Binimetinib Encorafenib Pembrolizumab +/- Stereotactic Radiosurgery in BRAFV600 Melanoma With Brain Metastasis

Brain Metastases Clinical Trial

— BEPCOME-MB  

Official title:

Randomised Phase 2 Trial Testing the Addition of Upfront Stereotactic Radiosurgery to Binimetinib Encorafenib Pembrolizumab Compared to Binimetinib Encorafenib Pembrolizumab Alone in BRAFV600 Mutation-positive Melanoma With Brain Metastasis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04074096
• Other study ID #: RAD06 - UC-0107/1810
• Secondary ID: 2021-006331-26
• Status: Recruiting
• Phase: Phase 2
• Start date: September 5, 2022
• Est. completion date: April 15, 2029

Study information

• Verified date: November 2023
• Source: UNICANCER
• Contact: Daniel Couch
• Phone: +33180501296
• Email: d-couch[@]unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates the addition of stereotactic radiosurgery (SRS) to the combination of binimetinib + encorafenib + pembrolizumab in the treatment of BRAFⱽ⁶⁰⁰ mutation-positive melanoma with brain metastases (MBM).

Description:

This is a Phase 2, randomised, controlled, open-label, multicentric, parallel trial with a safety lead-in phase, to assess the efficacy and safety of adding upfront SRS to binimetinib-encorafenib-pembrolizumab combination therapy in the treatment of BRAFⱽ⁶⁰⁰ mutation-positive MBM. The study will incorporate a safety lead-in (SLI) phase to assess the tolerability of binimetinib-encorafenib-pembrolizumab combination therapy +/- SRS in the first six patients enrolled. Safety will be assessed by the occurrence of predefined dose limiting toxicity (DLT) events. The safety data will be reviewed by an independent data monitoring committee (IDMC). The trial plans to enrol 150 patients who will be randomly assigned (1:1) to receive treatment with either: - Arm A: Encorafenib + binimetinib + pembrolizumab - Arm B: Upfront stereotactic radiosurgery of all lesions ≥5 mm in diameter (or ≥3 mm if other cerebral metastases >5 mm); followed by encorafenib + binimetinib + pembrolizumab . The treatment should be started more than 24 hours and less than 8 days (excluded) after the SRS. Patients will be treated until disease progression. Pembrolizumab will be discontinued after a maximum of 35 administrations. Treatment may also be terminated early at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient All patients will be followed for a total of 5 years post-randomisation.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: April 15, 2029
• Est. primary completion date: April 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

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/or neurosurgeon at the investigative centre. This should be documented in the patient file.

7. Absence of previous systemic treatment with BRAF inhibitors, MEK inhibitors or anti-PD-1 for distant metastatic melanoma. Patients having received such treatments as adjuvant therapy are allowed provided adjuvant treatment has been stopped for 6 months or more.

8. No more than one previous local intracranial therapy for one lesion (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 MRI.

10. At least one measurable intracranial lesion for which all of the following criteria

have to be met:

1. Previously untreated (no local therapy including local radiotherapy, resection, radiosurgery) or progressive after previous local therapy.

2. 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.

3. Cumulative Intracranial Target Volume =12 cm? 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 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):

1. Absolute neutrophil count (ANC) =1.5 x 10?/L;

2. Haemoglobin =9 g/dL without transfusions;

3. Platelets =100 x 10?/L without transfusions;

4. Aspartate aminotransferase and alanine aminotransferase =2.5 × upper limit of normal (ULN); =5 x ULN is acceptable for patient with liver metastases;

5. Total bilirubin =2 x ULN;

6. 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):

• Left ventricular ejection fraction (LVEF) = local lower normal limit (LLN) as determined by a multigated acquisition (MUGA) scan or echocardiogram;
• 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.

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 which 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:

1. Left ventricular ejection fraction < local LLN as determined by a MUGA scan or echocardiogram;

2. A QT interval corrected for heart rate QTc > 480 ms according to local standard formula;

3. A history or evidence of current clinically significant uncontrolled arrhythmias. Note: Patients with atrial fibrillation controlled for >30 days prior to randomisation are eligible.

4. A history or evidence of current >Class II congestive heart failure as defined by the New York Heart Association guidelines;

5. 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;

6. Patients with intra-cardiac defibrillators;

7. 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 breastfeeding female. Note: WOCBP must have a negative 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

Related Conditions & MeSH terms

• BRAF V600 Mutation
• Brain Metastases
• Brain Neoplasms
• Malignant Melanoma
• Melanoma
• Neoplasm Metastasis

Intervention

Radiation:
• Stereotaxic radiosurgery (SRS)
For patients randomised to arm B only: Upfront SRS of all lesions =5 mm in diameter (or =3 mm if other cerebral metastases >5 mm).

