Clinical trial NCT03898908: Encorafenib and Binimetinib Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Melanoma
Brain Metastases
Keywords: metastases
melanoma
encorafenib
binimetinib
Lead sponsor: Grupo Español Multidisciplinar de Melanoma
Sponsor class: OTHER
Collaborators: name: Pierre Fabre Medicament
name: MFAR
First posted: 2019-04-02
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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).
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
timeFrame: 24 months after start of treatment
Secondary outcomes:
measure: Duration of Intracranial Response
timeFrame: Throughout the study period, up to approximately 24 months
measure: Intracranial Progression-free Survival (iPFS) by RECIST 1.1
timeFrame: Throughout the study period, up to approximately 24 months
measure: Extracranial Progression-free Survival (ePFS) in Both Cohorts
timeFrame: Throughout the study period, up to approximately 24 months
measure: Intracranial Progression-free Rates
timeFrame: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
measure: Overall Survival
timeFrame: Throughout the study period, up to approximately 24 months
measure: Overall Survival Rates
timeFrame: at 6 months, 12 month and 24-month
measure: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
timeFrame: Throughout the study period, up to approximately 24 months
measure: Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale
timeFrame: 8 weeks
measure: Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale
timeFrame: 24 weeks
measure: Extracranial Progression-free Rates
timeFrame: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
Other outcomes:
Locations:
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Baleares
city: Barcelona
country: Spain
facility: Institut Català d'Oncología Hospitalet
state: Barcelona, Spain
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Barcelona
country: Spain
facility: Hospital Universitario Quirón Dexeus
state: Cataluña
city: Las Palmas de Gran Canaria
country: Spain
facility: Complejo Hospitalario Universitario Insular de Canarias
state: Las Palmas
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Lugo
country: Spain
facility: Hospital Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: H. U. Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
affiliation: Hospital General Universitario Gregorio Marañón
name: Iván Márquez Rodaz, M.D.
role: STUDY_CHAIR
affiliation: Hospital Universitario General de Valencia
name: Alfonso Berrocal Jaime, M.D.
role: STUDY_CHAIR
References: