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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol Multidisciplinar De Melanoma

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 May 2025 → ongoing

Decision date (initial)

2025-04-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

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.‬

Secondary objectives 2

1. ‭Secondary Efficacy Objectives‬ ‭To assess the following efficacy endpoints:‬ ‭‬ ● 12 month icPFS rate‬ ● ‭Intracraneal PFS (icPFS)‬ ● ‭Extracraneal PFS (ecPFS)‬ ‭●Global PFS (PFS)‬ ●‭Overall survival (OS)‬ ●‭Intracranial objective response rate (icORR) at 2 and 6 months‬ ●‭Extracraneal ORR (ecORR) at 2 and 6 months‬ ●‭Basal Quality of Life (QoL), at 2 and 6 months‬ ●‭Basal systemic steroids decrease at 2 and 6 months‬ ‭●Modified Barthel index improvement at 2 and 6 months‬
2. Secondary Safety Objectives: To assess the following the safety profile of the combination through continuous assessment of Adverse events (AE) and Treatment-related AEs (TRAEs).

Conditions and MedDRA coding

Melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.
2. 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.
3. Patients with brain metastasis that debut as symptomatic, regardless of corticosteroid use. The definition of symptoms will be: a. 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. b. Any symptom related to focal neurologic deficit. c. Epilepsy Note: Patients could have or not these symptoms controlled with corticosteroids at the inclusion of the clinical trial.
4. A documented mutation in BRAFV600 in the tumor tissue.
5. Modified Barthel Index of Activities of Daily Living > 10 (see Appendix 5).
6. Subjects aged ≥ 18 years.
7. Performance status ECOG PS 0-2 (see Appendix 7).
8. Able to swallowing
9. Adequate hematologic function: a. Haemoglobin ≥ 9 g/dL (may have been transfused). b. Platelet count ≥ 75 × 10 9 /L. c. Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 /L.
10. 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).
11. Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
12. 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.
13. 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.
14. 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: h. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments i. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the postmenopausal range j. Radiation induced oophorectomy with last menses >1 year ago k. Chemotherapy induced menopause with >1 year interval since last menses l. Surgical sterilization (bilateral oophorectomy or hysterectomy) m. 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) n. 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).
15. 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.
16. 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.
17. Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures.