Drug:
• Binimetinib Oral Tablet
All patients: binimetinib 45 mg PO BID.
• Encorafenib Oral Capsule
All patients: encorafenib 450 mg PO QD
• Pembrolizumab
All patients: pembrolizumab 200 mg IV Q3W

Locations

Country	Name	City	State
France	APHP - Hôpital Avicenne	Bobigny
France	CHU de Bordeaux - Hôpital Saint André	Bordeaux
France	GH Sud CHU Bordeaux - Hôpital Levêque	Bordeaux
France	APHP - Hôpital Ambroise Paré	Boulogne-Billancourt
France	CHU de Caen	Caen
France	CLCC - Centre Jean François Baclesse	Caen
France	APHP - Hôpital Henri Mondor	Créteil
France	CHU de Dijon - Hopital Du Bocage	Dijon
France	CLCC - Centre Georges François Leclerc	Dijon
France	CLCC - Centre Léon Bérard	Lyon
France	APHM - Hopital De La Timone	Marseille
France	CHU De Montpellier - Hopital Saint Eloi	Montpellier
France	CLCC - Institut de Cancerologie de Montpellier	Montpellier
France	CHU Nice - Hôpital de l'Archet	Nice
France	CLCC - Centre Antoine Lacassagne	Nice
France	APHP - L'hôpital de la Pitié-Salpêtrière	Paris
France	CHU de Nantes - Hôtel Dieu	Saint-Herblain
France	CLCC - Institut de Cancerologie de l'Ouest - Nantes	Saint-Herblain
France	CLCC - IUCT-0 / Institut Claudius Regaud	Toulouse
France	CHU de TOURS - Hôpital Bretonneau	Tours
France	CLCC - Gustave Roussy	Villejuif

Sponsors (4)

Lead Sponsor	Collaborator
UNICANCER	European Association of Dermato Oncology, Merck Sharp & Dohme LLC, Pierre Fabre Medicament

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Intracranial (IC) progression-free survival (PFS)	Time from randomisation until IC-progressive disease (PD) as evaluated by centralized assessment using modified response evaluation criteria in solid tumours version 1.1 (RECIST v1.1), or death, whichever occurs first.	From randomisation until IC-PD, or death, whichever occurs first, up to 12 months.
Secondary	Intracranial-response rate (RR)	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.	From randomisation until IC-CR or IC-PR, up to 60 months.
Secondary	Intracranial disease control (DC)	Percentage of patients with an IC-CR or IC-PR or stable intracranial disease as assessed by the investigator using modified RECIST v1.1.	From randomisation until IC-CR or IC-PR or stable intracranial disease, up to 60 months.
Secondary	Extracranial (EC) response rate	Percentage of patients with a confirmed EC-CR or EC-PR as assessed by the investigator using modified RECIST v1.1.	From randomisation until confirmed EC-CR or EC-PR, up to 60 months.
Secondary	Overall response rate (ORR)	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.	From randomisation until confirmed CR or PR, up to 60 months.
Secondary	Duration of intracranial, extracranial, and overall response	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.	Time from first observation of, IC-, EC-, or overall response respectively (i.e. CR or PR), until disease progression (PD), up to 60 months.
Secondary	Duration of response of treated target lesions	Time from first documented response (i.e. CR or PR) until PD of treated target lesions or death, whichever occurs first.	From first documented response (i.e. CR or PR) until PD of treated target lesions or death, whichever occurs first, up to 60 months.
Secondary	Progression-free survival (PFS)	Time from randomisation until IC-PD according to modified RECIST v1.1, EC-PD according to RECIST v1.1, or death, whichever occurs first.	From randomisation until IC-PD, EC-PD or death, whichever occurs first, up to 60 months.
Secondary	Overall survival (OS)	Time from randomisation until death due to any cause.	From randomisation until death due to any cause, up to 60 months.
Secondary	Global Quality of Life (HRQOL) - QLQ-C30	This self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.; The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.; All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	From randomisation until end of treatment, up to 60 months.
Secondary	Quality of Life (HRQOL) in patients with brain metastases - QLQ-BN20	This EORTC brain cancer specific questionnaire is intended to supplement the QLQ-C30 questionaire.; The QLQ-BN20 contains 20 items organized into four scales (three items each: future uncertainty, visual disorder, motor dysfunction, and communication deficit), and seven single items (headaches, seizures, drowsiness, hair loss, itchy skin, weakness of legs, and bladder control). All items are rated on a four-point Likert-type scale (1 = "not at all," 2 = "a little," 3 = "quite a bit," and 4 = "very much"), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms.	From randomisation until end of treatment, up to 60 months.
Secondary	Cognitive performance	Assessed using the Montreal Cognitive Assessment (MoCA).	From randomisation until end of treatment, up to 60 months.
Secondary	Incidence of dose-limiting toxicities	Occurrence of adverse events predefined as dose-limiting toxicities in any patient during the safety lead-in phase of the trial	From randomisation until completion of 2 cycles of treatment
Secondary	Frequency and severity of adverse events	Assessed according to National Cancer Institute - Common terminology criteria for adverse events version 5.0 (NCI-CTCAE v5.0).	From randomisation until end of treatment, up to 60 months.