MelanomaPhase 2PlugINNCT06906822
PLUG-IN: Pembrolizumab Combined With Enfortumab Vedotin for Advanced Melanoma Patients
A Phase 2 study testing enfortumab vedotin and pembrolizumab in people with Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 13 sites in Spain.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- enfortumab vedotin and pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 13 sitesSpain
- Study dates
- 10 Jun 2025to Jun 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 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:
Show all 20Show fewer
- 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:
- 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.
- 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.
- BRAF mutated patients should have received BRAF/MEK inhibitors and PD1/PDL1 therapy c. Prior CTLA4 therapy is allowed.
- 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.
- 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.
- 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.
- 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.
Who cannot join
- 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.
Show all 29Show fewer
- 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.
- Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
- Participants with conditions requiring systemic doses of corticosteroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required corticosteroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV) infection.
- 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
- Has not adequately recovered from major surgery or has ongoing surgical complications.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of contraception period.
- Has had an allogenic tissue/solid organ transplant.
- History of Clinical Tuberculosis
Trial locations and contacts
13 sites in 1 country.
13 sites in 1 country
Spain13 sites
Complexo Hospitalario Universitario de A Coruña
A Coruña, A Coruña, 15006
Institut Català D'Oncologia - Badalona
Badalona, Barcelona, 08916
Hospital Universitari Dexeus
Barcelona, Barcelona, 08028
Hospital Universitario Valle de Hebrón
Barcelona, Barcelona, 08035
Hospital Clinic de Barcelona
Barcelona, Barcelona, 08036
Hospital Universitario Ramón y Cajal
Madrid, Madrid, 28034
Hospital Universitario 12 de Octubre
Madrid, Madrid, 28041
Hospital Universitario La Paz
Madrid, Madrid, 28046
Hospital Clínico Universitario Virgen de la Arrixaca
Murcia, Murcia, 30120
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, 39008
Hospital Virgen del Rocío
Seville, Sevilla, 41013
Hospital General de Valencia
Valencia, Valencia, 46014
Hospital Universitario Miguel Servet
Zaragoza, Zaragoza, 50009
About this study
Official title: A Phase II, Open-label, Multicenter, Non-Randomized Study of the Efficacy and Safety of Enfortumab Vetodin in Combination With Pembrolizumab Previously Treated Advanced Melanoma
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.
Read more
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
Read the detailed description
- RATIONALE 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 and pembrolizumab has shown synergistic effect in various solid tumors. Enfortumab vedotin and pembrolizumab may have a dual effect on clinical outcomes:
- Enfortumab vedotin could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells.
- Enfortumab vedotin could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy.
- OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S)
2.1 Primary Objective(s), Hypothesis(es), and Endpoint(s) Objective: This study will evaluate the efficacy of EV plus 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.
The combination of EV+Pembrolizumab may have a dual effect on outcomes:
- EV could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells.
- EV could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy. Primary Endpoint:
- 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. 2.2 Secondary Objective(s), Hypothesis(es), and Endpoint(s) Secondary Endpoint:
- Progression-free Survival (PFS) as assessed by RECIST 1.1. PFS is defined as the time from first dose of study treatment to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurs first.
- Overall Survival (OS), defined as the time from first dose of study treatment to the date of death from any cause.
- Clinical Benefit Rate (CBR), defined as proportion of patients with complete response (CR) or partial response (PR), according to ORR definition for the trial, or maintained stable disease (SD) as their overall best response, assessed by imaging follow-up (CT scan/MRI) and RECIST V1.1 criteria. Stable disease should be maintained for at least 4 months to be considered as a CBR event.
- Duration of Response (DoR) as Assessed by RECIST 1.1. DoR is considered an acceptable measure of clinical benefit when considered with ORR.
- 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.
- Treatment-free Interval (TFI), defined as the time from the end study treatment until the start of subsequent treatment.