Exclusion criteria 32

1. Uveal melanoma.
2. Patients in the need of urgent brain surgery before inclusion. However, patients are allowed to enter in the clinical trial after brain surgery, providing they meet the rest of inclusion and exclusion criteria, especially having at least one measurable lesion as per modified RECIST criteria after this surgery.
3. Brain radiotherapy will not be allowed before entering the clinical trial. Patients can receive brain radiotherapy during the clinical trial, if they progress into the brain, as per institutional guidelines ONLY if (must fulfill the three): a. They have received at least TWO doses of cemiplimab and fianlimab AND b. The event of an intracranial progressive disease happens during cemiplimab and fianlimab AND c. They comply to receive encorafenib and binimetinib as rechallenge. Encorafenib and binimetinib should be stopped 24h before, during and 24h after radiotherapy.
4. History or current evidence of significant (CTCAE grade ≥2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication.
5. Active infection requiring therapy.
6. Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment.
7. Uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes: a. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. b. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. c. Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. d. Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg, infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial.
8. Impaired cardiovascular function or clinically significant (i.e., active) cardiovascular diseases such as: 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 as per institutional guidelines, or serious cardiac arrhythmia requiring medication or a triplicate average 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.
9. TnT or troponin I TnI > 2x institutional ULN at baseline. Note: Patients with TnT or TnI 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 may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgment in the patient’s best interest.
10. Uncontrolled arterial hypertension despite medical treatment.
11. Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment
12. History of leptomeningeal metastases unless they are a finding in the Brain MRI that does not explain, according to the investigator criteria, the main neurological symptoms of the patient
13. Impairment of gastrointestinal function. Inability to swallow tablets or capsules.
14. Neuromuscular disorders associated with high concentrations of creatine kinase.
15. Another non-cured cancer in the last 2 years, except for in situ carcinoma of the cervix, breast, prostate or squamous cell carcinoma of the skin adequately treated or limited basal cell skin cancer adequately controlled. Patients with cured cancer should be free of any adjuvant treatment (i.e chemotherapy or targeted therapy/monoclonal antibodies) with the exception of hormonal therapy for completed cured localized breast cancer or localized prostate cancer
16. History of allogeneic organ transplant.
17. History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease (RDD).
18. History of interstitial lung disease.
19. Systemic immunotherapy treatment for melanoma would be allowed only in the adjuvant/neoadjuvant setting (regardless if the brain relapse was during or after that) providing that ALL the following criteria are met: a. The immunotherapy regimen did not contain anti LAG-3 treatment. b. Patients did not have brain metastases (whether they were symptomatic or asymptomatic) prior to this adjuvant/neoadjuvant immunotherapy setting. c. Patient was treated with adjuvant/neoadjuvant for at least 6 months. d. No other treatments different than the one in adjuvant/neoadjuvant before symptomatic brain metastases were applied. e. Patient did not discontinue immunotherapy due to related adverse events.
20. Targeted therapy against BRAF and/or MEK will not be allowed in any setting, including adjuvant.
21. Chemotherapy will not be allowed in any setting.
22. Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 4 weeks (28 days) prior to the first dose of trial treatment, other than steroids required for brain metastasis symptoms control.
23. History of pneumonitis within the last 5 years.
24. Active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis).
25. 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.
26. Known hypersensitivity to the active substances or to any of the excipients.
27. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 5.0; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable.
28. 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 intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing.
29. 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 6 months after the last dose of study treatment.
30. Known alcohol or drug abuse.
31. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
32. Total lactase deficiency or glucose-galactose malabsorption.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint for ENCEFALO is the 6 month intracranial progression-free survival (icPFS), defined as the proportion of patients alive and free of icPFS according to modified RECIST criteria (Section 10.3 and Appendix 3) at 6 month evaluation (week 24 +/- 3 weeks) after the start of study treatment. The icPFS will be assessed locally by investigators.

Secondary endpoints 9

1. Efficacy Endpoints: 12-months icPFS: Percentage of patients free of icPFS according to modified RECIST criteria (Section 10.3 and Appendix 3) at 12 month evaluation (week 48 +/- 3 weeks).
2. Efficacy Endpoints: icPFS locally assessed according to modified RECIST criteria, median and global curve estimated by kaplan meier method
3. Efficacy Endpoints: ecPFS locally assessed according to modified RECIST criteria (Appendix 3), median and global curve estimated by kaplan meier method
4. Efficacy Endpoints: PFS locally assessed according to modified RECIST criteria (Appendix 3), median and global curve estimated by kaplan meier method
5. Efficacy Endpoints: OS locally assessed, median and global curve estimated by kaplan meier method
6. Efficacy Endpoints: Change in patient reported outcomes in Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3 (Appendix 4).
7. Efficacy Endpoints:Changes in Barthel score from baseline (Appendix 5).
8. Efficacy Endpoints: Change in systemic steroids usage from baseline.
9. Safety Endpoints: Type, incidence, frequency, severity and relation to the treatment of reported adverse events, physical examinations and laboratory tests: ○ Frequency and severity of adverse events assessed by NCI CTCAE v5.0 (Appendix 6). ○ Frequency of treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0. ○ Frequency of AEs leading to treatment discontinuation.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol Multidisciplinar De Melanoma

Sponsor organisation

Grupo Espanol Multidisciplinar De Melanoma

Address

Calle De Velazquez 7 Floor 3

City

Madrid

Postcode

28001

Country

Spain

Scientific contact point

Organisation

Grupo Espanol Multidisciplinar De Melanoma

Contact name

A person designed by the Sponsor

Public contact point

Organisation

Grupo Espanol Multidisciplinar De Melanoma

Contact name

A person designed by the Sponsor

Third parties 3

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications