| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAFV600E-mutant metastatic Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung Cancer with BRAF V600E mutation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075676 |
| E.1.2 | Term | BRAF V600E mutation positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of encorafenib + binimetinib in patients with BRAFV600E-mutant NSCLC as measured by ORR in first line and second line and in patients with BRAF non V600E-mutant in second or third line. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of encorafenib + binimetinib in patients with BRAFV600E-mutant NSCLC as measured by DOR, DCR, PFS (investigator-assessed and assessed by independent reviewer) and ORR as assessed by independent reviewer.
- To evaluate the efficacy of encorafenib + binimetinib with respect to OS.
- To evaluate the safety and tolerability of encorafenib + binimetinib in patients with BRAFV600E-mutant NSCLC.
- To evaluate the efficacy of docetaxel in 2nd line in patients with stage IV BRAF V600E mutant NSCLC (Cohorte B).
- To evaluate the quality of life in patients with BRAFV600E-mutant NSCLC receiving encorafenib + binimetib or docetaxel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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.
2. Male or female aged at least 18 years old.
3. Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a, M1b or M1c AJCC 8th edition).
4. ECOG performance status of 0-1.
5. Able to swallow and retain oral medication.
6. Presence of a BRAFV600E mutation in lung cancer tissue as determined by a local laboratory assay.
7. 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 8 to 15 unstained slides of analyzable tissue.
8. Patients
i) (COHORT A) who are either treatment-naïve (e.g., no prior systemic therapy for advanced/metastatic disease),
ii) (COHORT B) who have received 1) first-line platinum-based chemotherapy OR 2) first-line treatment with an anti-PD-1/L-1 inhibitor given alone or in combination with platinum-based 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), and present with new lesions or evidence of disease recurrence (e.g., metastatic disease), within 12 months of completing chemotherapy, 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.
9. Presence of measurable disease based on RECIST v1.1.
10. 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).
11. Adequate hepatic and renal function characterized by the following at screening:
i) Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL; 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.
12. Female patients of childbearing potential as described in Appendix 1, must have a negative serum β HCG test result.
13. 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.
14. 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 or until 6 months after the last dose of docetaxel.
15. Patient covered by a national health insurance |
|
| E.4 | Principal exclusion criteria |
1. Patients with nonsquamous carcinoma who have documentation of any of the following: EGFR mutation, ALK fusion oncogene or ROS1 rearrangement.
2. Previous treatment with any other BRAF inhibitor (e.g., dabrafenib, vemurafenib…), or any other MEK inhibitor (e.g., trametinib, cobimetinib…) prior to screening and enrolment.
3. Previous treatment with docetaxel for Cohorte B
4. Patients who have received more than 1 prior line of systemic therapy in the advanced/metastatic setting for Cohorte B.
5. 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, or antineoplastic biologic therapy (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.
6. Patients who have had major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment.
7. 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.
8. Current use of a prohibited medication (including herbal medications, supplements, or foods), or use of a prohibited medication ≤1 week prior to the start of study treatment.
9. 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).
10. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
i) History of acute 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.
11. 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 does not result in hemodynamic instability are allowed to enrol as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled.
12. 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.
13. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
14. Evidence of active, noninfectious pneumonitis, history of interstitial lung disease that required oral or intravenous glucocorticoid steroids for management.
15. 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.
16. Patient who has a known history of a positive test for HIV or known AIDS.
17. Active infection requiring systemic therapy.
18. Patients with symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases are not eligible.
19. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• 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.
• DCR defined as the proportion of patients have 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.
• PFS 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.
• 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.
• TTP, 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.
• 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.
• OS defined as the time from the date of first dose of study drug to the date of death due to any cause
• 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.
• 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.
• Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) at all scheduled time points. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| One randomised open cohort and one open label cohort with one arm |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 50 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 6 months after the last visit of the last treated patient to be sure that all the objectives will be study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
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