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

Study Overview
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Brief Summary
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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.

Official Title
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Multicenter, Open-label, Phase 1 Study Investigating the Safety and Tolerability of Encorafenib Monotherapy in BRAF V600E-mutated Chinese Patients With Advanced Metastatic Solid Tumors

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

Intervention / Treatment
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* Drug: Encorafenib


Participation Criteria
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Eligibility Criteria
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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: Bowen's disease. Cured basal cell or squamous cell skin cancer. Gleason 6 prostate cancer. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: encorafenib<br>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). | Drug: Encorafenib<br>* oral capsule<br>* Other names: ONO-7702;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) experienced during Cycle 1 |  | At the end of Cycle 1. Each cycle is 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, nature and severity of treatment emergent adverse events (TEAEs) | Incidence, nature and severity 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 will be reported. | 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 is 28 days. | 
| Incidence of treatment emergent adverse events (TEAEs) related to notable change from baseline of blood hematology parameters | Clinically notable shift from baseline in blood hematology parameters data [Hemoglobin (Low/High); Leukocytes (Low/ High); Neutrophils (Low); Platelets (Low/High); Lymphocytes (Low/High)] will be graded using NCI CTCAE Version 4.03. Clinically notable shift is 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 will be reported. | 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 is 28 days. | 
| Incidence of treatment emergent adverse events (TEAEs) related to notable change from baseline of blood clinical chemistry parameters | 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)] will be graded using NCI-CTCAE, Version 4.03. Clinically notable shift is 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 will be reported. | 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 is 28 days. | 
| Incidence of treatment emergent adverse events (TEAEs) related to notable change from baseline of coagulation parameters | Clinically notable shift from baseline in coagulation parameters parameter values [activated partial thromboplastin time (seconds), international normalized ratio (INR) or prothrombin time (seconds)] will be graded using NCI-CTCAE, Version 4.03. Number of participants with abnormal levels or notable shift during study will be reported. | 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 is 28 days. | 
| Incidence of treatment emergent adverse events (TEAEs) related to notable change from baseline of dipstick urinalysis | Quantitative assessment of appearance, color, specific gravity, blood, glucose, leukocytes, ketones, pH and protein at each visit and changes from baseline (for quantitative parameters) will be calculated and tabulated. Microscopy findings (normal/abnormal and clinical significance) will be recorded. Number of participants with abnormal/ clinical significant changes during study will be reported. | Days -28 to -1,Cycle1 Day1 (if not done w/in 72 hours before first dose),Cycle1 Day15,on Day1 each subsequent cycle,end of treatment visit 30 day safety FU visit,approx. up to 6 months. Add'l urinalysis in Cycle 1 Days 8 and 22. Each cycle is 28 days. | 
| Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs from baseline of vital sign examinations. | Clinically notable elevated values: Systolic blood pressure (BP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic BP: ≥ 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 BP: ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic BP: ≤ 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 TEAEs related to notable changes to the vital signs after the start of study drug will be reported. | 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 is 28 days. | 
| Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs) | 12-lead ECGs will be 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 TEAEs related to abnormal or notable changes to ECG parameters after the start of study drug will be reported. | Screening (Days -28 to -1), Cycle 1 Day 8, 15 and 22, Day 1 of each subsequent even cycle (Cycle 2, 4, 6, …) and the end of treatment visit, approximately up to 6 months. Each cycle is 28 days. | 
| Incidence of targeted treatment emergent adverse events (TEAEs) of special interest | Adverse event of special interest (AESI) are as follows: acute renal failure, cutaneous non-squamous cell carcinoma, cutaneous squamous cell carcinoma, melanomas, palmar-plantar erythrodysaesthesia syndrome, photosensitivity, rash, severe cutaneous adverse reactions, facial paresis, tachycardia, haemorrhage, hepatic failure, liver function test abnormalities, myopathy and uveitis-type events. Number and percentage of participants with at least one event of any AESI and of each category of AESI will be reported in participants. | 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. | 
| 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 is 28 days. | 
| Plasma pharmacokinetics (PK) of encorafenib metabolite (LHY746): 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 is 28 days. | 
| 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 is 28 days. | 
| 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 is 28 days. | 
| 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 is 28 days. | 
| 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 is 28 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Melanoma, BRAF V600E mutation