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

Phase 1

Completed

Conditions: BRAF V600E Unresectable or Metastatic Melanoma
Melanoma
BRAF V600E Metastatic NSCLC

Interventions: Drug: Encorafenib

Registration Number: NCT05003622

Lead Sponsor: Pierre Fabre Medicament

Brief Summary: This is a phase 1, multicenter, open-label, single-arm study to investigate the safety and tolerability of encorafenib 300 mg once daily (QD) monotherapy in adult Chinese participants with B-RAF Proto-oncogene, Serine/threonine Kinase V600E (BRAF V600E) mutant advanced solid tumors (unresectable metastatic melanoma or metastatic non-small cell lung cancer (NSCLC)), who are BRAF-inhibitor treatment-naïve and have failed the previous therapy(ies) in the metastatic setting or are not eligible to standard therapy. Participants will be eligible for the study based on identification of a BRAF V600E mutation in tumor tissue by a local National Medical Products Administration (NMPA) approved assay obtained prior to screening.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Provide a signed and dated informed consent form (ICF).
Chinese male or female with age ≥18 years old at the time of the informed consent.
Documented histology- and/or cytology-confirmed metastatic melanoma or non-small cell lung cancer (NSCLC) (i.e. adenocarcinoma, large cell carcinoma, squamous cell carcinoma).
Presence of B-RAF Proto-oncogene, Serine/threonine Kinase V600E Mutant (BRAF V600E) mutation as determined by a local laboratory with a National Medical Products Administration (NMPA) approved BRAF test.
BRAF inhibitor treatment-naïve participants and having failed the previous therapy(ies) for metastatic disease or are not eligible to standard therapy.
At least one tumor lesion as per investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, which has neither been irradiated nor biopsied during the screening period. The irradiated lesion is acceptable only if it is proven as disease progression deemed measurable prior to study.
Life expectancy ≥3 months.
Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1.
Adequate hematologic function at screening and baseline
Adequate hepatic function at screening and baseline
Adequate renal function at screening and baseline
Able to comply with the study protocol as per investigator assessment including oral drug intake, complying scheduled visits, treatment plan, laboratory tests and other study procedures.
Women are either postmenopausal for at least 1 year, or are surgically sterile for at least 6 weeks, or women of childbearing potential (WOCBP) must agree to take appropriate precautions to avoid pregnancy.
Men must agree not to father child until 90 days after the last dose of study treatment.

Exclusion Criteria

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to encorafenib, or its excipients.
For metastatic NSCLC: documented anaplastic lymphoma kinase (ALK) fusion oncogene, ROS1 (c-ros oncogene 1) rearrangement or epidermal growth factor receptor (EGFR) sensitizing or driver mutation.
Receipt of anticancer medications or investigational drugs within intervals before the first administration of study treatment.
Symptomatic brain metastasis.
Leptomeningeal disease.
Participant has not recovered to ≤Grade 1 from toxic effects of prior therapy and/or complications from prior surgical treatment before starting study treatment.
Current use of prohibited medication ≤1 week prior to start of the study treatment and/or concomitantly.
Impairment of gastrointestinal function or disease which may significantly alter the absorption of oral study treatment.
Impaired cardiovascular function or clinically significant cardiovascular diseases.
Participants with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) or any other severe viral active infection (e.g. severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection).
Evidence of active, non-infectious pneumonitis, history of interstitial lung disease that required oral or intravenous glucocorticoid steroids for management.
Known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Testing for HIV must be performed at sites where mandated locally.
Participants who have had major surgery (e.g. inpatient procedure with regional or general anesthesia) within 6 weeks prior to start of study treatment.
Previous or concurrent malignancy within 2 years of study entry.

Except:
1. Bowen's disease.
2. Cured basal cell or squamous cell skin cancer.
3. Gleason 6 prostate cancer.
4. Treated in-situ carcinoma of cervix.
Participant's conditions that contraindicates the use of study treatment and may affect interpretation of results or that may render the participant at high risk from treatment complications.
Pregnant (confirmed by positive serum beta-human Chorionic Gonadotropin (ß-HCG) test), lactating or breast-feeding women.
Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician).
Is in a position likely to represent a conflict of interest.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
encorafenib	Encorafenib	Encorafenib hard capsule will be orally self-administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib will be administered once-daily (QD).

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicities (DLTs) Experienced During Cycle 1	At the end of Cycle 1. Each cycle was 28 days.	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.

Secondary Outcome Measures

Name	Time	Method
Plasma Pharmacokinetics (PK) of Encorafenib: ARAUC After Single and Repeated Administration of Encorafenib	at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.	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
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib	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.	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.
Occurrence of Treatment Emergent Adverse Events (TEAEs)	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.	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.
Notable Change From Baseline of Blood Clinical Chemistry Parameters	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.	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.
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)	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.	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.
Notable Change From Baseline of Coagulation Parameters	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.	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.
Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations.	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.	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.
Occurrence of Targeted Treatment Emergent Adverse Events (TEAEs) of Special Interest	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.	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.
Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes.	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.	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.
Notable Change From Baseline of Dipstick Urinalysis	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.	The appearance of dipstick, at each visit by participant is presented.
Plasma Pharmacokinetics (PK) of Encorafenib: Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib	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.	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
Plasma Pharmacokinetics (PK) of Encorafenib: Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib	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.	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.
Plasma Pharmacokinetics (PK) of Encorafenib: Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib	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.	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.
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib	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.	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.
Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs)	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.	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.
Plasma Pharmacokinetics (PK) of Encorafenib: Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib	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.	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.
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib Metabolite (LHY746)	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.	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
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): ARAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746)	at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days.	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
Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): MRAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746)	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.	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