CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN |
|
| URINALYSIS - Urobilinogen (EU) >= 1 |
|
| QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% |
|
| QT INTERVAL (MSEC) Value >=500 msec |
|
| QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec |
|
| QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec |
|