ENCORAFENIB for BRAF V600E-mutant metastatic non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.\n- Adequate bone marrow function characterized by the following at screening: i) ANC ≥ 1.5 × 109/L; ii) Platelets ≥ 100 × 109/L; iii) Hemoglobin ≥ 8.5 g/dL (with or without blood transfusions).\n- Adequate hepatic and renal function characterized by the following at screening: i) Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL (or ≤ 3 x UNL and ≤ 3,0 mg/dL in case of documented Gilbert's syndrome or liver metastases ); OR total bilirubin >1.5 × ULN with indirect bilirubin < 1.5 × ULN; ii) ALT and AST ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases; iii) Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration rate>50 mL/min/1.73m².\n- Female patients of childbearing potential as described in Appendix 1, must have a negative serum β HCG test result.\n- Female patients of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1, and to not donate ova from Screening until 30 days after the last dose of study treatment.\n- Male patients must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1, and to not donate sperm from Screening until 90 days after the last dose of encorafenib and binimetinib.\n- Patient covered by a national health insurance\n- Male or female aged at least 18 years old.\n- Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a, M1b or M1c AJCC 8th edition). If there is any doubt about the diagnosis please contact IFCT. If diagnosis of NSCLC is only confirmed cytologically, patient may be eligible if a cytoblock is available - this must be discussed and approved by IFCT prior to inclusion.\n- ECOG performance status of 0-1.\n- Able to swallow and retain oral medication.\n- Presence of a BRAFV600E mutation in lung cancer tissue as determined by a local laboratory assay.\n- The Investigator must confirm prior to enrolment that the patient has adequate tumor tissue available to determine BRAFV600E mutation status by central laboratory for confirmation. Note: Tumor tissue collected after the patient was diagnosed with metastatic disease is preferred. Tumor tissue sample must not be from locations previously radiated. Tumor sample must be 1 block (or 10 to 15 unstained slides of analyzable tissue) and 1 H&E slide.\n- Patients i) (COHORT A) who are either treatment-naïve (e.g., no prior systemic therapy for advanced/metastatic disease), ii) (COHORT B) who are in progression after having received 1) firstline platinum-based chemotherapy OR 2) first-line treatment with an anti-PD-1/L-1 inhibitor given alone or in combination with platinumbased chemotherapy or in combination with immunotherapy (e.g, ipilimumab) with or without platinum-based chemotherapy. Note: Alternative chemotherapy regimens are acceptable if the patient was platinum intolerant or ineligible. Patients with early stage disease (e.g., Stages I-III) who have had surgery followed by chemotherapy (e.g., treatment in the adjuvant setting), radiation therapy and/or immunotherapy, and present with new lesions or evidence of disease recurrence (e.g., metastatic disease), within 12 months of completing chemotherapyadjuvant treatment, would be considered as had received a first-line therapy. Maintenance therapy given after first-line therapy in the metastatic setting will not be considered a separate regimen, provided there was no documentation of disease progression between completion of first-line therapy and the start of maintenance therapy.\n- Presence of measurable disease based on RECIST v1.1."}

Exclusion criteria

• {"criterion_text":"- Patients with nonsquamous carcinoma who have documentation of any of the following: EGFR mutation, ALK fusion oncogene or ROS1 rearrangement.\n- History of thromboembolic or cerebrovascular events ≤12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Patients with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enrol as long as they are stable, asymptomatic and on a stable dose of anticoagulants for at least 2 weeks. Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled.\n- History or current evidence of RVO (Retinal Vein Occlusion) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyper viscosity or hypercoagulability syndromes); history of retinal degenerative disease.\n- Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).\n- Evidence of active, noninfectious pneumonitis, history of interstitial lung disease that required oral or intravenous glucocorticoid steroids for management.\n- Evidence of HBV or HCV infection. Note: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled. Note: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may enrol.\n- Patient who has a known history of a positive test for HIV or known AIDS.\n- Active infection requiring systemic therapy.\n- Patients with symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases are not eligible. Note: Patients with previously treated or not treated brain metastases may participate provided they are stable and any neurologic symptoms must have returned to baseline. Patients must have no evidence of new or enlarging brain metastases or CNS edema. Patient must have discontinued use of steroids at least 7 days before the first dose of study treatment.\n- Concurrent or previous other malignancy within 2 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason 6 prostate cancer.\n- Known sensitivity or contraindication to any component of study treatment or their excipients.\n- Previous treatment with any other BRAF inhibitor, or any other MEK inhibitor prior to screening and enrolment.\n- Pregnancy confirmed by a positive β-HCG laboratory test result, or breastfeeding (lactating).\n- Other severe, acute or chronic medical or psychiatric condition(s) or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.\n- Patients who have received more than 1 prior line of systemic therapy in the advanced/metastatic setting for Cohorte B.\n- Receipt of anticancer therapies or investigational drugs within the following intervals before the first administration of study treatment: i) ≤14 days for chemotherapy, targeted small molecule therapy, radiation therapy, immunotherapy (e.g., erlotinib, crizotinib, bevacizumab etc.). ii) ≤14 days or 5 half-lives (minimum of 14 days) for investigational agents or devices. For investigational agents with long half-lives (e.g., > 5 days), enrolment before the fifth half-life requires sponsor approval. iii) Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.\n- Patients who have had major surgery ≤ 6 weeks prior to start of study treatment.\n- For cohort B : Patient has not recovered to ≤Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study treatment.\n- Current use of a prohibited medication, or use of a prohibited medication ≤1 week prior to the start of study treatment.\n- Impairment of gastrointestinal function or disease which may significantly alter the absorption of oral study treatment (e.g., uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection).\n- Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: i) History of myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment; ii) Congestive heart failure requiring treatment (New York Heart Association Grade ≥2); iii) LVEF < 50% as determined by MUGA or ECHO; iv) Uncontrolled hypertension defined as persistent systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg despite optimal therapy; v) History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); vi) Baseline QTcF interval ≥480 ms or a history of prolonged QT syndrome."}

