A study comparing combination of Encorafenib + Binimetinib in Patients with BRAF V600-mutant Non-small Cell Lung Cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Aug 2019 → 3 Oct 2025

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc., 66 Hudson Boulevard East, New York, NY 10001, USA

External identifiers

EU CT number

2024-515929-28-00

EudraCT number

2019-000417-37

ClinicalTrials.gov

NCT03915951

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenetic, Efficacy, Safety, Pharmacokinetic

To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC as measured by ORR

Secondary objectives 3

1. To evaluate the efficacy of encorafenib + binimetinib in treatmentnaïve and previously treated patients with BRAFV600E-mutant NSCLC as measured by DOR, DCR, PFS, and TTR
2. To evaluate the efficacy of encorafenib + binimetinib in treatmentnaïve and previously treated patients with BRAFV600E-mutant NSCLC with respect to OS
3. To evaluate the safety and tolerability of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600Emutant NSCLC.

Conditions and MedDRA coding

Non-small Cell Lung Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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 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 ×10^9/L; b. Platelets ≥ 100 × 10^9/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.

Exclusion criteria 21

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.
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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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
2. 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

Secondary endpoints 5

1. Confirmed ORR by Investigator per RECIST v1.1
2. 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
3. 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
4. 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.
5. TTR (by IRR and 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 5

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications