Encorafenib and biNimetinib Followed by CEmiplimab and FiAnLimab in Patients With BRAF Mutant melanOma and Symptomatic Brain Metastases

Inclusion Criteria:

Patients eligible for inclusion in this study must meet all the following criteria:

• Written informed consent approved by the Independent Ethics Committee (IEC), priorto 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 50mm, measured by contrast enhanced MRI.

• Patients with brain metastasis that debut as symptomatic, regardless ofcorticosteroid use. The definition of symptoms will be:

1. Any symptom related with intracranial hypertension, providing the patient hasan Eastern cooperative Oncology Group performance status (ECOG PS) 0-2 and theother inclusion and exclusion criteria are met.

2. Any symptom related to focal neurologic deficit.

3. Epilepsy Note: Patients could have or not these symptoms controlled withcorticosteroids 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:

1. Haemoglobin ≥ 9 g/dL (may have been transfused).

2. Platelet count ≥ 75 × 109/L.

3. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.

• Adequate hepatic function defined by a total bilirubin level ≤ 2.0 × the upper limitof normality (ULN) and AST and ALT levels ≤ 2.5 × ULN; or AST and ALT levels ≤ 5 xULN (for subjects with documented metastatic disease to the liver).

• Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min accordingto 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:

1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments

2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levelsin the postmenopausal range

3. Radiation induced oophorectomy with last menses >1 year ago

4. Chemotherapy induced menopause with >1 year interval since last menses

5. Surgical sterilization (bilateral oophorectomy or hysterectomy)

6. Women <50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the post-menopausal range for the institution or underwent surgicalsterilization (bilateral oophorectomy or hysterectomy)

7. Women ≥50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, or underwent surgical sterilization (bilateral oophorectomy, bilateralsalpingectomy or hysterectomy).

• Male study participants with WOCBP partners are required to use condoms duringthe study and until 6 months after the last dose of study treatment unless theyare vasectomized or practice sexual abstinence.

• WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction 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 afterreceiving the last therapy dose.

• Willingness and ability to attend scheduled visits, follow the treatmentschedule and undergo clinical tests and other study procedures.

Exclusion Criteria:

Patients meeting any of the following criteria are excluded from the study:

• Uveal melanoma.

• History of leptomeningeal metastases unless they are a finding in the Brain MRI thatdoes not explain the main neurological symptoms of the patient, according tophysician criteria.

• Another non-cured cancer in the last 2 years, except for in situ carcinoma of thecervix, breast, prostate or squamous cell carcinoma of the skin adequately treatedor limited basal cell skin cancer adequately controlled. Patients with cured cancershould be free of any adjuvant treatment (i.e chemotherapy or targetedtherapy/monoclonal antibodies) with the exception of hormonal therapy for completedcured localized breast cancer or localized prostate cancer.

• History of allogeneic organ transplant.

• History of or current evidence of central serous retinopathy (CSR), retinal veinocclusion (RVO) or history of retinal degenerative disease (RDD).

• History of interstitial lung disease.

• Systemic immunotherapy treatment for melanoma would be allowed only in theadjuvant/neoadjuvant setting (regardless if the brain relapse was during or afterthat) providing that ALL the following criteria are met:

1. The immunotherapy regimen did not contain anti LAG-3 treatment.

2. Patient did not have brain metastases (whether they were symptomatic orasymptomatic) prior to this adjuvant/neoadjuvant immunotherapy setting.

3. Patient was treated with adjuvant/neoadjuvant for at least 6 months.

4. No other treatments different than the one in adjuvant/neoadjuvant beforesymptomatic brain metastases were applied.

5. Patient did not discontinue immunotherapy due to related adverse events.

• Targeted therapy against BRAF and/or MEK will not be allowed in any setting,including adjuvant.

• Chemotherapy will not be allowed in any setting.

• Patients in the need of urgent brain surgery before inclusion. However, patients areallowed to enter in the clinical trial after brain surgery, providing they meet therest of inclusion and exclusion criteria, especially having at least one measurablelesion as per modified RECIST criteria after this surgery.

