Encorafenib and biNimetinib Followed by CEmiplimab and FiAnLimab in Patients With BRAF Mutant melanOma and Symptomatic Brain Metastases

NCT06887088 | Recruiting Phase 2 DMC

• 2 other identifiers: GEM-23012024-513375-40-00
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 18

Brief Summary

Brain metastases in patients with advanced and metastatic melanoma are a frequent complication and a significant cause of morbidity and mortality in this patient population. As the incidence of brain metastases continues to increase in patients with metastatic melanoma, it is urgent that the investigators identify effective therapies. ENCEFALO is a Phase II, single arm, multicentre clinical trial designed to evaluate the activity of encorafenib plus binimetinib followed by cemiplimab and fianlimab in patients with BRAF mutated melanoma and symptomatic brain metastases, following the simon design Two-stage minimax. The objective main is to evaluate the 6 month intracranial progression-free survival (icPFS) proportion of Encorafenib plus Binimetinib followed by Cemiplimab plus Fianlimab in patients with BRAF-mutated melanoma and symptomatic brain metastases according RECIST criteria The trial hypothesis is: For patients with BRAF-mutated melanoma and symptomatic brain metastases, an induction treatment with encorafenib and binimetinib (EB) for about two months (i.e. 8 weeks) followed by cemiplimab plus fianlimab (CF) would allow a 6 month icPFS rate of 40% in comparison to historical control of 20% based on CM204 symptomatic arm (Tawbi et al 2021).

Conditions

Melanoma BRAF V600E/K Mutated; Melanoma and Brain Metastases

Keywords

Melanoma; Encorafenib; Binimetinib; Cemiplimab; Fianlimab; BRAF mutant

Outcome Measures

Primary Outcomes (1)

• intracranial progression-free survival (icPFS) follow-up

  Contrast enhanced brain MRI and/or color digital photography will be performed baseline and every 8 weeks (+/-1 week) up to 12 months and according to standard practice thereafter until disease progression, independently of the end of treatment (except for documentation of disease progression).

  Throughout the study period, at 12 months from the start of treatment

Secondary Outcomes (5)

• Extracraneal PFS (ecPFS) follow-up

  Throughout the study period, at 12 months from the start of treatment

• Overall survival (OS)

  Throughout the study period, at 6, 12 and 24 months from start of treatment

• Barthel index follow-up

  Throughout the study period, at weeks 8 and 24 after the start of study treatment.

• Adverse events (AE)

  Throughout the study period, at 24 month from start treatment

• Serious adverse events (SAEs) assessment

  Throughout the study period, at 24 month from start treatment

Study Arms (1)

Encorafenib+biNimetinib followed Cemiplimab+Fianlimab in BRAF mutated melanoma and brain metastses

EXPERIMENTAL

Patients with BRAF mutant melanoma and symptomatic brain metastases will treatment with encorafenib plus binimetinib followed by cemiplimab and fianlimab Induction treatment with oral encorafenib 450 mg once daily (QD) + binimetinib 45 mg twice daily (BID)(combination: EB) for approximately two months (i.e. 8 weeks) followed by cemiplimab 350 mg + fianlimab 1600 mg combination every 3 weeks (Q3W)(Combination: CF) administered to patients intravenously (IV) for up to two years. Treatment may be discontinued due to death, PD or non-acceptable toxicity. Encorafenib plus binimetinib should be discontinued at least 72 hours prior to the first dose of cemiplimab plus fianlimab. Rechallenge with encorafenib 450mg QD + binimetinib 45 mg BID will be mandatory for those patients that progress under CF, with the exception of patients with intracranial response or stabilization and only extracranial PD in which case CF could be continued at the physician criteria. In the case of continuing treat

Drug: Encorafenib + Binimetinib; Drug: cemiplimab+fianlimab

Interventions

Encorafenib + Binimetinib DRUG

Induction treatment with oral encorafenib 450 mg once daily (QD) + binimetinib 45 mg twice daily (BID)(combination: EB) for approximately two months (i.e. 8 weeks)

Encorafenib+biNimetinib followed Cemiplimab+Fianlimab in BRAF mutated melanoma and brain metastses

cemiplimab+fianlimab DRUG

cemiplimab 350 mg + fianlimab 1600 mg combination every 3 weeks (Q3W)(Combination: CF) administered to patients intravenously (IV) for up to two years.

