Phase II, Single Arm, Multicentre Clinical Trial to Evaluate the Activity of Encorafenib Plus Binimetinib Followed by Cemiplimab And Fianlimab in Patients With BRAF Mutated Melanoma and Symptomatic Brain Metastases
Brain metastases in patients with advanced and metastatic melanoma are a frequent complication and a significant cause of morbidity and mortality in this patient population. As the incidence of brain metastases continues to increase in patients with metastatic melanoma, it is urgent that the investigators identify effective therapies. ENCEFALO is a Phase II, single arm, multicentre clinical trial designed to evaluate the activity of encorafenib plus binimetinib followed by cemiplimab and fianlimab in patients with BRAF mutated melanoma and symptomatic brain metastases, following the simon design Two-stage minimax. The objective main is to evaluate the 6 month intracranial progression-free survival (icPFS) proportion of Encorafenib plus Binimetinib followed by Cemiplimab plus Fianlimab in patients with BRAF-mutated melanoma and symptomatic brain metastases according RECIST criteria The trial hypothesis is: For patients with BRAF-mutated melanoma and symptomatic brain metastases, an induction treatment with encorafenib and binimetinib (EB) for about two months (i.e. 8 weeks) followed by cemiplimab plus fianlimab (CF) would allow a 6 month icPFS rate of 40% in comparison to historical control of 20% based on CM204 symptomatic arm (Tawbi et al 2021).
• Patients eligible for inclusion in this study must meet all the following criteria:
• Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
• Histologically confirmed diagnosis of unresectable metastatic BRAF-mutated melanoma (stage IV, AJCC v9), with one or more brain metastases with a diameter of 5 to 50 mm, measured by contrast enhanced MRI.
• Patients with brain metastasis that debut as symptomatic, regardless of corticosteroid use. The definition of symptoms will be:
∙ Any symptom related with intracranial hypertension, providing the patient has an Eastern cooperative Oncology Group performance status (ECOG PS) 0-2 and the other inclusion and exclusion criteria are met.
‣ Any symptom related to focal neurologic deficit.
‣ Epilepsy Note: Patients could have or not these symptoms controlled with corticosteroids at the inclusion of the clinical trial.
• A documented mutation in BRAF-V600 in the tumor tissue.
• Modified Barthel Index of Activities of Daily Living \> 10 (see Appendix 5).
• Subjects aged ≥ 18 years.
• Performance status ECOG PS 0-2 (see Appendix 7).
• Able to swallowing
• Adequate hematologic function:
∙ Haemoglobin ≥ 9 g/dL (may have been transfused).
‣ Platelet count ≥ 75 × 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).
• Immunotherapy allowed if administered in the adjuvant/neoadjuvant setting, any grade 3-4 prior toxicity must be resolved to grade 0 or at baseline levels.
• Steroids or anticonvulsants are allowed if clinically needed. No dose limit of steroids is pre-specified as long as they are not in an increasing dose for the last 5 days prior to start of study treatment.
• \- Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to Appendix 8) for the duration of the study treatment and for 6 months after the last dose of study treatment.
• A woman is considered of childbearing potential ( i.e. fertile) following menarche and until becoming postmenopausal unless permanently sterile. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
⁃ Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments
⁃ Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the postmenopausal range
⁃ Radiation induced oophorectomy with last menses \>1 year ago
⁃ Chemotherapy induced menopause with \>1 year interval since last menses
⁃ Surgical sterilization (bilateral oophorectomy or hysterectomy)
⁃ Women \<50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
⁃ Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
∙ Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence.
‣ WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment. All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose.
‣ Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures.