PLUG-IN: Pembrolizumab Combined With Enfortumab Vedotin for Advanced Melanoma Patients

NCT06906822 | Recruiting Phase 2

• 2 other identifiers: GEM 23032024-514163-26-00
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 13

Brief Summary

There is a lack of strategies for patients who progress after responding to PD-1/l-1 in melanoma. High expression of Nectin4 in skin and melanomas may serve as a new target in advanced melanomas. The combination of enfortumab/vedotin (EV) and pembrolizumab has shown synergistic effect in various solid tumors. Enfortumab vedotin and pembrolizumab may have a dual effect on clinical outcomes. PLUGIN is a multicenter, non-randomized open-label, 2-cohort, phase 2 study to evaluate the ORR of pembrolizumab in combination with enfortumab vedotin (EV) in previously treated participants with unresectable stage III or IV melanoma and disease progression on standard therapy. The primary objective is evaluate the efficacy of enfortumab/vedotin and pembrolizumabplus pembrolizumab in advanced melanoma. Hypothesis: 1) High expression of Nectin4 in skin and melanomas may serve as a new target in advanced melanomas; 2)EV+Pembrolizumab has shown synergistic effect in various solid tumors; 3) There is a lack of strategies for patients who respond to PD1-mAbs in melanoma. Primary Endpoint: Objective Response Rate (ORR) as assessed by the investigator according RECIST 1.1 A total of 60 patients will be enrolled in this study to evaluate efficacy and outcomes in two different cohorts: Cohort 1: patients who did not have BRAF mutation V600E and had disease progression on immune (IO) therapy. Cohort 2, patients with activating BRAF mutations, must have progressed on IO therapy and BRAF/MEKi

Conditions

Melanoma

Keywords

Melanoma; Enfortumab; vedotin; pembrolizumab

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Objective Response Rate (ORR) as assessed by the investigator through Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). This will be considered as the percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study. Estimates of the ORR along with the associated 95% exact binomial confidence intervals will be provided. The binomial probability that the observed melanoma ORR is \> 0.15 will be calculated. Best confirmed response will be summarized. Response of melanoma will be measured by CT or MRI and assessed according to RECIST 1.1 by the investigator. If there are no assessments, the response will be taken to be unconfirmed and a non-response. Changes in tumor size from baseline will be calculated and displayed graphically, where appropriate.

  Throughout the study period,period, from initiation of treatment up to 2 years

Secondary Outcomes (11)

• Progression-free Survival (PFS) 6 months

  Throughout the study period, from initiation of treatment up to 6 months

• Progression-free Survival (PFS) 12 months

  Throughout the study period, from initiation of treatment up to 12 months

• Overall survival (OS)

  Throughout the study period, from initiation of treatment up to 12 months

• Overall survival (OS)

  Throughout the study period, from initiation of treatment up to 24 months

• Clinical Benefit Rate (CBR)

  Throughout the study period, from initiation of treatment up to 24 months

Study Arms (2)

Cohort 1

EXPERIMENTAL

patients who did not have BRAF mutation V600E and had disease progression on immune (IO) therapy.

Drug: enfortumab vedotin; Drug: pembrolizumab

Cohort 2

EXPERIMENTAL

patients with activating BRAF mutations, must have progressed on IO therapy and BRAF/MEKi

Drug: enfortumab vedotin; Drug: pembrolizumab

Interventions

enfortumab vedotin DRUG

Enfortumab vedotin 1.25 mg/kg be administered on Days 1,8,22 and 29 of every 6-week cycle by IV infusion given over approximately 30 minutes.

Cohort 1; Cohort 2

pembrolizumab DRUG

Pembrolizumab 400 mg on day 1 of each 42-day cycle (Q6W)

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants are eligible to be included in the study only if all of the following criteria apply:
• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of unresectable or metastatic melanoma will be enrolled in this study.
• Participants must have measurable disease by investigator assessment according to RECIST v1.1 Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.
• Male participants:
• a. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for 9 months after last dose of EV or 4 months after pembrolizumab, whichever occurs last; and refrain from donating sperm during this period.
• Female participants:
• A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR
• WOCBP should remain on contraception for 12 months after the last dose of EV or 4 months after pembrolizumab, whichever occurs last.
• Participants must have received prior systemic therapy for locally advanced or metastatic melanoma:
• a. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: i. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
• Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1.
• The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression.
• ii. Progressive disease / recurrence has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. Progressive disease is determined according to iRECIST. This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.
• b. BRAF mutated patients should have received BRAF/MEK inhibitors and PD1/PDL1 therapy c. Prior CTLA4 therapy is allowed.

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Participants who have previously received enfortumab vedotin or other MMAE-based ADCs.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the scheduled date of starting the study treatment.
• Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids.
• Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted.
• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Participants with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms that are not otherwise explained.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Known additional malignancy that is progressing or has required active treatment within the past 2 years.
• Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Participants with known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
• Participants with active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.

Sponsors & Collaborators

• Grupo Español Multidisciplinar de Melanoma: lead
• Merck Sharp & Dohme LLC: collaborator
• Astellas Pharma Inc: collaborator

Study Sites (13)

Complexo Hospitalario Universitario de A Coruña

A Coruña, A Coruña, 15006, Spain

RECRUITING

Institut Català D'Oncologia - Badalona

Badalona, Barcelona, 08916, Spain

RECRUITING

Hospital Universitari Dexeus

Barcelona, Barcelona, 08028, Spain

NOT YET RECRUITING

Hospital Universitario Valle de Hebrón

Barcelona, Barcelona, 08035, Spain

RECRUITING

Hospital Clinic de Barcelona

Barcelona, Barcelona, 08036, Spain

RECRUITING

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, 39008, Spain

RECRUITING

Hospital Universitario Ramón y Cajal

Madrid, Madrid, 28034, Spain

RECRUITING

Hospital Universitario 12 de Octubre

Madrid, Madrid, 28041, Spain

RECRUITING

Hospital Universitario La Paz

Madrid, Madrid, 28046, Spain

RECRUITING

Hospital Clínico Universitario Virgen de la Arrixaca

Murcia, Murcia, 30120, Spain

RECRUITING

Hospital Virgen del Rocío

Seville, Sevilla, 41013, Spain

RECRUITING

Hospital General de Valencia

Valencia, Valencia, 46014, Spain

RECRUITING

Hospital Universitario Miguel Servet

Zaragoza, Zaragoza, 50009, Spain

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

enfortumab vedotin; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Guillermo de Velasco, M.D., Ph.D.

  Hospital Universitario 12 de Octubre

  STUDY DIRECTOR

• Ainara Soria, M.D., Ph.D.

  Hospital Universitario Ramón y Cajal

  STUDY DIRECTOR

Central Study Contacts

A responsible person designated by the sponsor, M.D., PhD.

CONTACT

+34 93 434 44 12; investigacio@mfar.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicenter, non-randomized open-label, 2-cohort, phase 2 study to evaluate the ORR of pembrolizumab in combination with enfortumab vedotin (EV) in previously treated participants with unresectable stage III or IV melanoma and disease progression on standard therapy. A total of 60 patients will be enrolled after signing the informed consent in two different cohorts: Cohort 1: patients who did not have BRAF mutation V600E and had disease progression on immune (IO) therapy. Cohort 2: patients with activating BRAF mutations, must have progressed on IO therapy and BRAF/MEKi

Study Record Dates

• First Submitted: March 26, 2025
• First Posted: April 2, 2025
• Study Start: June 10, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: September 18, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

ES (13)