Phase 2 Study of Encorafenib and Binimetinib Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Melanoma Who Progressed During or After Prior Treatment with Anti−PD-1 Therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 May 2023 → 3 Feb 2026

Decision date (initial)

2024-06-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc

External identifiers

EU CT number

2023-509471-17-00

EudraCT number

2021-003640-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Safety, Others, Efficacy

To compare the efficacy of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus nivolumab and ipilimumab (Control Arm) with respect to ORR.

Secondary objectives 2

1. To compare the efficacy of the Triplet Arm versus the Control Arm with respect to PFS.
2. To compare the efficacy of the Triplet Arm versus the Control Arm with respect to OS.

Conditions and MedDRA coding

Metastatic or unresectable locally advanced BRAF V600E/K mutation positive melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female participants ≥18 years of age at the time of informed consent.
2. Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
3. Documented evidence of a BRAF V600E or V600K mutation.
4. Availability of adequate tumor tissue for central laboratory testing of biomarkers is required for all participants during the screening period.
5. 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).
6. 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).
7. Have at least 1 measurable lesion per RECIST v1.1.
8. ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging.

Exclusion criteria 12

1. Mucosal or ocular melanoma.
2. 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.
3. Clinically significant cardiovascular diseases.
4. History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
5. History or current evidence of RVO or current risk factors for RVO.
6. Concurrent neuromuscular disorder that is associated with the potential of elevated CK.
7. Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
8. Current noninfectious pneumonitis/ILD or history of noninfectious pneumonitis/ILD requiring steroids.
9. Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
10. 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.
11. 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 anticancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.
12. Previous participation in the Pfizer C4221016 STARBOARD Study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR, defined as the proportion of participants with a confirmed best overall response of either CR or PR, as determined by investigator assessment per RECIST v1.1 from randomization to the earliest of PD, start of subsequent anticancer therapy, or death due to any cause.

Secondary endpoints 10

1. PFS, defined as the interval of time between 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.
2. OS, defined as the time from date of randomization to the date of death due to any cause or the last known alive date.
3. DOR, defined as the 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.
4. DCR, defined as the proportion of participants with a confirmed best overall response of CR, PR or SD, as determined by investigator assessment per RECIST v1.1.
5. TTR, defined as the 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.
6. PFS2, defined as the time from the date of randomization to the date of discontinuation of next-line treatment after first objective disease progression by investigator assessment per RECIST v1.1, second objective disease progression after initiation of next-line treatment, as determined by investigator assessment, or death due to any cause, whichever occurs first.
7. Incidence and severity of AEs, and changes in clinical laboratory parameters, vital signs, and cardiac assessments.
8. EORTC QLQ-C30: change from baseline in the global health status/QoL score and all other subscales scores.
9. EQ-5D-5L: change from baseline in the index score and VAS.
10. BRAF V600E/K VAF and/or overall mean VAF from ctDNA analysis of plasma samples collected at baseline and on treatment.

Investigational products

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

Test 3

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Adam Schayowitz

Public contact point

Organisation

Pfizer Inc.

Contact name

Adam Schayowitz

Third parties 3

Locations

5 EU/EEA countries · 17 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 32 files

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

Application history

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