Clinical trial NCT05926960: A Study Comparing 3 Study Medicines (Encorafenib, Binimetinib, Pembrolizumab) to 2 Study Medicines (Ipilimumab and Nivolumab) in Patients With Advanced Melanoma
Official title: A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS NIVOLUMAB AND IPILIMUMAB IN PARTICIPANTS WITH BRAF V600E/K MUTATION-POSITIVE MELANOMA WHO PROGRESSED DURING OR AFTER PRIOR TREATMENT WITH ANTI-PD-1 THERAPY
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Melanoma
Keywords: BRAF
BRAF V600E/K melanoma
metastatic melanoma
advanced melanoma
skin cancer
portside
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-07-03
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to learn about the effects of 3 study medicines (encorafenib, binimetinib, pembrolizumab) compared to 2 study medicines (ipilimumab and nivolumab) given for the treatment of melanoma.

Melanoma is a type of cancer that starts in the cells that give color to your skin.

The study is seeking participants who:

* have advanced or metastatic melanoma (has spread to other parts of the body);
* have a certain abnormal gene called "BRAF".
* have taken nivolumab or pembrolizumab treatment before this study.

Participants will either receive:

* pembrolizumab given by intravenous infusion (directly into a vein) every 3 weeks at the study clinic. Participants will also receive encorafenib and binimetinib by mouth every day at home,
* or will receive ipilimumab and nivolumab given by intravenous infusion (directly into a vein) every 3 weeks at the study clinic 4 times. This will be followed by nivolumab given by intravenous infusion every 4 weeks at the study clinic.

Both pembrolizumab and nivolumab will be given for a maximum of around 2 years. However, there is no time limit for encorafenib and binimetinib treatment.

The study team will see how each participant is doing after receiving the study treatments during regular visits to the study clinic.

Detailed description: The purpose of the study is to compare the efficacy of a triplet therapy (encorafenib, binimetinib, pembrolizumab) versus a doublet/control therapy (nivolumab and ipilimumab). Participants will have metastatic or unresectable locally advanced BRAF V600E/K-mutant melanoma, which progressed during or after prior treatment in the adjuvant or first-line metastatic setting, with an approved anti-PD-1 monotherapy (pembrolizumab or nivolumab),

Approximately 150 participants will be randomized in a 1:1 ratio to the triplet or the doublet/control therapy (75 participants in each arm). Randomization will be stratified by baseline serum LDH level, and by type of PD-1 resistance.

Eligibility criteria: Inclusion Criteria:

* Male or female participants ≥18 years of age at the time of informed consent.
* Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
* Documented evidence of a BRAF V600E or V600K mutation.
* Availability of adequate tumor tissue (archival or newly obtained; block or slides) to submit to the sponsor central laboratory(ies) during the screening period for central biomarker analyses .
* Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab)
* Must have anti-PD-1 resistant disease (primary or secondary) with confirmed disease progression per RECIST v1.1 either during or after receipt of an approved anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to the SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020).
* Have at least one measurable lesion per RECIST v1.1.
* ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging.

Exclusion Criteria:

* Mucosal or ocular melanoma.
* Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment with chronic systemic steroid therapy or any other form of immunosuppressive therapy within the past 2 years.
* Clinically significant cardiovascular diseases.
* History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
* History or current evidence of RVO or current risk factors for RVO.
* Concurrent neuromuscular disorder that is associated with the potential of elevated CK.
* Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
* Current non-infectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids.
* Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
* Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity or will be unable to tolerate combination therapy based on investigator judgement are excluded.
* Prior treatment with ipilimumab; prior combined immunotherapy blockade with anti-PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administration of an investigational anti-cancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.

Primary outcomes:
measure: Objective Response Rate (ORR) is defined as the proportion of participants in each treatment arm with a confirmed best overall response of either Complete Response (CR) or Partial Response (PR), as determined by investigator assessment per RECIST v1.1
timeFrame: Time from the date of randomization to the earliest date disease progression, or start of subsequent anticancer therapy, or death due to any cause (assessed up to approximately 48 months).
Secondary outcomes:
measure: Progression Free Survival in each treatment arm
timeFrame: Time from the date of randomization to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (assessed up to approximately 48 months)
measure: Overall Survival in each treatment arm
timeFrame: Time from date of randomization to the date of death due to any cause or the last known alive date (assessed up to approximately 48 months)
measure: Duration of Response (CR or PR) in each treatment arm
timeFrame: Time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause (assessed up to approximately 48 months)
measure: Disease Control Rate (proportion of participants with a confirmed best overall response of CR, PR or SD) in each treatment arm
timeFrame: Time from the date of randomization to the earliest date of disease progression, or start of subsequent anticancer therapy (assessed up to approximately 48 months)
measure: Time to Response (CR or PR)
timeFrame: Time from the date of randomization to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1.1 (assessed up to approximately 48 months)
measure: Progression Free Survival 2 in each treatment arm
timeFrame: Time from date of randomization to date of discontinuation of next-line treatment after 1st disease progression, 2nd disease progression after initiation of next line treatment, or death due to any cause (assessed up to approximately 48 months)
measure: Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments.
timeFrame: Time from first dose of study intervention through 28 days after the last dose of study intervention
measure: Patient Reported Outcomes using EORTC QLQ-C30 questionnaires in each treatment arm
timeFrame: Change from Baseline until Progressive Disease, death, withdrawal of consent, lost to follow-up, or end of study, whichever occurs first (assessed up to approximately 48 months)
measure: Patient Reported Outcomes using EuroQOL EQ-5D-5L questionnaires in each treatment arm
timeFrame: Change from Baseline until Progressive Disease, death, withdrawal of consent, lost to follow-up, or end of study, whichever occurs first (assessed up to approximately 48 months)
measure: BRAF V600E/K Variant Allele Frequency and/or overall mean Variant Allele Frequency from circulating tumour DNA analysis in each treatment arm
timeFrame: Change from baseline, Day 1 of Cycle 2 (after 3 weeks), and End of Treatment (assessed up to approximately 48 months)
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: Universitaetsklinikum Tuebingen
state: Baden-württemberg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein-westfalen
city: Münster
country: Germany
facility: Fachklinik Hornheide
state: Nordrhein-westfalen
city: Mainz
country: Germany
facility: Universitätsmedizin Johannes Gutenberg Universität Mainz
state: Rheinland-pfalz
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
state: Schleswig-holstein
city: Rome
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
state: Roma
city: Palermo
country: Italy
facility: A.O.U. Policlinico Paolo Giaccone
state: Sicilia
city: Candiolo
country: Italy
facility: Istituto di Candiolo IRCCS - Fondazione del Piemonte per l'Oncologia
state: Torino
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese
state: Toscana
city: Perugia
country: Italy
facility: AO Santa Maria della Misericordia
state: Umbria
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
state: Veneto
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia IRCCS
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Bratislava
country: Slovakia
facility: Narodny onkologicky ustav
city: Bratislava
country: Slovakia
facility: Neovizia, s.r.o.
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona [barcelona]
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Barcelona [barcelona]
city: L'Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncologia - L'Hospitalet
state: Catalunya [cataluña]
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
state: Valenciana, Comunitat
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: