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

Metastatic Melanoma Clinical Trial

— EBRAIN-MEL  

Official title:

Phase II, Multicentre Clinical Trial to Evaluate the Activity of Encorafenib and Binimetinib Administered Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03898908
• Other study ID #: GEM-1802
• Secondary ID: 2018-002530-20
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 18, 2019
• Est. completion date: October 10, 2023

Study information

• Verified date: July 2023
• Source: Grupo Español Multidisciplinar de Melanoma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: October 10, 2023
• Est. primary completion date: October 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Melanoma
• Metastatic Melanoma
• Neoplasm Metastasis

Intervention

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

Radiation:
• Whole brain radiation therapy
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.
• Radiosurgery/stereotactic radiosurgery
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.

Locations

Country	Name	City	State
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Quirón Dexeus	Barcelona	Cataluña
Spain	Institut Català d'Oncología Hospitalet	Barcelona	Barcelona, Spain
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	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 Lucus Augusti	Lugo
Spain	H. U. Gregorio Marañón	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Regional Universitario de Málaga	Málaga
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Baleares
Spain	Clínica Universidad de Navarra	Pamplona
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Miguel Servet	Zaragoza

Sponsors (3)

Lead Sponsor	Collaborator
Grupo Español Multidisciplinar de Melanoma	MFAR, Pierre Fabre Medicament

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Intracranial objective response by RECIST 1.1 before local radiotherapy treatment in cohort 1	iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment in cohort 1. The final statistical analysis of this endpoint is expected to be performed within 3 months after the local treatment of the last patient in cohort 1. This outcome will be assessed on day 56, and every 8 weeks up to 24 months after start of treatment	24 months after start of treatment
Secondary	Intracranial objective response by RECIST 1.1 before local radiotherapy treatment in cohort 2	ORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment in cohort 1. The final statistical analysis of this endpoint is expected to be performed within 3 months after the local treatment of the last patient in cohort 2. This outcome will be assessed on day 56, and every 8 weeks up to 24 months after start of treatment	24 months after start of treatment
Secondary	Global intracranial response in both cohorts		24 months
Secondary	Duration of intracranial response in both cohorts		24 months
Secondary	Duration of global response in both cohorts		24 months
Secondary	Intracranial progression-free survival (PFS) by RECIST 1.1 in both cohorts		24 months
Secondary	Global (intracranial and extracranial) progression-free survival in both cohorts		24 months
Secondary	Percentage of patients free of progression (intracraneal and extracraneal)		24 months
Secondary	Overall survival in both cohorts		24 months
Secondary	Percentage of patients alive in both cohorts		24 months
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 until local treatment in both cohorts		24 months
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 after local treatment in both cohorts		24 months
Secondary	Change on Quality of life at week 8 in both cohorts based on the EORTC QLQ 30 scale	Compared to baseline evaluation evaluated after 8 weeks since the start of treatment	8 weeks
Secondary	Change on Quality of life at week 24 in both cohorts based on the EORTC QLQ 30 scale	Compared to baseline evaluation evaluated after 24 weeks since the start of treatment	24 weeks