Primary endpoints

• {"endpoint_text":"- ORR, which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST v1.1 criteria. Each cohort will be analysed separately.","definition_or_measurement_approach":"ORR defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST v1.1 criteria; each cohort analysed separately (investigator assessment per RECIST v1.1)."}

Secondary endpoints

• {"endpoint_text":"- DOR (Duration Response Rate) defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1, or death due to any cause.","definition_or_measurement_approach":"Time from first documented response (CR or PR) to earliest date of disease progression or death; assessed by Investigator review and independent reviewer using radiographic assessments per RECIST v1.1."}
• {"endpoint_text":"- DCR (Disease Control Rate) defined as the proportion of patients having achieved a confirmed best overall response of CR, PR or SD, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1.","definition_or_measurement_approach":"Proportion of patients with best overall response CR, PR or SD; determined by Investigator review and independent reviewer per RECIST v1.1."}
• {"endpoint_text":"- PFS (Progression Free Survival) defined as the time from the date of inclusion to the earliest date of disease progression, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1, or death due to any cause.","definition_or_measurement_approach":"Time from inclusion to disease progression or death; assessed by Investigator and independent reviewer per RECIST v1.1."}
• {"endpoint_text":"- ORR, which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by independent reviewer as per RECIST v1.1 criteria.","definition_or_measurement_approach":"ORR assessed by independent reviewer per RECIST v1.1 (percentage with confirmed CR or PR)."}
• {"endpoint_text":"- TTP (Time To Tumour Progression) defined as the time from the date of inclusion to the earliest date of disease progression, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1.","definition_or_measurement_approach":"Time from inclusion to earliest date of documented tumour progression; assessed by Investigator and independent reviewer per RECIST v1.1."}
• {"endpoint_text":"- PFS L2 defined as the time between the start date of the second line and the first of documented progression after the start L2, as determined by Investigator review of radiographic disease assessments per RECIST v1.1, or death due to any cause.","definition_or_measurement_approach":"Time between start of second-line therapy and first documented progression after start of second-line, or death; determined by Investigator per RECIST v1.1."}
• {"endpoint_text":"- OS (Overall Survival) defined as the time from the date of first dose of study drug to the date of death due to any cause","definition_or_measurement_approach":"Time from first dose to death from any cause."}
• {"endpoint_text":"- Incidence and severity of AEs graded according to the NCI CTCAE version 4.03 and changes in clinical laboratory parameters, vital signs, ECGs and ECHO/MUGA scans.","definition_or_measurement_approach":"Adverse events graded per NCI CTCAE v4.03; monitoring of labs, vital signs, ECGs, and ECHO/MUGA."}
• {"endpoint_text":"- Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) at all scheduled time points.","definition_or_measurement_approach":"Change from baseline in EQ-5D-5L scores at scheduled assessments."}

France

Earliest CTIS Part Ii Submission Date

12-09-2024

Latest Decision Or Authorization Date

31-10-2024

Processing Time Days

49

Number Of Sites

38

Number Of Participants

119

Primary sponsor

Full Name

Intergroupe Francophone De Cancerologie Thoracique

Organisation Type

Patient organisation/association

Country Of Registered Address

France