Übersicht

Eignung

Details zum Design

Arme & Interventionen

Ergebnismessungen

Studienzentren

Quelle: NCT06906822

Rekrutiert

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

Interventionsstudie

Phase 2

Hospital Universitario de Marqués de Valdecilla

Sponsor: Grupo Español Multidisciplinar de Melanoma

Zuletzt aktualisiert: 18. September 2025
Hinweis - Die Informationen stammen aus öffentlichen Registern und spiegeln möglicherweise nicht die Echtzeitänderungen am lokalen Studienzentrum wider.

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

Detaillierte Beschreibung anzeigen

Behandlungskategorie

Monoklonaler Antikörper, Checkpoint-Inhibitoren

Erforderliche Mutationen

Keine

Studie gestartet

10. Juni 2025

Zuletzt vom Sponsor aktualisiert

18. September 2025

Voraussichtlicher Abschluss

1. Juni 2027

Studienkontakt

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

E-Mail:investigacio@mfar.net

Telefon:+34 93 434 44 12

Eignung

Einschlusskriterien

Participants are eligible to be included in the study only if all of the following criteria apply:

1. 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.

2. 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.

3. 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.

4. 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:

1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR

2. WOCBP should remain on contraception for 12 months after the last dose of EV or 4 months after pembrolizumab, whichever occurs last.

5. 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.

6. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible.

Note: Patients who had cutaneous adverse events grade 3 or superior are not eligible for the study.

7. Provide representative formalin-fixed paraffin-embedded/FFPE paraffin block obtained after last treatment progression. Patients who have no archival tumor tissue after the last treatment progression will be required to provide a fresh biopsy, if the procedure is feasible and safe for the patient. Older archival tumor samples are allowed for patients with no recent archival tissue (after last treatment progression) and not capable of undergoing a new tumor biopsy before the first dose of study treatment.. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

9. Have adequate organ function as defined in the following table (see Table 3 in protocol). Specimens must be collected within 10 days prior to the start of study intervention.

Ausschlusskriterien

1. 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.

2. Participants who have previously received enfortumab vedotin or other MMAE-based ADCs.

3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the scheduled date of starting the study treatment.

4. 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.

5. 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.

6. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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).

12. 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.

13. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)

14. Participants with conditions requiring systemic doses of corticosteroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded.

15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required corticosteroids or has current pneumonitis/interstitial lung disease.

16. Has an active infection requiring systemic therapy.

17. Has a known history of Human Immunodeficiency Virus (HIV) infection.

18. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.

Note: Hepatitis B and C screening tests are not required unless:

Known history of HBV and HCV infection As mandated by local health authority

19. Has not adequately recovered from major surgery or has ongoing surgical complications.

20. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of contraception period.

23. Has had an allogenic tissue/solid organ transplant.

24. History of Clinical Tuberculosis

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Design-Details

ZuteilungNon-Randomized

InterventionsmodellParallel Assignment

MaskierungNone (Open Label)

Anzahl der Teilnehmer60

Arme & Interventionen

Arme

Interventionen

Typ: Experimental

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

Interventionen:

enfortumab vedotin
pembrolizumab

Ergebnismessungen

Primäre Ergebnismessungen

Objective response rate (ORR)Throughout the study period,period, from initiation of treatment up to 2 years

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.

Sekundäre Ergebnismessungen

Overall survival (OS)Throughout the study period, from initiation of treatment up to 12 months

Overall survival (OS): defined as the time elapsed from the first dose of study treatment until death from any cause. Patients alive and free of events at the date of the analysis will be censored at their last known contact. OS will be summarized using the Kaplan-Meier method and displayed graphically where appropriate. Confidence intervals (CIs) for the 25th, 50th and 75th percentiles will be reported. The Cox proportional hazards model will be fitted to compute the hazard ratios on potential stratified groups if applicable. OS will be calculated as median / mean (95% CI) and OS rate for different timepoints deemed appropriate at the time of the analysis (i.e.1-year OS rate) will also be calculated.

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

Clinical Benefit Rate (CBR): Assessed locally by the investigator through imaging follow-up (CT scan/MRI) using RECIST 1.1. CBR will include the percentage/proportion of patients with CR, PR, or SD (maintained > 4 months) as their overall best response throughout the study period. The CBR will be estimated by binomial proportion, dividing the number of patients with CR, PR or SD for at least 4 months for CBR by the total number of patients studied in the population. The corresponding exact 2-sided 95% CIs will be provided. Changes in tumor size from baseline will be calculated and displayed graphically, where appropriate.