Encorafenib+biNimetinib followed Cemiplimab+Fianlimab in BRAF mutated melanoma and brain metastses

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
• Histologically confirmed diagnosis of unresectable metastatic BRAF-mutated melanoma (stage IV, AJCC v9), with one or more brain metastases with a diameter of 5 to 50 mm, measured by contrast enhanced MRI.
• Patients with brain metastasis that debut as symptomatic, regardless of corticosteroid use. The definition of symptoms will be:

You may not qualify if:

• Any symptom related to focal neurologic deficit.
• A documented mutation in BRAF-V600 in the tumor tissue.
• Modified Barthel Index of Activities of Daily Living \> 10 (see Appendix 5).
• Subjects aged ≥ 18 years.
• Performance status ECOG PS 0-2 (see Appendix 7).
• Able to swallowing
• Adequate hematologic function:
• Haemoglobin ≥ 9 g/dL (may have been transfused).
• Platelet count ≥ 75 × 109/L.
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
• Adequate hepatic function defined by a total bilirubin level ≤ 2.0 × the upper limit of normality (ULN) and AST and ALT levels ≤ 2.5 × ULN; or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
• Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
• Immunotherapy allowed if administered in the adjuvant/neoadjuvant setting, any grade 3-4 prior toxicity must be resolved to grade 0 or at baseline levels.
• Steroids or anticonvulsants are allowed if clinically needed. No dose limit of steroids is pre-specified as long as they are not in an increasing dose for the last 5 days prior to start of study treatment.
• \- Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to Appendix 8) for the duration of the study treatment and for 6 months after the last dose of study treatment.

Sponsors & Collaborators

• Grupo Español Multidisciplinar de Melanoma: lead
• Regeneron Pharmaceuticals: collaborator
• MFAR: collaborator
• Pierre Fabre Laboratories: collaborator

Study Sites (18)

Complejo Hospitalario Universitario A Coruña

A Coruña, A Coruña, 15006, Spain

RECRUITING

Quiron Dexeus - IOR

Barcelona, Barcelona, 08028, Spain

RECRUITING

Hospital Universitario Vall d´Hebron

Barcelona, Barcelona, 08035, Spain

RECRUITING

Hospital Clínic de Barcelona

Barcelona, Barcelona, 08036, Spain

RECRUITING

Instituto Catalán de Oncología - Hospital Duran i Reynals

Barcelona, Barcelona, 08908, Spain

RECRUITING

Hospital Universitario de Burgos

Burgos, Burgos, 09006, Spain

RECRUITING

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, 39008, Spain

RECRUITING

Hospital Universitario San Pedro de Alcántara

Cáceres, Cáceres, 10003, Spain

RECRUITING

Onkologikoa (Donostia)

Donostia / San Sebastian, Donostia, 20014, Spain

RECRUITING

Hospital Universitario Gregorio Marañon

Madrid, Madrid, 28007, Spain

NOT YET RECRUITING

Hospital Universitario Ramón y Cajal

Madrid, Madrid, 28034, Spain

RECRUITING

Hospital Clinico San Carlos

Madrid, Madrid, 28040, Spain

RECRUITING

Hospital Universitario Puerta del Hierro

Majadahonda, Madrid, 28222, Spain

RECRUITING

Clinico Universitario Virgen de la Arrixaca

Murcia, Murcia, 30120, Spain

RECRUITING

Hospital Regional Universitario de Málaga

Málaga, Málaga, 29010, Spain

RECRUITING

Hospital Virgen de la Macarena (Sevilla)

Seville, Sevilla, 41009, Spain

RECRUITING

Hospital Clínico Universitario Valencia.

Valencia, Valencia, 46010, Spain

RECRUITING

Hospital General Universitario de Valencia

Valencia, Valencia, 46014, Spain

RECRUITING

Related Publications (12)

• Marquez-Rodas I, Alvarez A, Arance A, Valduvieco I, Berciano-Guerrero MA, Delgado R, Soria A, Lopez Campos F, Sanchez P, Romero JL, Martin-Liberal J, Lucas A, Diaz-Beveridge R, Conde-Moreno AJ, Alamo de la Gala MDC, Garcia-Castano A, Prada PJ, Gonzalez Cao M, Puertas E, Vidal J, Foro P, Aguado de la Rosa C, Corona JA, Cerezuela-Fuentes P, Lopez P, Luna P, Aymar N, Puertolas T, Sanagustin P, Berrocal A. Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study). Neuro Oncol. 2024 Nov 4;26(11):2074-2083. doi: 10.1093/neuonc/noae116.

