| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF(V600) mutation-positive melanoma with brain metastasis (MBM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| BRAF(V600) mutation-positive melanoma with brain metastasis (MBM) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the trial is to demonstrate improved intracranial (IC) progression-free survival (PFS) in BRAFV600 mutation-positive melanoma patients with brain metastasis when upfront SRS is added to binimetinib-encorafenib plus pembrolizumab combination therapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in the treatment of intracranial disease in terms of intracranial-response rate (RR).
- To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in the treatment of intracranial disease in terms of intracranial disease control (DC).
- To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in the treatment of extracranial disease in terms of extracranial (EC) response rate.
- To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of overall response rate (ORR).
- To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of duration of intracranial, extracranial, and overall response.
Etc...
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
TRANSLATIONAL/ANCILLARY/EXPLORATORY OBJECTIVES
- To evaluate whether circulating tumour DNA (ctDNA) levels at baseline and during therapy are associated with the patient characteristics and outcome.
- To describe the genetic landscape of ctDNA at baseline and during therapy, and its association with treatment efficacy. |
|
| E.3 | Principal 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 study treatment and for 120 days after completing treatment. Male participants must agree to refrain from donating sperm during this period.
16. Patient affiliated to or a beneficiary of the local social security system or equivalent.
17. 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. |
|
| E.4 | Principal 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 <local LLN as determined by a MUGA scan or echocardiogram;
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 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.
20. Has received a live vaccine within 30 days prior to the first dose of study drug.
21. Active infection requiring systemic therapy.
22. Known history of active TB (Bacillus Tuberculosis).
23. Allogenic tissue/solid organ transplant.
24. Person deprived of their liberty or under protective custody or guardianship.
25. Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, social or psychological reasons. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Intracranial progression-free survival defined as the time from randomisation until IC-progression 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
- Intracranial-response rate (RR), 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.
Additionally, centralised evaluation of IC-RR according to the Response Assessment in Neuro-Oncology assessment criteria for brain metastases (RANO MB) will be performed at the end of the study.
- Intracranial disease control (DC), 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.
- Extracranial (EC) response rate, defined as the percentage of patients with a confirmed EC-CR or EC-PR assessed by the investigator using RECIST v1.1.
- Overall response rate (ORR), 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.
- 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 disease progression (PD) according to modified RECIST v1.1 (intracranial disease) or RECIST v1.1 (extracranial disease) or death, whichever occurs first.
- 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.
- Progression-free survival (PFS), 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.
- Overall survival (OS), defined as the time from randomisation until death due to any cause.
- Health Related Quality of Life (HRQOL) assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ-C30 and BN20).
- Cognitive performance assessed using the Montreal Cognitive Assessment (MoCA).
Safety:
- Frequency and severity of adverse events assessed according to NCI-CTCAE v5.0.
- Other skin, laboratory, vital-sign, cardiac function, and neurological assessment data.
Translational / Ancillary Endpoint(s) :
- Quantitative ctDNA detection at inclusion and during treatment.
- Qualitative ctDNA analysis at inclusion and during treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| SRS + binimetinib - encorafenib - pembrolizumab vs. binimetinib - encorafenib - pembrolizumab |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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