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

Phase 2

Completed

Conditions: Metastatic Melanoma
Brain Metastases

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

Registration Number: NCT03898908

Lead Sponsor: Grupo Español Multidisciplinar de Melanoma

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 48

Inclusion Criteria

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.

Exclusion Criteria

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.
Known hypersensitivity to encorafenib, binimetinib or their components.
Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable.
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of study treatment.
Known alcohol or drug abuse.
Inability to swallow tablets or capsules.
Total lactase deficiency or glucose-galactose malabsorption.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
COMBO450	Radiosurgery/stereotactic radiosurgery	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.
COMBO450	Whole brain radiation therapy	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.
COMBO450	encorafenib	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.
COMBO450	binimetinib	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.

Primary Outcome Measures

Name	Time	Method
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset	24 months after start of treatment	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Intracranial Response	Throughout the study period, up to approximately 24 months	Calculated as the time from the date of first documented CR or PR to the first documented intracranial progression or death due to underlying cancer accoridng to modified RECIST 1.1, in patients with documented intracranial CR or PR before local treatment.
Intracranial Progression-free Survival (iPFS) by RECIST 1.1	Throughout the study period, up to approximately 24 months	Defined as the time from the date of inclusion to the date of the first documented intracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (modified RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Extracranial Progression-free Survival (ePFS) in Both Cohorts	Throughout the study period, up to approximately 24 months	Defined as the time from the date of inclusion to the date of the first documented extracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Intracranial Progression-free Rates	at 6 months (week 24), 12 months (week 48) and 24-month (week 96)	Proportion of patients free of intracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
Overall Survival	Throughout the study period, up to approximately 24 months	Calculated as the time from date of inclusion to date of death due to any cause.
Overall Survival Rates	at 6 months, 12 month and 24-month	Proportion of of patients alive at 6 months, 12 month and 24-month considering date of inclusion estimated using Kaplan-Meier. Patients alive at the moment of the analysis were censored on the date of their last follow-up.
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	Throughout the study period, up to approximately 24 months	Number of patients experiencing treatment related adverse events. These events were graded accrding to CTCAE, a scale that ranges from 0 (less intense; no event) to 5 (death) . Here we report the number of patients experiencing any grade toxicities and the number of patients experiencing high grade (grade 3-5) toxicities.
Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale	8 weeks	The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale	24 weeks	The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Extracranial Progression-free Rates	at 6 months (week 24), 12 months (week 48) and 24-month (week 96)	Proportion of patients free of extracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method

Trial Locations

Locations (21): Hospital Clínico Universitario Virgen de la Arrixaca
🇪🇸
El Palmar, Murcia, Spain
Complejo Hospitalario Universitario Insular de Canarias
🇪🇸
Las Palmas de Gran Canaria, Las Palmas, Spain
Hospital Clínico San Carlos
🇪🇸
Madrid, Spain
Hospital Universitario Son Espases
🇪🇸
Palma De Mallorca, Baleares, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸
Santander, Cantabria, Spain
Institut Català d'Oncología Hospitalet
🇪🇸
Barcelona, Barcelona, Spain, Spain
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Hospital Universitario Quirón Dexeus
🇪🇸
Barcelona, Cataluña, Spain
Hospital Lucus Augusti
🇪🇸
Lugo, Spain
Hospital Clínic de Barcelona
🇪🇸
Barcelona, Spain
Hospital Universitario Reina Sofía
🇪🇸
Córdoba, Spain
Hospital del Mar
🇪🇸
Barcelona, Spain
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
Clínica Universidad de Navarra
🇪🇸
Pamplona, Spain
Hospital Regional Universitario de Málaga
🇪🇸
Málaga, Spain
Hospital General Universitario de Valencia
🇪🇸
Valencia, Spain
Hospital Universitario Virgen Macarena
🇪🇸
Sevilla, Spain
Hospital Miguel Servet
🇪🇸
Zaragoza, Spain
Hospital Universitario y Politécnico La Fe
🇪🇸
Valencia, Spain
Hospital Universitario Ramón y Cajal
🇪🇸
Madrid, Spain
H. U. Gregorio Marañón
🇪🇸
Madrid, Spain