A Study of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutant Metastatic NSCLC
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Interventions
- Registration Number
- NCT04452877
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This was a single-arm, open label, multicenter phase II, study of dabrafenib in combination with trametinib in Chinese participants with BRAF V600E mutation positive, stage IV NSCLC (American joint committee on cancer staging 8th edition). Approximately 40 Chinese adults were to be enrolled in this study. Participants were to be treated with dabrafenib in combination with trametinib until disease progression, start of a new anti-neoplastic therapy, unacceptable toxicity, pregnancy, withdrawal of consent, lost to follow-up, physician's decision, death, or if study be terminated by the sponsor. The general study design was discussed and agreed with China National Medical Products Administration and was based on a similar design used in the global pivotal phase II study (Study 113928 / NCT01336634).
- Detailed Description
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:
1. 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)
2. 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
-
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 participants 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
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Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as assessed by ECHO or MUGA scan
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dabrafenib in combination with trametinib Dabrafenib Dabrafenib 150 mg twice daily, trametinib 2 mg once daily Dabrafenib in combination with trametinib Trametinib Dabrafenib 150 mg twice daily, trametinib 2 mg once daily
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR), Central Independent Review Assessed by RECIST v1.1 From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 50 months from treatment initiation Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per central independent review assessment and according to RECIST 1.1.
- Secondary Outcome Measures
Name Time Method Overall Response Rate (ORR), Investigator Assessed by RECIST v1.1 From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 50 months from treatment initiation Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) by Investigator assessment as per RECIST 1.1 criteria.
Progression Free Survival (PFS), Investigator Assessed by RECIST v1.1 From baseline until disease progression or death due to any cause, whichever occurs first, assessed up to approximately 50 months from treatment initiation Progression Free Survival (PFS) was defined as the time from the date of first dose to the date of the first documented progression or death due to any cause. PFS was assessed via local review according to RECIST 1.1. PFS was censored if no PFS event was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-neoplastic therapy is started. The censoring date was the date of the last adequate tumor assessment prior to cut-off/start of new anti-neoplastic therapy.
Duration of Response (DoR), Investigator Assessed by RECIST v1.1 From first documented response until first documented progression or death due to any cause, whichever occurs first, assessed up to approximately 50 months from treatment initiation Duration of Response (DoR) only applies to participants whose Best Overall Response (BOR) was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to any cause. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment.
Overall Survival (OS) From baseline until death due to any cause, assessed up to approximately 50 months from treatment initiation Overall Survival (OS) was defined as the time from date of first dose to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date).
Trough Concentration of Dabrafenib Pre-dose sample at visits week 3, 6 and 12 Plasma concentration of dabrafenib were calculated by visit/sampling time point and summarized using descriptive statistics.
Trough Concentration of Dabrafenib Metabolites (Hydroxy-dabrafenib, and Desmethyl-dabrafenib) Pre-dose sample at visits week 3, 6 and 12 Plasma concentration of dabrafenib metabolites (hydroxy-dabrafenib, and desmethyl-dabrafenib) were calculated by visit/sampling time point and summarized using descriptive statistics.
Trough Concentration of Trametinib Pre-dose sample at visits week 3, 6 and 12 Plasma concentration of trametinib were calculated by visit/sampling time point and summarized using descriptive statistics.
Mean Change From Baseline in the European Quality of Life (EuroQol)- 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Baseline (BL), Week 12, End of Treatment (up to approximately 50 months after treatment initiation) The EQ-5D-5L is a standardized tool for measuring health-related quality of life (HRQoL). The instrument includes a descriptive system and a visual analogue scale. The descriptive system covers five dimensions (Mobility, Self-care, Usual activities, Pain/discomfort, Anxiety/depression), each with five severity levels ranging from 0 (no problems) to 5 (extreme problems) resulting in a 5-digit health code. In China, a country-specific value set is used to convert the five-digit health state into a utility score, ranging from \<0 (worse than death) to 1.0 (perfect health). A positive change from baseline indicates improvement; a negative change indicates deterioration. The Visual Analog Scale (VAS) is a 0-100 self-rated health scale, where 0 is the worst and 100 the best imaginable health. A positive change reflects perceived improvement.
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale Baseline (BL), Week 12, End of Treatment (up to approximately 50 months after treatment initiation) The EORTC QLQ-C30 is a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It includes five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale. The GHS/QoL scale has seven possible response scores ranging from 1 (very poor) to 7 (excellent), which are averaged and transformed to a 0-100 scale. A higher score on this scale indicates a better quality of life. The change from baseline in GHS/QoL scores is calculated. A positive change from baseline indicated improvement in the patient's quality of life.
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Lung Cancer Specific Module (EORTC QLQ-LC13) Baseline (BL), Week 12, End of Treatment (up to approximately 50 months after treatment initiation) The EORTC QLQ-LC13 is a lung cancer-specific module designed to supplement the EORTC QLQ-C30 core questionnaire. It focuses on symptoms and side effects particularly relevant to lung cancer patients, including: Cough, Dyspnea (Shortness of breath), Hemoptysis (Coughing up blood), Sore Mouth/Tongue, Dysphagia (Trouble swallowing), Peripheral neuropathy (Tingling Hands/Feet), Alopecia (Hair Loss) and Pain in chest, arm, shoulder, or other areas and an additional dimension (Q13A: "How much did the pain medication help") if Q13: "did you take any medicine for pain" is answered "yes". Each item is scored on a 1 to 4 Likert scale (1 = "Not at all", 4 = "Very much") and then linearly transformed to a 0-100 scale. Improvements in QoL are indicated by decreased scores for the 13 main dimensions and an increased score for question 13A.
Percentage of Participants With Adverse Events (AEs) From baseline until end of study, assessed up to approximately 50 months An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.
Treatment Emergent Adverse Events (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after last dose.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇨🇳Shanghai, China
Novartis Investigative Site🇨🇳Shanghai, China