BINIMETINIB for Melanoma with brain metastases (BRAF V600 mutation-positive)

Inclusion criteria

• {"criterion_text":"- Provided written informed consent prior to any trial specific procedures.\n- At least one measurable intracranial lesion\n- All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be resolved or Grade 1 according to National Cancer Institute – Common terminology criteria for adverse events, version 5.0 (NCI-CTCAE v5.0).\n- Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption (malabsorption syndrome, major resection of the stomach or bowels).\n- Adequate bone marrow, organ function, and laboratory parameters.\n- Adequate cardiac function\n- Women of childbearing potential (WOCBP) or men must agree to refrain from sexual activity or use adequate contraception for the duration of study treatment and for 120 days after completing treatment. Male participants must agree to refrain from donating sperm during this period.\n- Affiliated to or a beneficiary of the local social security system or equivalent.\n- Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.\n- Aged ≥18 years old.\n- An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.\n- Histologically confirmed Stage IV M1d cutaneous melanoma or unknown primary melanoma that is metastatic to the brain. Patients with mucosal melanomas are not considered eligible for this study.\n- Presence of BRAFV600E/K/D/R mutation according to a locally validated BRAF Assay.\n- Candidacy for SRS therapy validated by the radiation oncologist and neurosurgeon at the investigative centre. This should be documented in the patient file.\n- Absence of previous combined systemic treatment for distant metastatic melanoma.\n- No more than one previous local intracranial therapy for one lesion (e.g. craniotomy, SRS).\n- Able to undergo gadolinium-enhanced magnetic resonance imaging (MRI)."}

Exclusion criteria

• {"criterion_text":"- More than 10 intracranial metastases.\n- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with laboratory evidence of cured HBV and/or HCV will be permitted).\n- A history or evidence of cardiovascular risk\n- A history or current evidence of retinal vein occlusion.\n- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, and their excipients.\n- Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption\n- Participation in another therapeutic trial within the 30 days prior to randomization\n- Pregnant or breastfeeeding female.\n- History of, or active interstitial lung disease or (non-infectious) pneumonitis.\n- Active, known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn’s disease (Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).\n- Diagnosis of immunodeficiency or systemic chronic steroid therapy (≥10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.\n- Presence of neurological symptoms related to intracranial metastases which induce alteration of the ECOG performance status to 2 or more or require immediate radiation treatment.\n- Has received a live vaccine within 30 days prior to the first dose of study drug.\n- Active infection requiring systemic therapy.\n- Known history of active TB (Bacillus Tuberculosis).\n- Allogenic tissue/solid organ transplant.\n- Person deprived of their liberty or under protective custody or guardianship.\n- Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, social or psychological reasons.\n- Ocular melanoma.\n- Brain metastases that necessitate immediate neurosurgery.\n- Any previous treatment with whole-brain radiation.\n- Presence of leptomeningeal disease or any parenchymal brain metastasis >30 mm in longest diameter.\n- Current or expected use of a strong inhibitor of CYP3A4.\n- History of malignancy other than disease under study occurring within 3 years of study enrolment with the exception of completely resected non-melanoma skin cancer or indolent second malignancies.\n- Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures."}

Primary endpoints

• {"endpoint_text":"- Intracranial progression-free survival defined as the time from randomisation until IC-progressive disease (PD) as evaluated by centralised assessment using modified response evaluation criteria in solid tumours version 1.1 (RECIST v1.1), or death, whichever occurs first.","definition_or_measurement_approach":"Time from randomisation until intracranial progressive disease (IC-PD) evaluated by centralised assessment using modified RECIST v1.1, or death, whichever occurs first."}

