A Study of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutant Metastatic NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of dabrafenib in combination with trametinib in Chinese patients with BRAF V600E mutation-positive metastatic Non-Small Cell Lung Cancer. The general study design has been discussed and agreed with Chinese Health Authority and is applying a similar design used for global pivotal phase II study (BRF113928).

Detailed Description
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This is a single arm, open label, multicenter phase II study evaluating the efficacy and safety of dabrafenib in combination with trametinib in Chinese participant with BRAF V600E mutation positive AJCC v8 stage IV Non-Small Cell Lung Cancer. Participants with stage IV BRAF V600E mutant Non-Small Cell Lung Cancer confirmed by local qualified assay (approved by China health authorities) will be enrolled in this study. Central confirmation testing for BRAF V600E will be performed. This study will enroll participants: who have not received any prior systemic anti-cancer therapy for metastatic disease (i.e. dabrafenib/trametinib will be the 1st line treatment for metastatic disease) who have relapsed or progressed on at least one prior platinum based chemotherapy prior to enrollment but cannot have received more than 3 prior systemic therapies for metastatic disease (i.e. dabrafenib/trametinib will be no less than second line treatment for metastatic disease). All participants must not have been previously exposed to a BRAF or MEK inhibitor. Participants will receive the recommended dose of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily). The primary endpoint for the study is Overall Response Rate, as determined by central independent review, using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Approximately 40 Chinese patients over 18 years old will be enrolled in this study and will receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) combination therapy until disease progression by RECIST 1.1, unacceptable toxicity, start of a new antineoplastic therapy, pregnancy, withdrawal of consent, lost to follow-up, physician's decision, death, or if study is terminated by the sponsor. Doses of study treatment may be modified and/or interrupted for management of toxicities associated with study treatment. Treatment beyond disease progression per RECIST is allowed if protocol specific criteria are met. The tumor assessments will be performed every 6 weeks until Week 36, and every 12 weeks thereafter until disease progression, death, lost of follow-up, or withdrawal of consent. Survival and new anti-cancer therapy follow-up will continue until study completion.

Official Title
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An Open-Label, Single-arm Study to Evaluate the Safety and Efficacy of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (according to AJCC 8th edition) that is BRAF V600E mutation-positive by local test result from a qualified assay (NMPA and/or MOH-approved) Previously treated or untreated for metastatic NSCLC: Participants previously treated should have received no more than 3 prior systemic therapies for metastatic disease, with at least one prior platinum based chemotherapy, and should have documented disease progression on a prior treatment regimen (i.e. RECIST 1.1) Participants who have received prior therapy with checkpoint inhibitor therapy (i.e. anti-PD-1/PD-L1) must have had objective evidence of disease progression (i.e. RECIST v1.1) while on or after this therapy prior to enrollment. Participants with EGFR or ALK mutation who have previously received therapy with EGFR or ALK inhibitor(s) respectively are eligible Measurable disease per RECIST v1.1 Anticipated life expectancy of at least 3 months ECOG performance status ≤ 2. Adequate bone marrow and organ function as defined by the following laboratory values without continuous supportive treatment (such as blood transfusion, coagulation factors and/or platelet infusion, or red/white blood cell growth factor administration) as assessed by local laboratory for eligibility: Hemoglobin ≥ 9 g/dL; Absolute neutrophil count ≥ 1.5 × 109/L; Platelets ≥ 100 × 109/L; PT/INR and PTT ≤ 1.5 x ULN; Serum creatinine < 1.5 mg/dL; Total bilirubin ≤ 1.5 × ULN (upper limit of normal) except for participantss with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN, except for participant with liver metastasis, who may only be included if AST/ALT ≤ 5.0 × ULN Albumin ≥ 2.5 g/dL Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as assessed by ECHO or MUGA scan Exclusion Criteria: Participants with brain or leptomeningeal metastases are excluded if their these metastases are: symptomatic or treated but not clinically and radiographically stable 3 weeks after local therapy or asymptomatic and untreated but >1 cm in the longest dimension Previous treatment with a BRAF inhibitor or a MEK inhibitor All prior anti-cancer treatment-related toxicities must be Grade 2 or less according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03; NCI, 2009) at the time of enrollment Prior anti-cancer treatment within the last 2 weeks, and prior treatment with immune checkpoint inhibitors within 4 weeks preceding the first dose of the study treatment. Current use of a prohibited medication Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). Participants with known history for testing positive for Human Immunodeficiency Virus (HIV) History of another malignancy <3 years prior to starting study treatment or any malignancy with confirmed activating RAS-mutation. Cardiac or cardiac repolarization abnormality A history or current evidence/risk of retinal vein occlusion (RVO) or serous retinopathy History or current interstitial lung disease or non-infectious pneumonitis Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the participant's safety, obtaining informed consent, or compliance with study procedures Pregnant or nursing (lactating) women. Sexually active males (including those that have had a vasectomy) must use a condom during intercourse and should not father a child during this period. The amount of time a patient must use a condom for 16 weeks post treatment discontinuation Participants with active Hepatitis B infection (HbsAg positive) Participants with positive test for hepatitis C ribonucleic acid (HCV RNA) Concurrent participation in other clinical trials using experimental therapies