  PMID: 38946469 BACKGROUND

• Lau PKH, Feran B, Smith L, Lasocki A, Molania R, Smith K, Weppler A, Angel C, Kee D, Bhave P, Lee B, Young RJ, Iravani A, Yeang HA, Vergara IA, Kok D, Drummond K, Neeson PJ, Sheppard KE, Papenfuss T, Solomon BJ, Sandhu S, McArthur GA. Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES). J Immunother Cancer. 2021 Oct;9(10):e002995. doi: 10.1136/jitc-2021-002995.

  PMID: 34625515 BACKGROUND

• Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutierrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. doi: 10.1056/NEJMoa2109970.

  PMID: 34986285 BACKGROUND

• Panella TJ, Thomas SS, McKean M, et al: A phase 3 trial comparing fianlimab (anti-LAG-3) plus cemiplimab (anti-PD-1) to pembrolizumab in patients with completely resected high-risk melanoma. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS9598-TPS9598.

  BACKGROUND

• Baramidze A, Gogishvili M, Makharadze T, et al: A phase 3 trial of fianlimab (anti-LAG-3) plus cemiplimab (anti-PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS9602-TPS960

  BACKGROUND

• Hamid O, Lewis KD, Weise A, McKean M, Papadopoulos KP, Crown J, Kim TM, Lee DH, Thomas SS, Mehnert J, Kaczmar J, Lakhani NJ, Kim KB, Middleton MR, Rabinowits G, Spira AI, Yushak M, Mehmi I, Fang F, Chen S, Mani J, Jankovic V, Wang F, Fiaschi N, Brennan L, Paccaly A, Masinde S, Salvati M, Fury MG, Kroog G, Lowy I, Gullo G. Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma. J Clin Oncol. 2024 Aug 20;42(24):2928-2938. doi: 10.1200/JCO.23.02172. Epub 2024 Jun 20.

  PMID: 38900987 BACKGROUND

• Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Marquez-Rodas I, Del Vecchio M, Lebbe C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):863-873. doi: 10.1016/S1470-2045(17)30429-1. Epub 2017 Jun 4.

  PMID: 28592387 BACKGROUND

• Long GV, Atkinson V, Lo S, et al: Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol. 2021;39(15_suppl):9508-950

  BACKGROUND

• Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.

  PMID: 19942357 BACKGROUND

• Ramanujam S, Schadendorf D, Long GV. Systemic therapies for melanoma brain metastases: which drug for whom and when? Chin Clin Oncol. 2015 Jun;4(2):25. doi: 10.3978/j.issn.2304-3865.2015.06.06.

  PMID: 26112811 BACKGROUND

• Chukwueke U, Batchelor T, Brastianos P. Management of Brain Metastases in Patients With Melanoma. J Oncol Pract. 2016 Jun;12(6):536-42. doi: 10.1200/JOP.2016.011882.

  PMID: 27288470 BACKGROUND

• Tawbi HA, Forsyth PA, Hodi FS, Algazi AP, Hamid O, Lao CD, Moschos SJ, Atkins MB, Lewis K, Postow MA, Thomas RP, Glaspy J, Jang S, Khushalani NI, Pavlick AC, Ernstoff MS, Reardon DA, Kudchadkar R, Tarhini A, Chung C, Ritchings C, Durani P, Askelson M, Puzanov I, Margolin KA. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021 Dec;22(12):1692-1704. doi: 10.1016/S1470-2045(21)00545-3. Epub 2021 Nov 10.

  PMID: 34774225 BACKGROUND

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

encorafenib; binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Ivan Marquez-Rodas, M.D., Ph.D.

  Hospital General Universitario Gregorio Marañón

  STUDY DIRECTOR

Central Study Contacts

A responsible person Designated by the sponsor, M.D., PhD.

CONTACT

+34 93 434 44 12; investigacio@mfar.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: ENCEFALO is a multicentre, single arm phase II clinical trial in patients with melanoma BRAF-mutated and symptomatic brain metastases that follows Simon Two Stages Minimax design. The trial will enroll competitively up to 33 patients. The study will enroll the first 18 patients and monitor for progression at 6 months (24-weeks assessment). If there are 4 or less patients free of progression at the 6-months tumor assessment the accrual will be closed. Otherwise, a minimum of 15 additional patients will be accrued for a total of 33 evaluable patients. All patients will have a histologically confirmed diagnosis of unresectable metastatic BRAF-mutated melanoma, with one or more brain metastases with a diameter of 5 to 50 mm and symptomatology associated with the disease, defined as symptom related with intracranial hypertension or cognitive impairment. all patients will be ≥ 18 years and ECOG PS 0-2.

Study Record Dates

• First Submitted: March 14, 2025
• First Posted: March 20, 2025
• Study Start: May 29, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028
• Last Updated: October 1, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

ES (18)