Encorafenib and Binimetinib Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

NCT03898908 | Completed Phase 2 Results DMC

• 2 other identifiers: GEM-18022018-002530-20
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 21

Brief Summary

Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.

Conditions

Metastatic Melanoma; Brain Metastases

Keywords

metastases; melanoma; encorafenib; binimetinib

Outcome Measures

Primary Outcomes (1)

• Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset

  iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.

  24 months after start of treatment

Secondary Outcomes (10)

• Duration of Intracranial Response

  Throughout the study period, up to approximately 24 months

• Intracranial Progression-free Survival (iPFS) by RECIST 1.1

  Throughout the study period, up to approximately 24 months

• Extracranial Progression-free Survival (ePFS) in Both Cohorts

  Throughout the study period, up to approximately 24 months

• Intracranial Progression-free Rates

  at 6 months (week 24), 12 months (week 48) and 24-month (week 96)

• Overall Survival

  Throughout the study period, up to approximately 24 months

Study Arms (1)

COMBO450

EXPERIMENTAL

Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.

Drug: encorafenib; Drug: binimetinib; Radiation: Whole brain radiation therapy; Radiation: Radiosurgery/stereotactic radiosurgery

Interventions

encorafenib DRUG

Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment. If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.

Also known as: Braftovi

COMBO450

binimetinib DRUG

Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.

Also known as: Mektovi

COMBO450

Whole brain radiation therapy RADIATION

The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.

COMBO450

Radiosurgery/stereotactic radiosurgery RADIATION

Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures. Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy. For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.

COMBO450

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 of approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities.
• Histologically confirmed diagnosis of unresectable metastatic cutaneous melanoma, or unknown primary melanoma with one or more brain metastasis with a diameter of 10 to 50 mm, measured by contrast enhanced MRI.
• Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue.
• Barthel Index of Activities of Daily Living \> 10.
• Subjects aged ≥ 18 years.
• ECOG 0-1 in asymptomatic patients (cohort 1), 0-2 in symptomatic patients (cohort 2).
• Adequate haematological function (Haemoglobin ≥ 9 g/dL, may have been transfused; Platelet count ≥ 100 × 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).
• Evidence of at least one measurable lesion as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
• Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for unresectable locally advanced or metastatic melanoma, but it must have ended at least 6 weeks prior to randomization; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), BRAF or MEK inhibitors can be used in the adjuvant setting, providing the relapse does not occur during the adjuvant treatment or within 12 months after the end of it, and providing the adjuvant treatment with targeted therapy did not cause in the patient any grade 3-4 toxicity not including medically serious and reversible/controlled toxicities (ex: GGT elevation, CPK elevation, vomiting).
• Steroids or anticonvulsants are allowed if clinically needed and are not being administered in an increasing dose.
• Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
• Normal functioning of daily living activities.
• Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures.

You may not qualify if:

• Uveal or mucosal melanoma.
• History of leptomeningeal metastases, with the exception that they are only seen in brain MRI and the patient has ECOG 0-1 and no neurological symptoms (except for cohort 2, where symptomatic patients will be allowed if ECOG is 0-2).
• Another cancer in the last five years, except for in situ carcinoma of the cervix or squamous cell carcinoma of the skin adequately treated or limited basal cell skin cancer adequately controlled.
• History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease (RDD).
• Any previous systemic chemotherapy treatment, extensive brain radiotherapy, targeted therapy for locally advanced unresectable or metastatic melanoma; Immunotherapy treatment is allowed but must have ended at least 6 weeks prior to randomization.
• History of Gilbert's syndrome.
• Previous treatment with a BRAF or MEK inhibitor in metastatic setting. This treatment will be allowed in the adjuvant setting (see above). Previous treatments with immunotherapy will be allowed in both the metastatic and adjuvant setting.
• Known positive serology for human immunodeficiency virus, or an active hepatitis B or hepatitis C infection, or both.
• Impaired cardiovascular function or clinically significant cardiovascular diseases "Clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), a LVEF \< 50% evaluated by MUGA or echocardiography, or serious cardiac arrhythmia requiring medication or a triplicate average baseline QTc interval \> 500 ms."
• Uncontrolled arterial hypertension despite medical treatment.
• Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment.
• Impairment of gastrointestinal function.
• Neuromuscular disorders associated with high concentrations of creatine kinase.
• Pregnant or nursing (lactating) women.
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study.

Sponsors & Collaborators

• Grupo Español Multidisciplinar de Melanoma: lead
• Pierre Fabre Medicament: collaborator
• MFAR: collaborator

Study Sites (21)

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Location

Institut Català d'Oncología Hospitalet

Barcelona, Barcelona, Spain, 08908, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, Spain

Location

Hospital Universitario Quirón Dexeus

Barcelona, Catalonia, Spain

Location

Complejo Hospitalario Universitario Insular de Canarias

Las Palmas de Gran Canaria, Las Palmas, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

El Palmar, Murcia, 30120, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Spain

Location

Hospital Lucus Augusti

Lugo, 27003, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

H. U. Gregorio Marañón

Madrid, Spain

Location

Hospital Clínico San Carlos

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Hospital Regional Universitario de Málaga

Málaga, Spain

Location

Clínica Universidad de Navarra

Pamplona, Spain

Location

Hospital Universitario Virgen Macarena

Seville, Spain

Location

Hospital General Universitario de Valencia

Valencia, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, Spain

Location

Hospital Miguel Servet

Zaragoza, Spain

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms; Neoplasm Metastasis

Interventions

encorafenib; binimetinib; Radiosurgery

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; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: GEM Technical Secretary
• Organization: Grupo Español Multidisciplinar en Melanoma (GEM)

secretaria@groupgem.es

0034934344412

Study Officials

• Iván Márquez Rodaz, M.D.

  Hospital General Universitario Gregorio Marañón

  STUDY CHAIR

• Alfonso Berrocal Jaime, M.D.

  Hospital Universitario General de Valencia

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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: Cohort 1 will include patients with asymptomatic brain metastases and without previous local treatment in the brain (N=48), while cohort 2 will include patients with symptomatic brain metastasis and without previous local treatment in the brain (N=15).

Study Record Dates

• First Submitted: March 27, 2019
• First Posted: April 2, 2019
• Study Start: July 18, 2019
• Primary Completion: October 10, 2022
• Study Completion: July 31, 2023
• Last Updated: May 21, 2025
• Results First Posted: May 13, 2025

Record last verified: 2025-05

Locations

ES (21)