Trial Outcomes & Findings for Phase 1 Safety Study of Encorafenib in Chinese Patients With Advanced Metastatic BRAF V600E Mutant Solid Tumors (NCT NCT05003622)

NCT ID: NCT05003622

Last Updated: 2024-06-24

Results Overview

The primary endpoint was the number of patients experiencing dose limiting toxicity (DLT) occurring within the first 28 days of study treatment (Cycle 1). A DLT was defined as any adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies resulting in the inability to tolerate at least 75% dose intensity \[(administered dose in mg/planned dose in mg) × 100\] that satisfied at least one of the prespecified criteria.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

3 participants

Primary outcome timeframe

At the end of Cycle 1. Each cycle was 28 days.

Results posted on

2024-06-24

Participant Flow

This study had no fixed duration and participants were expected to be treated until progressive disease. The three enrolled participants were to be treated until death, disease progression.

Participant milestones

Participant milestones
Measure
Encorafenib
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Overall Study
STARTED
3
Overall Study
COMPLETED
0
Overall Study
NOT COMPLETED
3

Reasons for withdrawal

Reasons for withdrawal
Measure
Encorafenib
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Overall Study
Progressive disease
2
Overall Study
Withdrawal by Subject
1

Baseline Characteristics

Phase 1 Safety Study of Encorafenib in Chinese Patients With Advanced Metastatic BRAF V600E Mutant Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Age, Continuous
64.0 years
STANDARD_DEVIATION 0 • n=93 Participants
Sex: Female, Male
Female
0 Participants
n=93 Participants
Sex: Female, Male
Male
3 Participants
n=93 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=93 Participants
Race (NIH/OMB)
Asian
3 Participants
n=93 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=93 Participants
Race (NIH/OMB)
Black or African American
0 Participants
n=93 Participants
Race (NIH/OMB)
White
0 Participants
n=93 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=93 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=93 Participants
Region of Enrollment
China
3 participants
n=93 Participants
Weight
65.73 kilograms
STANDARD_DEVIATION 4.87 • n=93 Participants
Height
163.07 centimeters
STANDARD_DEVIATION 5.01 • n=93 Participants
Body Mass Index
24.773 kilograms/meters squared
STANDARD_DEVIATION 2.437 • n=93 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status
Performance Status 0
0 Participants
n=93 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status
Performance Status 1
3 Participants
n=93 Participants
Smoking history
Never smoked
0 Participants
n=93 Participants
Smoking history
Stopped smoking more than or equal to 10 years ago
0 Participants
n=93 Participants
Smoking history
Stopped smoking less than 10 years ago
3 Participants
n=93 Participants
Smoking history
Smoker
0 Participants
n=93 Participants
BRAF V600E Mutation Result (Local)
Positive
3 Participants
n=93 Participants
BRAF V600E Mutation Result (Local)
Negative
0 Participants
n=93 Participants
Diagnosis at study entry
Metastatic Melanoma
0 Participants
n=93 Participants
Diagnosis at study entry
Metastatic NSCLC
3 Participants
n=93 Participants

PRIMARY outcome

Timeframe: At the end of Cycle 1. Each cycle was 28 days.

Population: Dose-determining Set. The Dose-determining set consisted of all evaluable participants from the Safety Analysis Set who either achieved the minimum exposure requirement (i.e., encorafenib dose intensity of 75% in Cycle 1) and had sufficient safety evaluations.

The primary endpoint was the number of patients experiencing dose limiting toxicity (DLT) occurring within the first 28 days of study treatment (Cycle 1). A DLT was defined as any adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies resulting in the inability to tolerate at least 75% dose intensity \[(administered dose in mg/planned dose in mg) × 100\] that satisfied at least one of the prespecified criteria.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Dose Limiting Toxicities (DLTs) Experienced During Cycle 1
0 participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment (EOT) visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

The occurrences of treatment emergent adverse events (TEAEs) graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03, TEAEs leading to dose interruption, reduction and discontinuation, treatment-emergent serious adverse events (SAEs) and deaths were reported. The number of events occurring in the three participants is presented.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs Overall
53 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs Related
17 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs Grade 3+
3 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs Related Grade 3+
2 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
Serious TEAE Overall
3 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
Serious TEAE Related
2 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
Serious TEAE Grade 3+
2 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
Serious TEAE Related Grade 3+
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
Serious TEAE Leading to Death
0 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE by severity grade Grade 1
37 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE by severity grade Grade 2
13 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE by severity grade Grade 3
3 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE leading to discontinuation of encorafenib regardless of causality Overall
0 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib dose modification (interruption or reduction) Overall
6 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib dose modification (interruption or reduction) Related
4 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib dose modification (interruption or reduction) Grade 3+
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib dose modification (interruption or reduction) Related Grade 3+
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib drug interruption Overall
5 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib drug interruption Related
4 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib drug interruption Grade 3+
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib drug interruption Related Grade 3+
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAEs leading to encorafenib dose reduction Overall
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE action taken with encorafenib Dose not Change
47 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE action taken with encorafenib Dose Reduced
1 events
Occurrence of Treatment Emergent Adverse Events (TEAEs)
TEAE action taken with encorafenib Drug Interrupted
5 events

