Adjuvant Pembrolizumab Versus Placebo in High-Risk Stage III Melanoma Post-Resection: A Randomized, Double-Blind Phase 3 EORTC Trial
- Trial ID
- 2023-509136-25-00
- Protocol
- MK3475-054
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to prospectively assess whether post-operative adjuvant therapy with **pembrolizumab** improves recurrence-free survival compared to placebo in high-risk patients with complete resection of Stage IIIA (>1 mm metastasis), IIIB, and IIIC melanoma. Additionally, the study aims to evaluate if pembrolizumab enhances recurrence-free survival in the subgroup of patients with PD-L1-positive tumor expression compared to placebo. This is clinically relevant as improving recurrence-free survival can significantly impact the long-term prognosis and quality of life for patients with high-risk Stage III melanoma.
Secondary objectives include: - To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves distant metastasis-free survival compared to placebo. - To evaluate if pembrolizumab enhances distant metastasis-free survival in patients with PD-L1-positive tumor expression. - To determine whether pembrolizumab improves overall survival compared to placebo. - To assess if pembrolizumab enhances overall survival in the subgroup of patients with PD-L1-positive tumor expression. - To compare adverse event profiles, including adverse events (AE) and serious adverse events (SAE), between patients receiving pembrolizumab and those in the placebo arm. - To evaluate the pharmacokinetics (PK) of pembrolizumab when administered at 200 mg every three weeks.
Participants
The clinical trial involves a total of **447 participants** diagnosed with **Stage III melanoma**, specifically those with histologically confirmed cutaneous melanoma metastatic to lymph nodes, classified as Stage IIIA with metastasis greater than 1 mm, and any Stage IIIB or IIIC, according to the AJCC 2010 criteria. The study population includes both male and female subjects, aged 18 years and older, with a focus on high-risk patients who have undergone complete resection of the melanoma. Participants were selected based on specific inclusion criteria, including the absence of mucosal or ocular melanoma, and the requirement for a tumor sample to be evaluated for PD-L1 expression. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is not limited to any specific health status beyond the criteria related to melanoma and its treatment history. The trial includes a vulnerable population, ensuring that all participants meet the eligibility criteria, which include adequate organ function and no active autoimmune disease requiring systemic treatment in the past two years.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **pembrolizumab**, an anti-PD-1 monoclonal antibody, as an adjuvant therapy compared to a placebo in patients with high-risk Stage III melanoma following complete resection. This is a randomized, double-blind, Phase 3 trial. The trial aims to assess whether pembrolizumab improves recurrence-free survival (RFS) and distant metastases-free survival (DMFS) in patients, particularly those with PD-L1-positive tumor expression. The trial is expected to conclude by July 31, 2026, with recruitment having started on October 2, 2015.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, melanoma stage, and PD-L1 expression. The screening process involves a three-step procedure: registration, central confirmation of PD-L1 expression, and enrollment/randomization. Following successful enrollment, participants will be randomly assigned to receive either pembrolizumab or a placebo. The treatment period will last up to 52 weeks, with pembrolizumab administered intravenously.
Throughout the trial, participants will attend regular follow-up visits to monitor their health status, assess treatment efficacy, and document any adverse events. These visits will include clinical examinations, imaging studies, and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. Participants may be withdrawn from the trial if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety.
The expected length of participant involvement is approximately one year, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial's primary endpoints are recurrence-free survival and RFS for patients with PD-L1-positive expression, while secondary endpoints include DMFS, overall survival, and pharmacokinetics of pembrolizumab. The trial is conducted in compliance with ICH/GCP guidelines and national/local regulations, ensuring the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, as the experimental medication. KEYTRUDA is provided as a 25 mg/mL **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The maximum daily and total dose is 200 mg, with a treatment period extending up to 52 weeks. Pembrolizumab is a biological product of biotechnological origin, specifically an anti-PD-1 monoclonal antibody, and is produced by Merck Sharp & Dohme B.V. The product is not a pediatric formulation and is identified by the sponsor product code MK-3475. The trial aims to evaluate the efficacy of pembrolizumab in improving recurrence-free survival in patients with high-risk Stage III melanoma following complete resection.
