A Study Comparing 3 Study Medicines (Encorafenib, Binimetinib, Pembrolizumab) to 2 Study Medicines (Ipilimumab and Nivolumab) in Patients With Advanced Melanoma (PORTSIDE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: pembrolizumab; Drug: encorafenib; Drug: binimetinib; Drug: ipilimumab; Drug: nivolumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pfizer CT.gov Call Center; Phone Number: 1-800-718-1021; Email: ClinicalTrials.gov_Inquiries@pfizer.com

Study Locations

• Czechia
  • Praha 2, Czechia, 12808
    • Not yet recruiting
    • Vseobecna fakultni nemocnice v Praze
  • Hradec Králové
    • Hradec Kralove, Hradec Králové, Czechia, 500 05
      • Not yet recruiting
      • Fakultni nemocnice Hradec Kralove
  • Moravskoslezský KRAJ
    • Ostrava, Moravskoslezský KRAJ, Czechia, 708 52
      • Not yet recruiting
      • Fakultni nemocnice Ostrava
  • Olomoucký KRAJ
    • Olomouc, Olomoucký KRAJ, Czechia, 779 00
      • Not yet recruiting
      • Fakultni nemocnice Olomouc
  • Praha 8
    • Prague, Praha 8, Czechia, 180 81
      • Not yet recruiting
      • Fakultni nemocnice Bulovka
• Germany
  • Bremen, Germany, 28325
    • Not yet recruiting
    • Klinikum Bremen-Ost
  • Baden-württemberg
    • Heidelberg, Baden-württemberg, Germany, 69120
      • Not yet recruiting
      • Universitaetsklinikum Heidelberg
    • Tübingen, Baden-württemberg, Germany, 72076
      • Recruiting
      • Universitaetsklinikum Tuebingen
  • Bayern
    • Regensburg, Bayern, Germany, 93053
      • Not yet recruiting
      • Universitätsklinikum Regensburg
  • Niedersachsen
    • Buxtehude, Niedersachsen, Germany, 21614
      • Not yet recruiting
      • Elbe Kliniken Stade-Buxtehude, Klinikum Buxtehude
    • Hannover, Niedersachsen, Germany, 30625
      • Recruiting
      • Medizinische Hochschule Hannover
  • Nordrhein-westfalen
    • Essen, Nordrhein-westfalen, Germany, 45147
      • Recruiting
      • Universitaetsklinikum Essen
    • Münster, Nordrhein-westfalen, Germany, 48157
      • Recruiting
      • Fachklinik Hornheide
  • Rheinland-pfalz
    • Mainz, Rheinland-pfalz, Germany, 55131
      • Recruiting
      • Universitätsmedizin Johannes Gutenberg Universität Mainz
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Not yet recruiting
      • Universitätsklinikum Leipzig
  • Schleswig-holstein
    • Lübeck, Schleswig-holstein, Germany, 23538
      • Recruiting
      • Universitätsklinikum Schleswig-Holstein
  • Thüringen
    • Erfurt, Thüringen, Germany, 99089
      • Not yet recruiting
      • Helios Klinikum Erfurt
    • Gera, Thüringen, Germany, 07548
      • Not yet recruiting
      • SRH Wald-Klinikum Gera
• Italy
  • Genova, Italy, 16132
    • Not yet recruiting
    • Ospedale San Martino
  • Milano, Italy, 20141
    • Recruiting
    • Istituto Europeo di Oncologia IRCCS
  • Napoli, Italy, 80131
    • Recruiting
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale
  • Roma
    • Rome, Roma, Italy, 00144
      • Recruiting
      • Istituto Nazionale Tumori Regina Elena
  • Sicilia
    • Palermo, Sicilia, Italy, 90127
      • Recruiting
      • A.O.U. Policlinico Paolo Giaccone
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Recruiting
      • Istituto di Candiolo IRCCS - Fondazione del Piemonte per l'Oncologia
  • Toscana
    • Siena, Toscana, Italy, 53100
      • Recruiting
      • Azienda Ospedaliero Universitaria Senese
  • Umbria
    • Perugia, Umbria, Italy, 06132
      • Recruiting
      • AO Santa Maria della Misericordia
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Recruiting
      • Istituto Oncologico Veneto IRCCS
• Poland
  • Gdansk, Poland, 80-214
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne Klinika Chirurgii Onkologicznej, Transplantacyjnej i Ogólnej
  • Krakow, Poland, 30-727
    • Recruiting
    • Pratia MCM Krakow
  • Olsztyn, Poland, 10-228
    • Recruiting
    • Samodzielny Publiczny Zakład Opieki Zdrowotnej MSWiA z Warmińsko - Mazurskim Centrum Onkologii
  • Poznan, Poland, 60-780
    • Recruiting
    • Uniwersytecki Szpital Kliniczny W Poznaniu
  • Warszawa, Poland, 02-781
    • Not yet recruiting
    • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • Not yet recruiting
    • Fakultna nemocnica s poliklinikou F.D. Roosevelta Banska Bystrica
  • Banska Bystrica, Slovakia, 975 17
    • Not yet recruiting
    • Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska Bystrica
  • Banska Bystrica, Slovakia, 975 17
    • Not yet recruiting
    • Fakultna nemocnica s poliklinikou F.D. Roosevelta
  • Bratislava, Slovakia, 833 10
    • Recruiting
    • Narodny onkologicky ustav
  • Bratislava, Slovakia, 851 07
    • Not yet recruiting
    • Euromedix, a.s.
  • Bratislava, Slovakia, 85101
    • Recruiting
    • Neovizia, s.r.o.
  • Kosice, Slovakia, 042 53
    • Not yet recruiting
    • Institut nuklearnej a molekularnej mediciny
  • Martin, Slovakia, 036 01
    • Not yet recruiting
    • Martinske Biopticke centrum, s.r.o.
  • Partizanske, Slovakia, 95801
    • Not yet recruiting
    • Nemocnica na okraji mesta, n.o.
  • Partizanske, Slovakia, 958 01
    • Not yet recruiting
    • DERMATOP s.r.o., MUDr. Frantisek Perutka
  • Poprad, Slovakia, 058 01
    • Not yet recruiting
    • POKO Poprad, s.r.o., Ambulancia klinickej onkologie
  • Poprad, Slovakia, 058 01
    • Not yet recruiting