SECONDARY outcome

Timeframe: Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

Clinically notable shift from baseline in blood hematology parameters data \[Hemoglobin (Low/High); Leukocytes (Low/ High); Neutrophils (Low); Platelets (Low); Lymphocytes (Low/High)\] was graded using NCI CTCAE Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. The number of participants with clinically notable shift from baseline is presented.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Hemoglobin (g/L) (Low)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Hemoglobin (g/L) (High)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Platelets (10^9/L) (Low)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Leukocytes (10^9/L) (Low)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Leukocytes (10^9/L) (High)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Lymphocytes (10^9/L) (Low)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Lymphocytes (10^9/L) (High)
0 Participants
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.
Neutrophils (10^9/L) (Low)
0 Participants

SECONDARY outcome

Timeframe: Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

Clinically notable shift from baseline in blood clinical chemistry parameter values \[Phosphate (Low); Alanine Aminotransferase (High); Albumin (Low); Alkaline Phosphatase (High); Aspartate Aminotransferase (High); Bilirubin (High); Calcium Corrected (Low/High); Creatinine (High); Glucose (Low/High); Magnesium (Low/High); Potassium (Low/High); Sodium (Low/High); amylase (high); Gamma Glutamyl Transferase (High); Lipase (High) and Urate (High)\] was graded using NCI-CTCAE, Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. Number of participants with at least one clinically notable shift during study was reported.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Albumin (g/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Alkaline Phosphatase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Alanine Aminotransferase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Aspartate Aminotransferase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Bilirubin (umol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Calcium Corrected (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Calcium Corrected (mmol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Creatine Kinase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Creatinine (umol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Gamma Glutamyl Transferase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Glucose (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Glucose (mmol/L) (High)
1 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Lipase (IU/L) (High)
1 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Amylase (IU/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Magnesium (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Magnesium (mmol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Phosphate (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Potassium (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Potassium (mmol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Sodium (mmol/L) (Low)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Sodium (mmol/L) (High)
0 Participants
Notable Change From Baseline of Blood Clinical Chemistry Parameters
Urate (umol/L) (High)
0 Participants

SECONDARY outcome

Timeframe: Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

The maximum post baseline values of coagulation parameters \[activated partial thromboplastin time (seconds) and prothtombin international normalized ratio (INR)\]. It was graded using NCI-CTCAE, Version 4.03. The number of participants is presented with their worst NCI-CTCAE grade post-baseline. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental ADL\*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL\*\*. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable Change From Baseline of Coagulation Parameters
Activated Partial Thromboplastin Time (sec) · Grade 0
3 Participants
Notable Change From Baseline of Coagulation Parameters
Activated Partial Thromboplastin Time (sec) · Grade 1
0 Participants
Notable Change From Baseline of Coagulation Parameters
Activated Partial Thromboplastin Time (sec) · Grade 2
0 Participants
Notable Change From Baseline of Coagulation Parameters
Activated Partial Thromboplastin Time (sec) · Grade 3
0 Participants
Notable Change From Baseline of Coagulation Parameters
Activated Partial Thromboplastin Time (sec) · Grade 4
0 Participants
Notable Change From Baseline of Coagulation Parameters
Prothrombin International Normalized Ratio (RATIO) · Grade 0
2 Participants
Notable Change From Baseline of Coagulation Parameters
Prothrombin International Normalized Ratio (RATIO) · Grade 1
1 Participants
Notable Change From Baseline of Coagulation Parameters
Prothrombin International Normalized Ratio (RATIO) · Grade 2
0 Participants
Notable Change From Baseline of Coagulation Parameters
Prothrombin International Normalized Ratio (RATIO) · Grade 3
0 Participants
Notable Change From Baseline of Coagulation Parameters
Prothrombin International Normalized Ratio (RATIO) · Grade 4
0 Participants

SECONDARY outcome

Timeframe: Days -28 to -1, Cycle1 Day1 (if not within 72 hours before first dose),Cycle1 Day15,on Day1 each subsequent cycle,end of treatment visit 30 day safety follow up visit, up to 6 months. Additional urinalysis in Cycle 1 Days 8 and 22. Each cycle was 28 days.