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: Dabrafenib in combination with trametinib<br>Dabrafenib 150 mg twice daily, trametinib 2 mg once daily | Drug: Dabrafenib<br>* Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-21 of a 21-day cycle.<br>* Other names: DRB436;Drug: Trametinib<br>* Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-21 of a 21-day cycle<br>* Other names: TMT212;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR), central independent review assessed by RECIST v1.1 | Overall Response Rate is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) by central independent review as per RECIST v1.1 criteria | From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 12 months from treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR), investigator assessed by RECIST v1.1 | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST 1.1 criteria | From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 12 months from treatment initiation | 
| Progression Free Survival (PFS), investigator assessed by RECIST v1.1 | PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1. | From baseline until disease progression or death due to any cause, whichever occurs first, assessed up to approximately 12 months from treatment initiation | 
| Duration of Response (DoR), investigator assessed by RECIST v1.1 | DoR is defined for the subset of participants with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression according to RECIST v1.1 per local review or death due to any cause | From first documented response until first documented progression or death due to any cause, whichever occurs first, assessed up to approximately 12 months from treatment initiation | 
| Overall Survival (OS) | OS is defined as the time from first dose until death due to any cause | From baseline until death due to any cause, assessed up to approximately 33 months from treatment initiation | 
| Trough concentration of dabrafenib | Mean trough concentration will be calculated at each timepoint | Pre-dose sample at visits week 3, 6 and 12 | 
| Trough concentration of dabrafenib metabolites (hydroxy-dabrafenib, and desmethyl-dabrafenib) | Mean trough concentration will be calculated at each timepoint | Pre-dose sample at visits week 3, 6 and 12 | 
| Trough concentration of trametinib | Mean trough concentration will be calculated at each timepoint | Pre-dose sample at visits week 3, 6 and 12 | 
| Mean change from baseline in the European Quality of Life (EuroQol)- 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score | EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients. | From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation) | 
| Mean change from baseline in the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) score | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. | From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation) | 
| Mean Change from Baseline in the European Organization for Research and Treatment of Cancer lung cancer specific module (EORTC QLQ-LC13) score | EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. | From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation) | 
| Number of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs) | Safety profile of dabrafenib in combination with trametinib. Incidence of Adverse Events and Serious Adverse events, including abnormal laboratory values or test results. | From baseline until end of study, assessed up to approximately 33 months from treatment initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Non-Small Cell Lung Cancer, NSCLC, Chinese patients, dabrafenib, trametinib, BRAF V600E, treatment naive, pre-treated