Efficacy and Safety Evaluation of Enfortumab Vedotin and Pembrolizumab in Advanced Melanoma: A Phase II, Open-Label, Multicenter Study
- Trial ID
- 2024-514163-26-00
- Protocol
- GEM 2303
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination of enfortumab vedotin and pembrolizumab in patients with advanced melanoma. This is clinically relevant as advanced melanoma is a challenging condition with limited treatment options, and assessing the efficacy of new therapeutic combinations could potentially improve patient outcomes.
Secondary objectives include:
- Assessing the **safety** of enfortumab vedotin plus pembrolizumab in this patient population.
- Evaluating patient-reported outcomes to understand the impact of the treatment on quality of life.
Participants
The clinical trial focuses on evaluating the efficacy of EV plus pembrolizumab in individuals diagnosed with **advanced melanoma**. The study population includes both male and female participants who are at least 18 years of age, with no upper age limit specified. Participants are required to have a histologically confirmed diagnosis of unresectable or metastatic melanoma and must have received prior systemic therapy for locally advanced or metastatic melanoma. The trial does not include vulnerable populations. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, such as having measurable disease according to RECIST v1.1 and adequate organ function. Lifestyle considerations, such as diet and physical activity, are not specified. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is a **Phase II**, open-label, multicenter, non-randomized study designed to evaluate the efficacy and safety of **enfortumab vedotin** in combination with **pembrolizumab** in patients with advanced melanoma. The trial aims to assess the **Objective Response Rate (ORR)** as the primary endpoint, with secondary endpoints including **Progression-free Survival (PFS)**, **Overall Survival (OS)**, and **Clinical Benefit Rate (CBR)**, among others. The study will involve the administration of the investigational products via **intravenous infusion** over a maximum treatment period of 24 months.
Participants will be required to attend several study visits throughout the trial. The initial visit will be a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and prior treatment history. Participants must have a histologically confirmed diagnosis of unresectable or metastatic melanoma and have received prior systemic therapy. Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse events. These visits will include imaging follow-ups using **CT scan/MRI** to evaluate disease progression according to **RECIST v1.1** criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement in the trial is up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be monitored for adverse events, and the severity of these events will be determined according to the **National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)**. The trial is estimated to conclude by January 30, 2027, with recruitment starting on January 30, 2025.
Treatment
The clinical trial involves the administration of **Padcev**, which is available in two formulations: 30 mg and 20 mg powder for concentrate for solution for infusion. The active substance in Padcev is **enfortumab vedotin**, a protein-based antibody-drug conjugate. The pharmaceutical form is a solution for infusion, and the medication is administered via **intravenous infusion**. The dosage is calculated based on body weight, with a maximum daily dose of 1.25 mg/kg and a total dose not exceeding 125 mg. The treatment period is set for a maximum of 24 weeks. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
Another experimental medication used in the trial is **KEYTRUDA**, which contains the active substance **pembrolizumab**. This medication is provided as a 25 mg/mL concentrate for solution for infusion. Like Padcev, KEYTRUDA is administered through **intravenous infusion**. The maximum daily and total dose for pembrolizumab is 400 mg, with a treatment duration of up to 24 weeks. Participant compliance is closely monitored to maintain the integrity of the study results.
Both medications are administered in combination to evaluate their efficacy and safety in patients with advanced melanoma. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The study is designed to assess the therapeutic potential of the combination of enfortumab vedotin and pembrolizumab in this patient population.
Efficacy
The efficacy of the combination of **enfortumab vedotin** and pembrolizumab in the treatment of advanced melanoma will be assessed using several primary and secondary endpoints. The primary endpoint is the Objective Response Rate (ORR), which will be evaluated by the investigator using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). ORR is defined as the percentage of patients who achieve a confirmed complete response (CR) or partial response (PR) as their best overall response during the study.
Secondary endpoints include Progression-free Survival (PFS), Overall Survival (OS), Clinical Benefit Rate (CBR), Duration of Response (DoR), Treatment-free Survival (TFS), and Treatment-free Interval (TFI). PFS is measured from the first dose of study treatment to the first documentation of progressive disease or death from any cause. OS is defined as the time from the first dose to death from any cause. CBR includes patients with CR, PR, or stable disease (SD) maintained for at least 4 months. DoR is assessed by RECIST 1.1 and is considered alongside ORR. TFS and TFI are measured from the end of study treatment to the start of subsequent treatment, progression, or death.
Additionally, the study will evaluate the safety of the treatment combination by monitoring the number of participants with adverse events (AEs), the incidence and severity of AEs according to NCI CTCAE v5.0, and the number of participants who discontinue treatment due to AEs. Health-related quality of life (HRQoL) will also be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) at specified time points.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Have adequate organ function as defined in the followgin table (Table 3). Specimens must be collected within 10 days prior to the start of study intervention.
- Participants must have measurable disease by investigator assessment according to RECIST v1.1. a). 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.
- A male participant must agree to use a contraception as detailed in Appendix 3 of the 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.
- 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: a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR b) 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. 1) Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1. 2) 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.
- 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.
- 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.
- 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.
Exclusion Criteria
- 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.
- 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 Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 30 Jan 2025 | 60 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Padcev 30 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1.25 | 24 | PRD9634494 |
Padcev 20 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1.25 | 24 | PRD9634490 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 400 | 24 | PRD4323105 |