Population: Safety Analysis Set

The appearance of dipstick, at each visit by participant is presented.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable Change From Baseline of Dipstick Urinalysis
Baseline · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Baseline · Cloudy
0 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 8 · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 8 · Cloudy
0 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 15 · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 15 · Cloudy
0 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 22 · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 1 Day 22 · Cloudy
0 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 2 Day 1 · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 2 Day 1 · Cloudy
0 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 3 Day 1 · Clear
2 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 3 Day 1 · Cloudy
1 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 4 Day 1 · Clear
3 Participants
Notable Change From Baseline of Dipstick Urinalysis
Cycle 4 Day 1 · Cloudy
0 Participants

SECONDARY outcome

Timeframe: Screening (Days -28 to -1), Cycle 1 Days 1, 8, 15 and 22, Day 1 of each subsequent cycle, the end of treatment visit and the 30-day safety follow-up visit, approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

Clinically notable elevated values: Systolic blood pressure (SBP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic blood pressure (DBP): ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate : ≥ 120 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Weight (kg) increase from baseline of ≥ 10%; Body temperature(°C) ≥ 37.5°C). Clinically notable low values: Systolic blood pressure (SBP): ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic blood pressure (DBP) : ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm; Weight: ≥ 20% decrease from baseline; Body temperature \[°C\]: ≤ 36 °C. Number of participants with clinically notable abnormalities in vital signs was reported.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable elevated value: SBP : ≥160 mmHg and an increase ≥ 20 mmHg from baseline
1 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable elevated values: DBP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline
1 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable elevated values: Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm
1 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable elevated values: Weight: increase from baseline of ≥ 10%
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable elevated values: Body temperature [C]: ≥ 37.5 C
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable low values: SBP: ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable low values: DBP: ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable low values: Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable low values: Weight: ≥ 20% decrease from baseline
0 Participants
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.
Clinically notable low values: Body temperature [C]: ≤ 36 C
1 Participants

SECONDARY outcome

Timeframe: Screening (Days -28 to -1), Cycle 1 Day 8, 15 and 22, Day 1 of each subsequent even cycle, and the end of treatment visit, approximately up to 6 months. Each cycle was 28 days.

Population: Safety Analysis Set

12-lead ECGs were obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT \[millisecond (ms)\] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline \> 30 ms; increase from baseline \> 60 ms, new \> 450 ms, new \> 480 ms, new \> 500 ms. Heart rate (beats/min): increase from baseline \> 25% to a value \> 100 bpm, decrease from baseline \> 25% and to a value \< 50 bpm. Number of participants with clinically notable values was reported.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QT Interval : New > 500 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QT Interval : Increase from baseline > 30 ms
1 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QT Interval : Increase from baseline > 60 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QT Interval : New > 450 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QT Interval : New > 480 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QTcF Interval : Increase from baseline > 30 ms
1 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QTcF Interval : Increase from baseline > 60 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QTcF Interval : New > 450 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QTcF Interval : New > 480 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
QTcF Interval : New > 500 ms
0 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
Heart rate : Increase from baseline > 25% to a value > 100 bpm
1 Participants
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)
Heart rate : Decrease from baseline > 25% and to a value < 50 bpm
0 Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment [EOT] visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months.

Population: Safety Analysis Set

Adverse event of special interest (AESI) were as follows: Cutaneous non-squamous cell carcinoma, cutaneous squamous cell carcinoma, melanomas, facial paresis, uveitis-type events, QT prolongation, non-cutaneous malignancies with RAS mutation. Number of participants with at least one event of any AESI is presented.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Occurrence of Targeted Treatment Emergent Adverse Events (TEAEs) of Special Interest
0 participants

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetics Set

All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib: Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 AUC0-tlast
21800 h*ng/mL
Standard Deviation 4620
Plasma Pharmacokinetics (PK) of Encorafenib: Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 AUC0-tlast
9550 h*ng/mL
Standard Deviation 1750

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib metabolite (LHY746) was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 1 Day 1 AUC0-tlast
2540 h*ng/mL
Standard Deviation 1150
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 2 Day 1 AUC0-tlast
6020 h*ng/mL
Standard Deviation 3330