The study also includes a **placebo** treatment, which is a saline solution. The saline solution serves as the comparator treatment in this randomized, double-blind Phase 3 trial. The placebo is used to assess the efficacy of pembrolizumab by providing a control group for comparison. The saline solution does not contain any active pharmaceutical ingredients and is not associated with any specific pharmaceutical form or route of administration in the context of this trial. The use of a placebo is critical in determining the true therapeutic effect of pembrolizumab on recurrence-free survival in the target patient population.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **recurrence-free survival (RFS)**, with a specific focus on patients with PD-L1-positive expression. Secondary endpoints include **distant metastases-free survival (DMFS)**, **overall survival (OS)**, and the pharmacokinetics (PK) of pembrolizumab. These parameters will be evaluated to determine the effectiveness of pembrolizumab as an adjuvant therapy compared to placebo in patients with high-risk Stage III melanoma following complete resection.
The trial is designed to prospectively assess whether pembrolizumab improves RFS in the overall study population and in the subgroup of patients with PD-L1-positive tumor expression. The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial, with the estimated end date set for July 31, 2026. The trial will adhere to rigorous standards to ensure the accuracy and reliability of the efficacy assessments, contributing to the understanding of pembrolizumab's potential benefits in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient enrollment will follow a three steps procedure as illustrated in Section 4 (step 1 registration, step 2 central confirmation of PD-L1 expression, step 3 enrollment and randomization through IVRS). Patients must meet all of the criteria described in Section 3 to be eligible for enrollment. 1) Registration- step 1 (ORTA Step 1) Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP, and national/local regulations. Note: if a patient signs the Registration Informed Consent before the complete lymph node dissection (CLND) was performed, please contact the medical monitor to assess eligibility before registering in ORTA. ♦ At least 18 years of age. ♦ No mucosal or ocular melanoma. ♦ Melanoma with unknown origin of the primary is eligible. ♦ Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC. No past or current in-transit metastases or satellitosis. ♦ Patient population IIIA (> 1 mm metastasis) is capped at a maximum of 20% of the total patient population. ♦ Mandatory to ship tumor sample for evaluation of PD-L1 expression. A tumor sample obtained at resection or tissue obtained from the biopsy must not be previously irradiated. During the screening period, the tumor sample must be sent to the central pathology laboratory for PD-L1 expression testing. Patients will be eligible to participate regardless of the level of PD-L1 expression. ♦ PD-L1 testing is mandatory: tumor material will be collected from positive lymph nodes (LN) embedded in paraffin. If the resection samples from LNs are not adequate for PD-L1 testing, the primary melanoma must be collected. Patients whose samples are inadequate for PD-L1 determination will not be enrolled. ♦ In addition the primary melanoma may also be collected if available to evaluate the PD-L1 expression.
- Central confirmation of PD-L1 expression - step 2 This central confirmation through EORTC is required for enrolling the patient in step 3.
- Enrollment and randomization -step 3 (ORTA Step 2) Before patient enrollment, written informed consent to participate in the trial must be given according to ICH/GCP, and national/local regulations. ♦ The resection of Stage III lymph nodes must have been performed in complete compliance with the Criteria for adequate surgical procedures for CLND that is displayed in Appendix F. This must be documented in the medical file (including pathology report); patients without documentation of adequate resection are not eligible. ♦ To be considered as adequate, the surgical and pathological procedures should have included at least the following: ♦ Head and Neck ♦ Minimum of 15 pathologically investigated nodes ♦ Face, ear, and anterior scalp: parotidectomy plus modified radical neck dissection ♦ Posterior scalp: modified radical neck dissection plus suboccipital nodes. For this specific localization, a CLND will be considered as adequate if at least 5 LN have been investigated ♦ Upper Extremity ♦ Minimum of 10 pathologically investigated nodes ♦ Axillary node dissection included at least 10 nodes taken from Levels I and II ♦ Level III nodes dissected if they were clinically involved ♦ Pectoralis minor muscle may be divided or sacrificed with the specimen at the discretion of the surgeon ♦ Lower Extremity ♦ Minimum of 5 pathologically investigated nodes ♦ Superficial inguinal node dissection was performed for nonpalpable nodal involvement ♦ If Cloquet’s node was positive, a deep inguinal node dissection was performed ♦ Lymph Node Dissection for Nodal Recurrence
