| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF V600E-mutant Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small Cell Lung Cancer |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC as measured by ORR |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC as measured by DOR, DCR, PFS and TRR
- To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC with respect to OS
- To evaluate the safety and tolerability of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent. Adult patients under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations.
2. Age ≥ 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a, M1b, M1c- AJCC 8th edition).
4. Presence of a BRAFV600E mutation in tumor tissue or blood (e.g., ctDNA genetic testing) as determined by a local laboratory assay. Other
Class 1 BRAFv600 mutations (e.g., K or D) will be permitted with prior discussion with the Sponsor.
5. The Investigator must obtain prior to enrollment that the patient has adequate tumor tissue for submission to a central laboratory for confirmation of BRAFV600 mutation status
6. Patients who are either treatment-naïve (e.g., no prior systemic therapy for advanced/metastatic disease), OR who have received 1) first-line platinum-based chemotherapy OR 2) first-line treatment with an anti-PD-1/PD-L1 inhibitor given alone or in combination with platinum-based chemotherapy, or in combination with immunotherapy (e.g., ipilimumab) with or without given alone or in combination with platinum-based chemotherapy.
7. Presence of measurable disease based on RECIST v1.1.
8. ECOG performance status of 0 or 1.
9. Adequate bone marrow function characterized by the following at screening: a. ANC ≥ 1.5 × 109/L;
b. Platelets ≥ 100 × 109/L;
c. Hemoglobin ≥ 8.5 g/dL (with or without blood transfusions).
10. Adequate hepatic and renal function characterized by the following at screening: a. Total bilirubin ≤ 1.5 × ULN ; b. ALT and AST ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases; c. 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.
11. Able to swallow, retain and absorb oral medications.
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
13. Female patients of childbearing potential as described in Appendix 1, must have a negative serum β-HCG test result. 14. 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. 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.
15. 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 study drug. |
|
| E.4 | Principal exclusion criteria |
1. Patients who have documentation of any of the following: EGFR mutation, ALK fusion oncogene or ROS1 rearrangement.
2. Patients who have received more than 1 prior line of systemic therapy in the advanced/metastatic setting. Prior therapies can be reviewed with the Array Medical Monitor.
3. Previous treatment with any BRAF inhibitor (e.g., dabrafenib, vemurafenib, XL281/BMS-908662, etc.), or any MEK inhibitor (e.g., trametinib, cobimetinib, selumetinib, RDEA119, etc.) prior to screening and enrollment.
4. Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study treatment: a. ≤ 14 days for chemotherapy, targeted small-molecule therapy, radiation therapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib, crizotinib, bevacizumab, etc.). b. ≤ 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), enrollment before the fifth half-life requires medical monitor approval.
c. Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.
5. Patients who have had major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment.
6. Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study treatment.
7. Current use of a prohibited medication (including herbal medications, supplements or foods), as described in Section 6.5.2, or use of a prohibited medication ≤ 1 week prior to the start of study treatment.
8. 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).
9. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
a. 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;
b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
c. LVEF < 50% as determined by MUGA or ECHO;
d. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite optimal therapy;
e. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
f. Triplicate average baseline QTcF interval ≥ 480 ms or a history of prolonged QT syndrome.
10. 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.
11. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
12. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
13. Evidence of active, noninfectious pneumonitis or history of interstitial lung disease.
14. Evidence of HBV or HCV infection.
15. Known history of a positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally.
16. Active infection requiring systemic therapy.
17. Patients with symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases are not eligible.
18. 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 cancer ≤ 6 prostate cancer. Patients with a
history of other curatively treated cancers must be reviewed with the Sponsor prior to entering the study.
19. Known sensitivity or contraindication to any component of study treatment (binimetinib and encorafenib), or their excipients.
20. Pregnancy or breastfeeding or patients who plan to become pregnant during the duration of the study.
21. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• ORR defined as the proportion of patients who have achieved a confirmed best overall response (CR or PR) as determined by IRR per RECIST v1.1 in the treatment-naïve setting
• ORR defined as the proportion of patients who have achieved a confirmed best overall response (CR of PR) as determined by IRR per RECIST v1.1 in the previously treated setting
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the time of review of radiographic disease assessments per RECIST v1.1 |
|
| E.5.2 | Secondary end point(s) |
• Confirmed ORR by Investigator per RECIST v1.1
• DOR (by IRR and by Investigator) defined as the time from the date of the first documented response (CR or PR) that is subsequently confirmed (by IRR and by Investigator, respectively) to the earliest date of disease progression, per RECIST v1.1, or death due to any cause
• DCR (by IRR and by Investigator), defined as the proportion of patients who have a confirmed CR or confirmed PR, or SD per RECIST v1.1
• PFS (by IRR and by Investigator), defined as the time from the date of first dose of study drug to the earliest date of disease progression, per RECIST v1.1, or death due to any cause
• TRR (by IRR and by Investigator), defined as the time from the date of first dose to the first documentation of objective response (CR or PR) which is subsequently confirmed (by IRR and by Investigator, respectively)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) At the time of review of radiographic disease assessments per RECIST v1.1, or death due to any cause
b) At the time of review of radiographic disease assessments per RECIST v1.1
c) At the time of review of radiographic disease assessments per RECIST v1.1, or death due to any cause
d) date of death due to any cause
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Italy |
| Netherlands |
| Spain |
|
| 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
|
| The end of study will occur 2 years after treatment initiation of the last enrolled patient or the point at which all patients have died or withdrawn consent or have been lost to follow up, whichever occurs first. At the end of the study, access to study treatment will be provided in accordance with applicable regulations and requirements to all patients who have not met the protocol-defined criteria for treatment withdrawal. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