    • KARDIO, s.r.o.
  • Poprad, Slovakia, 058 01
    • Not yet recruiting
    • MR Poprad s.r.o., Pracovisko magnetickej rezonancie
  • Poprad, Slovakia, 058 01
    • Not yet recruiting
    • Nemocnica Poprad, a.s., Dermatovenerolgicka ambulancia
  • Poprad, Slovakia, 05801
    • Not yet recruiting
    • Nemocnica Poprad, a.s.
  • Trencin, Slovakia, 91101
    • Not yet recruiting
    • Ocne centrum Sokolik, s.r.o.
• Spain
  • Alicante, Spain, 03010
    • Recruiting
    • Hospital General Universitario de Alicante
  • Barcelona, Spain, 08036
    • Not yet recruiting
    • Hospital Clinic de Barcelona
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28007
    • Recruiting
    • Hospital General Universitario Gregorio Marañón
  • Sevilla, Spain, 41009
    • Not yet recruiting
    • Hospital Universitario Virgen Macarena
  • Zaragoza, Spain, 50009
    • Recruiting
    • Hospital Universitario Miguel Servet
  • Andalucía
    • Malaga, Andalucía, Spain, 29010
      • Not yet recruiting
      • H.R.U Málaga - Hospital General
  • Barcelona [barcelona]
    • Badalona, Barcelona [barcelona], Spain, 08916
      • Recruiting
      • Hospital Germans Trias i Pujol
    • Barcelona, Barcelona [barcelona], Spain, 08035
      • Recruiting
      • Hospital Universitari Vall d'Hebron
  • Catalunya [cataluña]
    • L'Hospitalet de Llobregat, Catalunya [cataluña], Spain, 08908
      • Recruiting
      • Institut Català d'Oncologia - L'Hospitalet
  • Valenciana, Comunitat
    • Valencia, Valenciana, Comunitat, Spain, 46014
      • Recruiting
      • Hospital General Universitario de Valencia
• United Kingdom
  • Nottingham, United Kingdom, NG5 1PB
    • Not yet recruiting
    • City Hospital, Nottingham University Hospitals NHS Trust
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Not yet recruiting
      • Addenbrooke's Hospital
  • Kensington AND Chelsea
    • London, Kensington AND Chelsea, United Kingdom, SW3 6JJ
      • Not yet recruiting
      • Royal Marsden Hospital (Chelsea)
  • Sutton
    • London, Sutton, United Kingdom, SM2 5PT
      • Not yet recruiting
      • Royal Marsden Hospital (Sutton)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triplet; encorafenib and binimetinib in combination with pembrolizumab	Drug: pembrolizumab; pembrolizumab; Other Names: KEYTRUDA®; Drug: encorafenib; encorafenib; Other Names: BRAFTOVI; Drug: binimetinib; binimetinib; Other Names: MEKTOVI
Active Comparator: Doublet; ipilimumab and nivolumab	Drug: ipilimumab; ipilimumab; Other Names: YERVOY; Drug: nivolumab; nivolumab; Other Names: OPDIVO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival in each treatment arm		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)
Overall Survival in each treatment arm		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)
Duration of Response (CR or PR) in each treatment arm		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)
Disease Control Rate (proportion of participants with a confirmed best overall response of CR, PR or SD) in each treatment arm		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)
Time to Response (CR or PR)		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)
Progression Free Survival 2 in each treatment arm		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)
Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments.	Number of participants with treatment emergent Adverse Events as as assessed per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.03).	Time from first dose of study intervention through 28 days after the last dose of study intervention
Patient Reported Outcomes using EORTC QLQ-C30 questionnaires in each treatment arm	EORTC (European Organization for Research and Treatment of Cancer) QLQ-30 includes 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/Quality of Life scale	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)
Patient Reported Outcomes using EuroQOL EQ-5D-5L questionnaires in each treatment arm	The EQ-5D-5L is a standardized measure of health utility that provides a single index value of health status and contains 1 item for each of 5 dimensions of HRQoL (ie, mobility, self-care, usual activities, pain or discomfort, and anxiety or depression).	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)
BRAF V600E/K Variant Allele Frequency and/or overall mean Variant Allele Frequency from circulating tumour DNA analysis in each treatment arm		Change from baseline, Day 1 of Cycle 2 (after 3 weeks), and End of Treatment (assessed up to approximately 48 months)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Merck Sharpe & Dohme LLC
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2023
• Primary Completion (Estimated): May 23, 2025
• Study Completion (Estimated): May 23, 2027

Study Registration Dates

• First Submitted: April 3, 2023
• First Submitted That Met QC Criteria: June 23, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: metastatic melanoma; skin cancer; BRAF; advanced melanoma; BRAF V600E/K melanoma; portside
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Pembrolizumab; Ipilimumab
• Other Study ID Numbers: C4221023; 2021-003640-24 (EudraCT Number); KEYNOTE-C92 (Other Identifier: Alias Study Number); MK-3475-C92 (Other Identifier: Merck Sharp & Dohme LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No