Secondary endpoints

• {"endpoint_text":"- Intracranial-response rate, defined as the percentage of patients with a confirmed IC-complete response (CR) or IC-partial response (PR) as assessed by the investigator using modified RECIST v1.1.","definition_or_measurement_approach":"Percentage of patients with confirmed IC-CR or IC-PR assessed by investigator using modified RECIST v1.1."}
• {"endpoint_text":"- Intracranial disease control, defined as the percentage of patients with an IC-CR or IC-PR or stable intracranial disease as assessed by the investigator using modified RECIST v1.1.","definition_or_measurement_approach":"Percentage of patients with IC-CR, IC-PR, or stable intracranial disease assessed by investigator using modified RECIST v1.1."}
• {"endpoint_text":"- Extracranial response rate, defined as the percentage of patients with a confirmed EC-CR or EC-PR assessed by the investigator using RECIST v1.1.","definition_or_measurement_approach":"Percentage of patients with confirmed EC-CR or EC-PR assessed by investigator using RECIST v1.1."}
• {"endpoint_text":"- Overall response rate, defined as the percentage of patients with a confirmed CR or PR as assessed by the investigator using modified RECIST v1.1 to assess IC-response and RECIST v1.1 for EC-response.","definition_or_measurement_approach":"Percentage of patients with confirmed CR or PR; IC-response assessed by modified RECIST v1.1 and EC-response by RECIST v1.1."}
• {"endpoint_text":"- Duration of intracranial, extracranial, and overall response, defined as the time from first observation of, IC-, EC-, or overall response respectively (i.e. CR or PR), until PD according to modified RECIST v1.1 (intracranial disease) or RECIST v1.1 (extracranial disease) or death, whichever occurs first.","definition_or_measurement_approach":"Time from first documented response (CR or PR) to PD per modified RECIST v1.1 for intracranial disease or RECIST v1.1 for extracranial disease, or death."}
• {"endpoint_text":"- Duration of response of treated target lesions, defined as the time from first documented response (i.e. CR or PR) as assessed by the investigator using modified RECIST v1.1, until PD of treated target lesions or death, whichever occurs first.","definition_or_measurement_approach":"Time from first documented response (CR or PR) for treated target lesions (investigator-assessed using modified RECIST v1.1) until PD of those lesions or death."}
• {"endpoint_text":"- Progression-free survival, defined as the time from randomisation until IC-PD according to modified RECIST v1.1, EC-PD according to RECIST v1.1, as assessed by the investigator, or death, whichever occurs first.","definition_or_measurement_approach":"Time from randomisation until IC-PD per modified RECIST v1.1, EC-PD per RECIST v1.1 (investigator-assessed), or death."}
• {"endpoint_text":"- Overall survival, defined as the time from randomisation until death due to any cause.","definition_or_measurement_approach":"Time from randomisation until death from any cause."}
• {"endpoint_text":"- Health Related Quality of Life assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ-C30 and BN20).","definition_or_measurement_approach":"HRQOL assessed using EORTC QLQ-C30 and BN20 questionnaires."}
• {"endpoint_text":"- Cognitive performance assessed using the Montreal Cognitive Assessment (MoCA).","definition_or_measurement_approach":"Cognitive performance assessed using the Montreal Cognitive Assessment (MoCA)."}
• {"endpoint_text":"- Frequency and severity of adverse events assessed according to NCI-CTCAE v5.0.","definition_or_measurement_approach":"Adverse events frequency and severity graded per NCI-CTCAE v5.0."}
• {"endpoint_text":"- Other skin, laboratory, vital-sign, cardiac function, and neurological assessment data.","definition_or_measurement_approach":"Collection and assessment of additional safety and clinical data (skin, labs, vitals, cardiac, neurological assessments) as described in protocol."}

France

Earliest CTIS Part Ii Submission Date

17-01-2024

Latest Decision Or Authorization Date

07-04-2025

Processing Time Days

446

Number Of Sites

11

Number Of Participants

150

Primary sponsor

Full Name

Unicancer

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"Pierre Fabre Médicament","duties_or_roles":"Monetary support","organisation_type":""}
• {"country":"","full_name":"Merck & Co. (MSD)","duties_or_roles":"Monetary support","organisation_type":""}