- Enrollment and randomization -step 3 (ORTA Step 2) – Continues ♦ Regional node recurrence was treated using the appropriate lymphadenectomy as above ♦ Diagnosis of regional node recurrence was made by fine needle aspiration technique to avoid contaminating the region with tumor, followed by CLND as above ♦ The maximum duration from surgery to first study drug treatment is 13 weeks. Treatment should start only after complete wound healing from the surgery. Note: if there is a delay of 1-7 days exceeding 13 weeks due to extreme unforeseen circumstances, the eligibility should be discussed with the medical monitor. ♦ Disease status for the post-surgery baseline assessment must be documented by full Chest/Abdomen/Pelvis CT and/or MRI with Neck CT and/or MRI (for Head and Neck primaries) and complete clinical examination after the informed consent and prior to enrollment. Note: if a patient had laboratory/imaging tests as part of local routine guidelines (standard of care) prior to signing informed consent, the procedures will be acceptable for screening purposes if they are within the window required by the protocol. ♦ Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for brain metastases. ♦ BRAF mutation status (known or not done). ♦ ECOG performance status of 0 or 1. ♦ Patient demonstrates adequate organ function ♦ Prior treatment for melanoma ♦ In case of an indication for post lymph node dissection radiotherapy, this must have been completed within the 13 weeks post-surgery period and prior to treatment start. Note: radiotherapy may alter the process of wound healing. If the wound healing is not complete patient will not be eligible. ♦ No prior therapy for melanoma except surgery for primary melanoma lesions; patients who have previously received IFN for thick primary melanomas without evidence of lymph node involvement are eligible. ♦ No history of (non-infectious) pneumonitis that required steroids or current pneumonitis. No history of or current interstitial lung disease. ♦ No history of another malignancy or a concurrent malignancy. Exceptions include patients who have been disease-free for 5 years, or patients with a history of completely resected nonmelanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ. ♦ No active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. ♦ No active infection requiring therapy. ♦ Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement will not be excluded. ♦ No diagnosis of immunodeficiency, no systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
- Enrollment and randomization -step 3 (ORTA Step 2) continues ♦ No known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C. ♦ Patients who received treatment with live vaccines within 30 days prior to the first dose of study medication are not eligible. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, seasonal flu, H1N1 flu, rabies, BCG and typhoid vaccine. ♦ Patient must not have received prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent. Examples of PD-1 inhibitors (include, but are not limited to): pembrolizumab (MSD); Nivolumab (also known as BMS-936558, MDX- 1106, ONO-4538) (Bristol-Myers Squibb); Pidilizumab (CT-11) (Cure- Tech/Teva); and AMP-224 (Amplimmune). Examples of PD-L1 inhibitors (include, but are not limited to): BMS- 936559 (also known as MDX-1105) (Bristol-Myers Squibb); MPDL3280A (also known as RG7446) (Roche Genentech); and MEDI4736 (MedImmune). ♦ Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to the first dose of treatment ♦ Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. ♦ WOCBP should use adequate birth control methods, as defined by the investigator, during the study treatment period and for a period of 120 days after the last dose of study drug. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. ♦ Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard. ♦ Appendix N is to be used where applicable for specific countries and sites adhering to Clinical Trial Facilitation Group guidelines for clinical trials (e.g. United Kingdom, Norway, Sweden, Portugal, etc). ♦ Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of study drug . ♦ Absence of any condition hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. ♦ Patient will not be eligible: if patient is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject. Once eligibility has been verified, the treatment arm will be randomly allocated to the patient. Important note: All eligibility criteria must be adhered to.
Exclusion Criteria
- Not available. According to study design, all exclusion criteria are included within inclusion criteria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 02 Oct 2015 | 6 |
 Belgium | Not Recruiting | 02 Oct 2015 | 15 |
 Denmark | Not Recruiting | 02 Oct 2015 | 24 |
 Finland | Not Recruiting | 02 Oct 2015 | 8 |
 France | Not Recruiting | 02 Oct 2015 | 161 |
 Germany | Not Recruiting | 02 Oct 2015 | 102 |
 Italy | Not Recruiting | 02 Oct 2015 | 110 |
 The Netherlands | Not Recruiting | 02 Oct 2015 | — |
 Norway | Not Recruiting | 02 Oct 2015 | 4 |
 Poland | Not Recruiting | 02 Oct 2015 | 20 |
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 |
|---|---|---|---|---|---|---|
Saline Solution | Placebo | N/A | — | — | — | N/A |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 52 | PRD4323105 |