- The safety objective for this study is to evaluate the safety of EV plus pembrolizumab on the basis of the following endpoints:
- Number of Participants with Adverse Events (AEs) Safety Objective Incidence and severity of adverse events, with severity determined according to b. National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
- Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)
- Mean change from baseline in health-related quality of life (HRQoL) scores as assessed through use of the two-item global health status (GHS)/HRQoL subscale of the European Organisation for Research and Treatment of Cancer Quality ofLifeCore 30 (EORTC QLQ-C30) at specified time points. 2.3. Exploratory Objective(s) Objective: Correlative studies (microbiome and transcriptomic analysis)
- TRIAL DESIGN 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. Specific procedures to be performed during the study, as well as their prescribed times and associated visit windows, are specifically outlined in the protcolo. The study will include a Screening Phase, a Treatment Phase, and a Posttreatment Follow-Up Phase. The Screening Phase assessments must be performed within 30 days before randomization. Potential participants will be screened to determine if they meet the required eligibility criteria. Assessments will include AE monitoring, concomitant medication review, physical examination and ophthalmological examination, vital signs, blood pressure, ECG, hematology, chemistry, urine dipstick, and ECOG performance status.
- TRIAL POPULATION 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. Patients are males/females, ≥18 years old, with measurable disease according to RECIST 1.1 and progressive disease / recurrence documented within 12 weeks from the last dose of previous anti-PD-1/L1. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, have recovered from previous toxicities and with an adequate organ function. Archival tumor tissue sample or newly obtained biopsy is requested. Patients with contraindications to receive immunotherapy, exposed previously to enfortumab vedotin and pregnant or breastfeeding women are excluded.
- STUDY TREATMENTS Enfortumab vedotin will be administered on Days 1, 8, 22 and 29 of every 6-week cycle by IV infusion given over approximately 30 minutes. Pembrolizumab 400 mg will be administered as a 30 minute IV infusion every 6 weeks. Enfortumab vedotin will be administered until progression of the disease, lack of benefit, death, consent withdrawal or unacceptable toxicity. Treatment with pembrolizumab will last a maximum of 18 cycles. Pembrolizumab may be discontinued earlier in case of progression of the disease, lack of benefit, death, consent withdrawal or unacceptable toxicity.
- Conditions
- Melanoma
- Being tested
- enfortumab vedotin, pembrolizumab
- Keywords
- Melanoma, Enfortumab, vedotin, pembrolizumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
enfortumab vedotinDrug
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.
pembrolizumabDrug
Pembrolizumab 400 mg on day 1 of each 42-day cycle (Q6W)
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | patients who did not have BRAF mutation V600E and had disease progression on immune (IO) therapy. Receives: Drug: enfortumab vedotin; Drug: pembrolizumab |
| Cohort 2 | Experimental | patients with activating BRAF mutations, must have progressed on IO therapy and BRAF/MEKi Receives: Drug: enfortumab vedotin; Drug: pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Throughout the study period,period, from initiation of treatment up to 2 years
Secondary outcomes (11)
Progression-free Survival (PFS) 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.
Measured: Throughout the study period, from initiation of treatment up to 6 months
Progression-free Survival (PFS) 12 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.
Measured: Throughout the study period, from initiation of treatment up to 12 months
Overall survival (OS)
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.
Measured: Throughout the study period, from initiation of treatment up to 12 months
Overall survival (OS)
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.
Measured: Throughout the study period, from initiation of treatment up to 24 months
Clinical Benefit Rate (CBR)
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.
Measured: Throughout the study period, from initiation of treatment up to 24 months
Duration of Response (DoR):
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.
Measured: Throughout the study period, from initiation of treatment up to 12 months
Treatment-free Survival (TFS)
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.
Measured: Throughout the study period, from initiation of treatment up to 24 months
Treatment-free Interval (TFI)
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.
