Phase 1

• Conditions: BRAF(V600) mutation-positive melanoma with brain metastasis (MBM); MedDRA version: 20.0Level: LLTClassification code 10027481Term: Metastatic melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-006331-26-FR
• Lead Sponsor: ICANCER

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2023-11-02
• Last Update Posted: 6 November 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Provided written informed consent prior to any trial specific procedures.
2. Aged =18 years old.
3. An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. 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.
5. Presence of BRAFV600E/K/D/R mutation according to a locally validated BRAF Assay.
6. Candidacy for SRS therapy validated by the radiation oncologist and neurosurgeon at the investigative centre. This should be documented in the patient file.
7. Absence of previous combined systemic treatment for distant metastatic melanoma.
a. Patients who received BRAFi and MEKi as adjuvant therapy and stopped for 6 months prior to the date of randomization can be included,
b. Patients who received anti-PD-1 as adjuvant therapy, and who progressed during or after therapy can be included,
c. Patients who received anti-PD-1 monotherapy for unresectable stage III/IV melanoma can be included if disease progression was documented during treatment or more in the 6 months following anti-PD-1 treatment discontinuation.
8. No more than one previous local intracranial therapy (e.g. craniotomy, SRS).
Note: Treatment with stereotactic radiosurgery must have been completed =14 days prior to randomisation and this lesion cannot be target lesion for radiosurgery.
9. Able to undergo gadolinium-enhanced magnetic resonance imaging (MRI).
10. At least one measurable intracranial lesion for which all of the following criteria have to be met:
a. Previously untreated (no local therapy including local radiotherapy, resection, radiosurgery) or progressive after previous local therapy.
b. Longest diameter =5 mm as determined by contrast-enhanced MRI. Longest diameter =3 mm is acceptable for other IC lesions provided there is at least one lesion =5 mm.
c. Cumulative Intracranial Target Volume (CITV) =12 cm3 as determined by contrast-enhanced MRI.
11. 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 (NCI-CTCAE v5.0).
12. 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).
13. Adequate bone marrow, organ function, and laboratory parameters; defined as the following (all criteria must be met):
a. Absolute neutrophil count =1.5 x 109/L;
b. Haemoglobin =9 g/dL without transfusions;
c. Platelets =100 x 109/L without transfusions;
d. Aspartate aminotransferase and alanine aminotransferase =2.5 × upper limit of normal (ULN); =5 x ULN is acceptable for patient with liver metastases;
e. Total bilirubin =2 x ULN;
f. Creatinine =1.5 mg/dL, or calculated creatinine clearance =50 mL/min (as determined using the MDRD method).
14. Adequate cardiac function, defined as the following (all criteria must be met):
a. Left ventricular ejection fraction (LVEF) = local lower normal limit (LLN) as determined by a multigated acquisition (MUGA) scan or echocardiogram;
b. Baseline QT interval corrected for heart rate QTc = 480 ms according to local standard formula.
15. Women of childbearing potential (WOCBP) or men must agree to refrain from sexual activity or use adequate contraception for the duration of

Exclusion Criteria

1. More than 10 intracranial metastases.
2. 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.
3. Ocular melanoma.
4. Brain metastases that necessitate immediate neurosurgery.
5. Any previous treatment with whole-brain radiation.
6. Presence of leptomeningeal disease or any parenchymal brain metastasis >30 mm in longest diameter.
Note: On MRI, the most common finding of leptomeningeal disease is pial enhancement and nodularity, typically over the cerebral convexities, in the basal cisterns, on the tentorium, or in the ventricular ependymal surfaces.
7. Current or expected use of a strong inhibitor of CYP3A4.
8. 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.
9. 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.
10. 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).
11. A history or evidence of cardiovascular risk including any of the following:
a. LVEF b. QTc >480 ms according to local standard formula
c. A history or evidence of current clinically significant uncontrolled arrhythmias;
Note: Patients with atrial fibrillation controlled for >30 days prior to randomisation are eligible.
d. A history or evidence of current >Class II congestive heart failure as defined by the New York Heart Association guidelines;
e. Treatment refractory hypertension defined as a systolic blood pressure of >140 mmHg and/ or diastolic blood pressure >90 mmHg, which cannot be controlled by antihypertensive therapy;
f. Patients with intra-cardiac defibrillators;
g. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting less than 6 months prior to enrolment.
12. A history or current evidence of retinal vein occlusion.
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, and their excipients.
14. Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
15. Participation in another therapeutic trial within the 30 days prior to randomization
16. Pregnant or breastfeeeding female.
Note: WOCBP must have a negative urine or serum pregnancy test within 14 days prior to enrolment.
17. History of, or active interstitial lung disease or (non-infectious) pneumonitis.
18. 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).
19. Diagnosis of immunodeficiency or systemic chronic steroid therapy (=10mg/day prednisone

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified