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

Sponsor

Pfizer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05926960

Collaborator

Merck Sharpe & Dohme LLC (Other)

150

Enrollment

Locations

Arms

47.3

Anticipated Duration (Months)

12.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: encorafenib Drug: binimetinib Drug: pembrolizumab Drug: ipilimumab Drug: nivolumab	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 13, 2023

Anticipated Primary Completion Date :

May 23, 2025

Anticipated Study Completion Date :

May 23, 2027

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Triplet

encorafenib and binimetinib in combination with pembrolizumab

Drug: encorafenib

encorafenib

Other Names:

BRAFTOVI

Drug: binimetinib

binimetinib

Other Names:

MEKTOVI

Drug: pembrolizumab

pembrolizumab

Other Names:

KEYTRUDA

Active Comparator: Doublet

ipilimumab and nivolumab

Drug: ipilimumab

ipilimumab

Other Names:

YERVOY

Drug: nivolumab

nivolumab

Other Names:

OPDIVO

Outcome Measures

Primary Outcome Measures

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

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. [Time from first dose of study intervention through 28 days after the last dose of study intervention]
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).
Patient Reported Outcomes using EORTC QLQ-C30 questionnaires in each treatment arm [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)]
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
Patient Reported Outcomes using EuroQOL EQ-5D-5L questionnaires in each treatment arm [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)]
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).
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, and Day 1 of Cycles 2, 3, 5, 7 (a cycle is every 3 or 4 weeks), and End of Treatment (assessed up to approximately 48 months)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

cutaneous melanoma, according to the AJCC 8th edition.

Documented evidence of a BRAF V600E or V600K mutation.
Submission of adequate tumor tissue for central laboratory testing of BRAF V600E-mutation and biomarkers is required for all participants during the screening period and prior to randomization.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Azienda Ospedaliero Universitaria Senese	Siena	Toscana	Italy	53100
2	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli		Italy	80131
3	Pratia MCM Krakow	Krakow		Poland	30-727
4	Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy	Warszawa		Poland	02-781
5	Nemocnica na okraji mesta, n.o.	Partizanske		Slovakia	95801
6	Hospital Universitari Vall d'Hebron	Barcelona	Barcelona [barcelona]	Spain	08035
7	Hospital General Universitario de Valencia	Valencia	Valenciana, Comunitat	Spain	46014
8	Hospital General Universitario de Alicante	Alicante		Spain	03010
9	Hospital Clínic de Barcelona	Barcelona		Spain	08036
10	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
11	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
12	Hospital Universitario Virgen Macarena	Sevilla		Spain	41009