• Brain radiotherapy will not be allowed before entering the clinical trial. Patientscan receive brain radiotherapy during the clinical trial, if they progress into thebrain, as per institutional guidelines ONLY if (must fulfill the three):

1. They have received at least TWO doses of cemiplimab and fianlimab AND

2. The event of an intracranial progressive disease happens during cemiplimab andfianlimab AND

3. They comply to receive encorafenib and binimetinib as rechallenge. Encorafeniband binimetinib should be stopped 24h before, during and 24h afterradiotherapy.

• History or current evidence of significant (CTCAE grade ≥2) local or systemicinfection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotictreatment within 2 weeks prior to the first dose of trial medication.

• Active infection requiring therapy.

• Ongoing or recent (within 2 years) evidence of an autoimmune disease that requiredsystemic treatment with immunosuppressive agents. The following arenon-exclusionary: vitiligo, childhood asthma that has resolved, residualhypothyroidism that requires only hormone replacement, psoriasis not requiringsystemic treatment.

• Uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis ofimmunodeficiency that is related to, or results in chronic infection.

Notes:

1. Patients with known HIV who have controlled infection (undetectable viral load andCD4 count above 350 either spontaneously or on a stable antiviral regimen) arepermitted. For patients with controlled HIV infection, monitoring will be performedper local standards.

2. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serumhepatitis B virus DNA PCR that is below the limit of detection AND receivinganti-viral therapy for hepatitis B) are permitted. Patients with controlledinfections must undergo periodic monitoring of HBV DNA per local standards and mustremain on anti-viral therapy for at least 6 months beyond the last dose ofinvestigational study drug.

3. Patients who are known hepatitis C virus antibody positive (HCV Ab+) who havecontrolled infection (undetectable HCV RNA by PCR either spontaneously or inresponse to a successful prior course of anti-HCV therapy) are permitted.

4. Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg,infectious disease or hepatologist) managing this disease prior to commencing andregularly throughout the duration of their participation in the trial.

• Impaired cardiovascular function or clinically significant (i.e., active)cardiovascular diseases such as: cerebrovascular accident/stroke (< 6 monthsprior to enrolment), myocardial infarction (< 6 months prior to enrolment),unstable angina, congestive heart failure (≥ New York Heart AssociationClassification Class II), a LVEF < 50% evaluated as per institutionalguidelines, or serious cardiac arrhythmia requiring medication or a triplicateaverage baseline QTc interval > 500 ms, history of myocarditis.

Note: Patients not fulfilling these cardiovascular criteria can be consulted to medical monitor and coordinating investigator for a case by case examination.

• TnT or troponin I TnI > 2x institutional ULN at baseline. Note: Patients with TnT orTnI levels between > 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are > 1 to 2x ULN within 24 hours, the subject mayundergo a cardiac evaluation and be considered for treatment by the investigatorbased on the medical judgment in the patient's best interest.

• Uncontrolled arterial hypertension despite medical treatment.

• Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment.

• Impairment of gastrointestinal function. Inability to swallow tablets or capsules.

• Neuromuscular disorders associated with high concentrations of creatine kinase.

• Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 14 weeks (28 days)prior to the first dose of trial treatment, other than steroids required for brainmetastasis symptoms control.

• History of pneumonitis within the last 5 years.

• Active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis).

• Medical, psychiatric, cognitive or other conditions that may compromise thepatient's ability to understand the patient information, give informed consent,comply with the study protocol or complete the study.

• Known hypersensitivity to the active substances or to any of the excipients.

• Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 5.0; however,alopecia and sensory neuropathy Grade ≤ 2 is acceptable.

• Have received a live vaccine within 30 days of planned start of study therapy. Note:Live or live attenuated vaccination with replicating potential. If a patient intendsto receive a COVID-19 vaccine before the start of study drug, participation in thestudy should be delayed at least 1 week after any COVID-19 vaccination. During thetreatment period, it is recommended to delay COVID-19 vaccination until patients arereceiving and tolerating a steady dose of study drug. A vaccine dose should not beless than 48 hours before or after study drug dosing.

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ highly effective birth controlfrom screening to 6 months after the last dose of study treatment.

• Known alcohol or drug abuse.

• Participation in any interventional drug or medical device study within 30 daysprior to treatment start.

• Total lactase deficiency or glucose-galactose malabsorption.