Measured: Throughout the study period, from initiation of treatment up to 24 months
Adverse Events (AEs) Safety Objective
Number of Participants with Adverse Events (AEs)
Measured: Throughout the study period, from the inclusion of the first patient up to 24 months
Incidence and severity of adverse events
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)
Measured: Throughout the study period, from the inclusion of the first patient up to 24 months
Discontinue Study Treatment Due to Adverse Events (AEs)
Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)
Measured: Throughout the study period, from the inclusion of the first patient up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2025
- Study start10 Jun 2025
- Primary completionJun 2027 (estimated)
- Study completionJun 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- 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
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Grupo Español Multidisciplinar de Melanoma
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Astellas Pharma Inc
- Responsible party
- Sponsor
- Investigators
- Guillermo de Velasco, M.D., Ph.D., Study director, Hospital Universitario 12 de OctubreAinara Soria, M.D., Ph.D., Study director, Hospital Universitario Ramon y Cajal
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06906822
- Sponsor's protocol ID
- GEM 2303
- Other IDs
- 2024-514163-26-00
- Acronym
- PlugIN
- Status last verified
- Sep 2026
- First submitted
- 26 Mar 2025
- Last updated
- 18 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II, Open-label, Multicenter, Non-Randomized Study of the Efficacy and Safety of Enfortumab Vetodin in Combination With Pembrolizumab Previously Treated Advanced Melanoma
- ClinicalTrials.gov ID
- NCT06906822
- Acronym / sponsor ID
- PlugIN / GEM 2303
- Conditions
- Melanoma
- Keywords
- Melanoma, Enfortumab, vedotin, pembrolizumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Grupo Español Multidisciplinar de MelanomaUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Astellas Pharma Inc
- Study start
- 10 Jun 2025 (actual)
- Primary completion
- Jun 2027 (estimated)
- Study completion
- Jun 2028 (estimated)
- First posted
- 2 Apr 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
- RATIONALE 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 and pembrolizumab has shown synergistic effect in various solid tumors. Enfortumab vedotin and pembrolizumab may have a dual effect on clinical outcomes:
- Enfortumab vedotin could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells.
- Enfortumab vedotin could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy.
- OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S)
2.1 Primary Objective(s), Hypothesis(es), and Endpoint(s) Objective: This study will evaluate the efficacy of EV plus 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.
The combination of EV+Pembrolizumab may have a dual effect on outcomes:
- EV could induce a tumor response based on a high dose of the microtubule disruptor in tumor cells.
- EV could enhance antitumor immunity and prolong the benefit of continuous PD1 therapy. Primary Endpoint:
- 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. 2.2 Secondary Objective(s), Hypothesis(es), and Endpoint(s) Secondary Endpoint:
- Progression-free Survival (PFS) as assessed by RECIST 1.1. PFS is defined as the time from first dose of study treatment to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurs first.
- Overall Survival (OS), defined as the time from first dose of study treatment to the date of death from any cause.
- Clinical Benefit Rate (CBR), defined as proportion of patients with complete response (CR) or partial response (PR), according to ORR definition for the trial, or maintained stable disease (SD) as their overall best response, assessed by imaging follow-up (CT scan/MRI) and RECIST V1.1 criteria. Stable disease should be maintained for at least 4 months to be considered as a CBR event.
- Duration of Response (DoR) as Assessed by RECIST 1.1. DoR is considered an acceptable measure of clinical benefit when considered with ORR.
- 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.
- Treatment-free Interval (TFI), defined as the time from the end study treatment until the start of subsequent treatment.
- The safety objective for this study is to evaluate the safety of EV plus pembrolizumab on the basis of the following endpoints:
- Number of Participants with Adverse Events (AEs) Safety Objective Incidence and severity of adverse events, with severity determined according to b. National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
- Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)
- Mean change from baseline in health-related quality of life (HRQoL) scores as assessed through use of the two-item global health status (GHS)/HRQoL subscale of the European Organisation for Research and Treatment of Cancer Quality ofLifeCore 30 (EORTC QLQ-C30) at specified time points. 2.3. Exploratory Objective(s) Objective: Correlative studies (microbiome and transcriptomic analysis)
- TRIAL DESIGN 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. Specific procedures to be performed during the study, as well as their prescribed times and associated visit windows, are specifically outlined in the protcolo. The study will include a Screening Phase, a Treatment Phase, and a Posttreatment Follow-Up Phase. The Screening Phase assessments must be performed within 30 days before randomization. Potential participants will be screened to determine if they meet the required eligibility criteria. Assessments will include AE monitoring, concomitant medication review, physical examination and ophthalmological examination, vital signs, blood pressure, ECG, hematology, chemistry, urine dipstick, and ECOG performance status.
