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

• ClinicalTrials.gov Identifier: NCT05926960
• Recruitment Status: Recruiting
• First Posted: July 3, 2023
• Last Update Posted: April 23, 2024
• Sponsor: Pfizer
• Collaborator: Merck Sharpe & Dohme LLC
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: April 3, 2023
• First Posted Date: July 3, 2023
• Last Update Posted Date: April 23, 2024
• Actual Study Start Date: June 13, 2023
• Estimated Primary Completion Date: May 23, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 23, 2023): 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 Frame: 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). ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 3, 2024)

• Progression Free Survival in each treatment arm [ Time Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Change from baseline, Day 1 of Cycle 2 (after 3 weeks), and End of Treatment (assessed up to approximately 48 months) ]

Original Secondary Outcome Measures (submitted: June 23, 2023)

• Progression Free Survival in each treatment arm [ Time Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: encorafenib
  encorafenib
  Other Name: BRAFTOVI
• Drug: binimetinib
  binimetinib
  Other Name: MEKTOVI
• Drug: pembrolizumab
  pembrolizumab
  Other Name: KEYTRUDA®
• Drug: ipilimumab
  ipilimumab
  Other Name: YERVOY
• Drug: nivolumab
  nivolumab
  Other Name: OPDIVO

Study Arms

• Experimental: Triplet
  encorafenib and binimetinib in combination with pembrolizumab
  Interventions:

  • Drug: encorafenib
  • Drug: binimetinib
  • Drug: pembrolizumab
• Active Comparator: Doublet
  ipilimumab and nivolumab
  Interventions:

  • Drug: ipilimumab
  • Drug: nivolumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 23, 2023): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 23, 2027
• Estimated Primary Completion Date: May 23, 2025 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: Czechia, Germany, Italy, Poland, Slovakia, Spain, United Kingdom

Administrative Information

• NCT Number: NCT05926960
• 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 )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharpe & Dohme LLC

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2024