Duration of Response (DoR):Throughout the study period, from initiation of treatment up to 12 months

Duration of Response (DoR): The DoR will be calculated for patients who achieve a CR or PR. Dates of progression and censoring for DoR will be determined as described for PFS. Kaplan-Meier methods will be used to estimate the distribution of DoR. Quartiles including the median will be estimated by KM method along with their 95% confidence intervals.

Treatment-free Survival (TFS)Throughout the study period, from initiation of treatment up to 24 months

Treatment-free Survival (TFS): defined as the time from the end of study treatment until the start of subsequent treatment, progression or death, whichever occurs first, will be determined as described for PFS. Kaplan-Meier methods will be used to estimate TFS.

Treatment-free Interval (TFI)Throughout the study period, from initiation of treatment up to 24 months

Treatment-free Interval (TFI): defined as the time from the end of study treatment until the start of subsequent treatment; will be determined as described for PFS. Kaplan-Meier methods will be used to estimate TFI.

Adverse Events (AEs) Safety ObjectiveThroughout the study period, from the inclusion of the first patient up to 24 months

Number of Participants with Adverse Events (AEs)

Incidence and severity of adverse eventsThroughout the study period, from the inclusion of the first patient up to 24 months

Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Discontinue Study Treatment Due to Adverse Events (AEs)Throughout the study period, from the inclusion of the first patient up to 24 months

Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)

Progression-free Survival (PFS) 6 monthsThroughout the study period, from initiation of treatment up to 6 months

Progression-free Survival (PFS) defined as the time from the start of treatment to disease progression or death from any cause, whichever occurs first. The PFS will be estimated by the Kaplan-Meier method. Patients alive and free of events at the date of the analysis will be censored at their last known tumor assessment. Patients who start a new treatment line without event will be censored on the date of first dose of the subsequent anticancer treatment. PFS will be displayed graphically where appropriate. PFS will be assessed by the median / mean (95% CI) and for different timepoints: Proportion of patients without progression at the end of follow-up. Proportion of patients at 6-months, 12-months and as deemed opportune by the time of the analysis. Confidence intervals (CIs) for the 25th, 50th and 75th percentiles will be reported. The Cox proportional hazards model will be fitted to compute the hazard ratios on potential stratified groups if applicable.

Progression-free Survival (PFS) 12 monthsThroughout the study period, from initiation of treatment up to 12 months

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Studienzentren

Diese Studie hat 13 Studienzentren

Hospital Universitario de Marqués de Valdecilla

Santander, Cantabria, ES

Name:A responsible person Selected by Sponsor,, M.D., Ph.D.

E-Mail:investigacion@mfar.net

Telefon:+34 93 434 44 12

Rekrutierend

Santander, Cantabria, 39008 ES

Hospital Universitario de Marqués de Valdecilla

Rekrutierend

Zaragoza, Zaragoza, 50009 ES

Hospital Universitario Miguel Servet

Rekrutierend

Madrid, Madrid, 28041 ES

Hospital Universitario 12 de Octubre

Rekrutierend

Madrid, Madrid, 28046 ES

Hospital Universitario La Paz

Rekrutierend

Badalona, Barcelona, 08916 ES

Institut Català D'Oncologia - Badalona

Rekrutierend

Madrid, Madrid, 28034 ES

Hospital Universitario Ramón y Cajal

Rekrutierend

A Coruña, A Coruña, 15006 ES

Complexo Hospitalario Universitario de A Coruña

Rekrutiert noch nicht

Barcelona, Barcelona, 08028 ES

Hospital Universitari Dexeus

Rekrutierend

Barcelona, Barcelona, 08035 ES

Hospital Universitario Valle de Hebrón

Rekrutierend

Barcelona, Barcelona, 08036 ES

Hospital Clinic de Barcelona

Rekrutierend

Murcia, Murcia, 30120 ES

Hospital Clínico Universitario Virgen de la Arrixaca

Rekrutierend

Seville, Sevilla, 41013 ES

Hospital Virgen del Rocío

Rekrutierend

Valencia, Valencia, 46014 ES

Hospital General de Valencia

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