- TRIAL POPULATION 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. Patients are males/females, ≥18 years old, with measurable disease according to RECIST 1.1 and progressive disease / recurrence documented within 12 weeks from the last dose of previous anti-PD-1/L1. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, have recovered from previous toxicities and with an adequate organ function. Archival tumor tissue sample or newly obtained biopsy is requested. Patients with contraindications to receive immunotherapy, exposed previously to enfortumab vedotin and pregnant or breastfeeding women are excluded.
- STUDY TREATMENTS Enfortumab vedotin will be administered on Days 1, 8, 22 and 29 of every 6-week cycle by IV infusion given over approximately 30 minutes. Pembrolizumab 400 mg will be administered as a 30 minute IV infusion every 6 weeks. Enfortumab vedotin will be administered until progression of the disease, lack of benefit, death, consent withdrawal or unacceptable toxicity. Treatment with pembrolizumab will last a maximum of 18 cycles. Pembrolizumab may be discontinued earlier in case of progression of the disease, lack of benefit, death, consent withdrawal or unacceptable toxicity.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: enfortumab vedotin, Drug: pembrolizumabpatients who did not have BRAF mutation V600E and had disease progression on immune (IO) therapy. |
| Cohort 2 | Experimental | Drug: enfortumab vedotin, Drug: pembrolizumabpatients with activating BRAF mutations, must have progressed on IO therapy and BRAF/MEKi |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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:
- Female participants:
Key exclusion criteria (29 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| enfortumab vedotinEnfortumab 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. | Drug | Cohort 1, Cohort 2 |
| pembrolizumabPembrolizumab 400 mg on day 1 of each 42-day cycle (Q6W) | Drug | Cohort 1, Cohort 2 |
Primary outcome
Objective response rate (ORR)
Time frame: 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.
11 secondary outcomes
Progression-free Survival (PFS) 6 months
Time frame: Throughout the study period, from initiation of treatment up to 6 months
Progression-free Survival (PFS) 12 months
Time frame: Throughout the study period, from initiation of treatment up to 12 months
Overall survival (OS)
Time frame: Throughout the study period, from initiation of treatment up to 12 months
Overall survival (OS)
Time frame: Throughout the study period, from initiation of treatment up to 24 months
Clinical Benefit Rate (CBR)
Time frame: Throughout the study period, from initiation of treatment up to 24 months
Duration of Response (DoR):
Time frame: Throughout the study period, from initiation of treatment up to 12 months
Treatment-free Survival (TFS)
Time frame: Throughout the study period, from initiation of treatment up to 24 months
Treatment-free Interval (TFI)
Time frame: Throughout the study period, from initiation of treatment up to 24 months
Adverse Events (AEs) Safety Objective
Time frame: Throughout the study period, from the inclusion of the first patient up to 24 months
Incidence and severity of adverse events
Time frame: Throughout the study period, from the inclusion of the first patient up to 24 months
Discontinue Study Treatment Due to Adverse Events (AEs)
Time frame: Throughout the study period, from the inclusion of the first patient up to 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2026.
- Individual participant dataSharing planned: No
Related trials for Melanoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Feasibility Study Utilizing Immune Recall to Increase Response to Checkpoint Therapy
Melanoma
Active, not recruitingPhase 1/2
A Study of Dapansutrile Plus Pembrolizumab in Patients With PD-1 Refractory Advanced Melanoma
Melanoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Guillermo de Velasco, M.D., Ph.D. study director
Hospital Universitario 12 de Octubre
Ainara Soria, M.D., Ph.D. study director
Hospital Universitario Ramon y Cajal
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing enfortumab vedotin and pembrolizumab in people with Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 13 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 18 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response rate (ORR) (time frame: Throughout the study period,period, from initiation of treatment up to 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2026.