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib: Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 Cmax
5590 (ng/mL)
Standard Deviation 351
Plasma Pharmacokinetics (PK) of Encorafenib: Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 Cmax
3630 (ng/mL)
Standard Deviation 1750

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 Cmax
610 ng/mL
Standard Deviation 247
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 Cmax
1420 ng/mL
Standard Deviation 582

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: pharmacokinetic set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib: Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 Cmin
NA ng/mL
Standard Deviation NA
values were below the limit of quantification
Plasma Pharmacokinetics (PK) of Encorafenib: Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 Cmin
10.5 ng/mL
Standard Deviation 6.76

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 Cmin
NA ng/mL
Standard Deviation NA
Values were below the limit of quantification
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 Cmin
109 ng/mL
Standard Deviation 91.7

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib: Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib
Cycle 1 Day 1 tmax
2.00 hours
Interval 1.0 to 4.03
Plasma Pharmacokinetics (PK) of Encorafenib: Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib
Cycle 2 Day 1 tmax
1.00 hours
Interval 1.0 to 4.0

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetic Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib Metabolite (LHY746) was assessed after single and repeated administrations.

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 1 Day 1 tmax
5.98 hours
Interval 5.92 to 6.0
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 2 Day 1 tmax
2.00 hours
Interval 1.97 to 4.0

SECONDARY outcome

Timeframe: at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetics Set

All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of Encorafenib was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib: ARAUC After Single and Repeated Administration of Encorafenib
0.440 ratio
Geometric Coefficient of Variation 40.2

SECONDARY outcome

Timeframe: at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetics Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): ARAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
2.27 ratio
Geometric Coefficient of Variation 18.2

SECONDARY outcome

Timeframe: First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.

Population: Pharmacokinetics Set

All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The MRAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. MRAUC = Metabolite Parent ratio based on AUC0-6

Outcome measures

Outcome measures
Measure
Encorafenib
n=3 Participants
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): MRAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 1 Day 1
0.141 ratio
Geometric Coefficient of Variation 53.1
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): MRAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746)
Cycle 2 Day 1
0.730 ratio
Geometric Coefficient of Variation 41.3

Adverse Events

Encorafenib

Serious events: 2 serious events
Other events: 3 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
Encorafenib
n=3 participants at risk
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Metabolism and nutrition disorders
Diabetes mellitus
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Dysplastic naevus
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.

Other adverse events

Other adverse events
Measure
Encorafenib
n=3 participants at risk
Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
Gastrointestinal disorders
Constipation
66.7%
2/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Gastrointestinal disorders
Nausea
66.7%
2/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Gastrointestinal disorders
Vomiting
66.7%
2/3 • Number of events 3 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Neutrophil count increased
100.0%
3/3 • Number of events 5 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Blood cholesterol increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Blood glucose increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
C-reactive protein increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Coagulation time prolonged
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Lipase increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Platelet count increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
Urinary occult blood
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Investigations
White blood cell count increased
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Renal and urinary disorders
Proteinuria
100.0%
3/3 • Number of events 3 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Renal and urinary disorders
Diabetic nephropathy
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Hyperkeratosis
66.7%
2/3 • Number of events 3 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Pigmentation disorder
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Rash
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Rash pruritic
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Skin and subcutaneous tissue disorders
Skin hyperpigmentation
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Blood and lymphatic system disorders
Leukocytosis
66.7%
2/3 • Number of events 3 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Blood and lymphatic system disorders
Anaemia
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Infections and infestations
Subcutaneous abscess
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Injury, poisoning and procedural complications
Postoperative wound complication
33.3%
1/3 • Number of events 2 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Metabolism and nutrition disorders
Diabetes mellitus
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Metabolism and nutrition disorders
Hyperlipidaemia
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Metabolism and nutrition disorders
Hypokalaemia
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Musculoskeletal and connective tissue disorders
Periarthritis
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Nervous system disorders
Neuritis
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Respiratory, thoracic and mediastinal disorders
Dysphonia
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
Vascular disorders
Hypertension
33.3%
1/3 • Number of events 1 • All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.

Additional Information

Jean Claude Vedovato

Pierre Fabre Medicament

Phone: +33 609828746

Results disclosure agreements

  • Principal investigator is a sponsor employee Except for the release of SAE of study drug/product defects of the institution, institution and/or investigator shall promptly notify sponsor of the content to be released before releasing other research information and obtain sponsor's consent. If there is no response from sponsor within 60 working days after issuance or specific reason for disagreement and modification suggestions are not listed in the response, it shall be deemed that sponsor agrees.
  • Publication restrictions are in place

Restriction type: OTHER