Binimetinib, Encorafenib and Pembrolizumab COmbination in MElanoma - Metastatic to the Brain

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer, Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Sep 2022 → ongoing

Decision date (initial)

2024-02-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pierre Fabre Médicament · Merck & Co. (MSD)

External identifiers

EU CT number

2023-505302-42-00

EudraCT number

2021-006331-26

ClinicalTrials.gov

NCT04074096

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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.

Secondary objectives 11

1. 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 intracranialresponse rate (RR).
2. 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).
3. 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.
4. To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of overall response rate (ORR).
5. 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.
6. To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of duration of response of treated target lesions.
7. To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of PFS.
8. To evaluate the efficacy of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in terms of overall survival (OS).
9. To evaluate the effect of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS on health-related quality of life (HRQOL).
10. To evaluate the effect of binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS on cognitive performance.
11. To evaluate the safety of, and tolerance to, binimetinib-encorafenib plus pembrolizumab combination therapy with or without upfront SRS in term of frequency and severity of adverse events.

Conditions and MedDRA coding

BRAF(V600) mutation-positive melanoma with brain metastasis (MBM)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

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.
8. No more than one previous local intracranial therapy for one lesion (e.g. craniotomy, SRS).
9. Able to undergo gadolinium-enhanced magnetic resonance imaging (MRI).
10. At least one measurable intracranial lesion
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 5.0 (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.
14. Adequate cardiac function
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. 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 25

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.
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
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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Intracranial progression-free survival defined as the time from randomisation until IC-progressive 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.

Secondary endpoints 12

1. Intracranial-response rate, 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.
2. Intracranial disease control, 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.
3. Extracranial response rate, defined as the percentage of patients with a confirmed EC-CR or EC-PR assessed by the investigator using RECIST v1.1.
4. Overall response rate, 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.
5. 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 PD according to modified RECIST v1.1 (intracranial disease) or RECIST v1.1 (extracranial disease) or death, whichever occurs first.
6. 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.
7. Progression-free survival, 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.
8. Overall survival, defined as the time from randomisation until death due to any cause.
9. Health Related Quality of Life assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ-C30 and BN20).
10. Cognitive performance assessed using the Montreal Cognitive Assessment (MoCA).
11. Frequency and severity of adverse events assessed according to NCI-CTCAE v5.0.
12. Other skin, laboratory, vital-sign, cardiac function, and neurological assessment data.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

AIT RAHMOUNE Nourredine

Public contact point

Organisation

Unicancer

Contact name

AIT RAHMOUNE Nourredine

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Locations

1 EU/EEA country · 11 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 18 files

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

Application history

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