Phase 3 Multicenter Trial of Neoadjuvant Ipilimumab and Nivolumab Versus Adjuvant Nivolumab in Patients with Macroscopic Stage III Melanoma
- Trial ID
- 2024-513519-28-00
- Protocol
- M23MAR
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicenter phase 3 trial is to compare the **event-free survival (EFS)** of patients with macroscopic stage III melanoma treated with neoadjuvant ipilimumab and nivolumab, followed by adjuvant nivolumab or dabrafenib plus trametinib in those not achieving a pathologic response, versus those receiving standard adjuvant nivolumab. This comparison is clinically relevant as it may provide insights into the efficacy of neoadjuvant therapy in improving EFS, potentially leading to changes in treatment protocols for stage III melanoma.
Secondary objectives include:
- Describing the **Overall Survival (OS)** in both treatment arms.
- Describing the **recurrence-free survival (RFS)** and **distant metastases-free survival (DMFS)** in both arms.
- Describing the **event-free survival (EFS)** including a new primary melanoma as an event in both arms.
- Evaluating the association between pathologic response and RFS, DMFS, and OS, including analyses of pathologic response subgroups and subgroup analyses in BRAF wildtype and BRAFV600 mutated patients.
- Describing the rate and type of **immune-related adverse events**.
- Describing **surgical morbidity**.
- Evaluating **health-related quality of life (HRQoL)** in both treatment arms.
- Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.
Participants
The clinical trial involves a total of **143 participants** diagnosed with **Stage III melanoma**. The study population includes both **men and women** aged 16 years and older, with a **World Health Organization (WHO) Performance Status** of 0 or 1, indicating they are in good general health. Participants were selected based on specific criteria, including cytologically or histologically confirmed resectable Stage III melanoma with macroscopic lymph node metastases. The trial excludes individuals with other malignancies unless adequately treated and with a cancer-related life expectancy of more than five years. Participants must not have received prior immunotherapy targeting CTLA-4, PD-1, PD-L1, or LAG-3, nor prior targeted therapy targeting BRAF and/or MEK. Additionally, no immunosuppressive medications are allowed within six months prior to study inclusion, except for low-dose steroids. The trial does not involve a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of neoadjuvant **ipilimumab** and **nivolumab** compared to standard adjuvant nivolumab in patients with stage III melanoma. The trial aims to assess event-free survival (EFS) as the primary endpoint, with secondary endpoints including overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). The study is expected to run until December 2028, with recruitment having commenced in July 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and laboratory values. Following randomization, participants will receive treatment via **intravenous infusion** over a maximum period of six months. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur upon completion of the treatment phase or in the event of disease progression, recurrence, or other endpoints being met.
The expected duration of participant involvement is approximately six months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study protocols. Participants will be closely monitored throughout the trial to ensure safety and adherence to the treatment regimen. The trial's design and procedures are structured to provide robust data on the comparative effectiveness of the treatment regimens, contributing valuable insights into the management of stage III melanoma.
Treatment
The clinical trial involves the administration of **OPDIVO** (nivolumab), a **concentrate for solution for infusion**. This pharmaceutical form is specifically designed for **intravenous infusion**. The active substance, **nivolumab**, is a protein-based therapeutic agent. The maximum daily dose of OPDIVO is 240 mg, with a total maximum dose of 480 mg over the treatment period. The treatment is administered as a **neo-adjuvant therapy**, although the marketing authorization is for adjuvant therapy. The treatment period is set for a maximum of 6 months. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
Another experimental medication used in the trial is **YERVOY** (ipilimumab), also a **concentrate for solution for infusion**. Like OPDIVO, YERVOY is administered via **intravenous infusion**. The active substance, **ipilimumab**, is similarly a protein-based therapeutic agent. The maximum daily dose for YERVOY is 80 mg, with a total maximum dose of 160 mg over the treatment period. This medication is also used as a **neo-adjuvant therapy**, with the marketing authorization being for adjuvant therapy. The treatment duration is up to 6 months, and compliance with the dosing schedule is closely monitored.
The trial compares the efficacy of the combination of neoadjuvant ipilimumab and nivolumab, followed by adjuvant nivolumab or dabrafenib plus trametinib in patients not achieving a pathologic response, against the standard adjuvant nivolumab in patients with macroscopic stage III melanoma. The study aims to evaluate the event-free survival (EFS) of the treatment regimens. No placebo or comparator treatment is used in this trial, as the focus is on comparing the experimental combination therapy with the standard-of-care therapy.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, defined as the time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. Secondary endpoints include Overall Survival (OS), defined as the time between the date of randomization and the date of death from any cause; Recurrence-Free Survival (RFS), defined as the time between the date of surgery and the date of melanoma recurrence, treatment-related death, or melanoma-related death; and Distant Metastasis-Free Survival (DMFS), defined as the time between the date of randomization and the date of first distant metastasis, treatment-related death, or melanoma-related death.
Additional secondary endpoints involve the pathologic response rate in the neoadjuvant arm, categorized into complete pathologic response (pCR), near-pCR, major pathologic response (MPR), partial pathologic response (pPR), and no pathologic response (pNR) according to INMC criteria. The correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS will also be evaluated. The frequency and duration of all grade and grade 3-5 treatment-related adverse events will be assessed according to CTCAE 5.0. Surgical complication rates will be classified according to the Clavien-Dindo surgical classification. Quality of life will be measured using various tools, including the EORTC QLQ C30, the Melanoma Subscale and Melanoma Surgery Subscale of FACT-M, the Cancer Worry Scale, HADS questionnaire, EQ-5D-5L, and an immunotherapy-specific questionnaire. Health technology assessments will compare the neoadjuvant arm with the standard adjuvant arm.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women, at least 16 years of age
- World Health Organization (WHO) Performance Status 0 or 1
- Cytologically or histologically confirmed resectable stage III melanoma of cutaneous or unknown primary origin with one or more macroscopic lymph node metastases (clinical detectable), that can be biopsied and a maximum of 3 additional resectable in-transit metastases. A concurrent resectable primary melanoma is allowed. Clinical detectable lymph nodes are defined as either one: o a palpable node, confirmed as melanoma by pathology; o a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology; o a PET scan positive lymph node of any size confirmed as melanoma by pathology;
- No other malignancies, except adequately treated and with a cancer-related lifeexpectancy of more than 5 years
- No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3
- No prior targeted therapy targeting BRAF and/or MEK
- No immunosuppressive medications within 6 months prior study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed);
- Screening laboratory values must meet the following criteria: WBC ≥2.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, hemoglobin ≥5.5 mmol/L, creatinine ≤1.5xupper limit of normal (ULN), AST ≤1.5x ULN, ALT ≤1.5x ULN, bilirubin ≤1.5x ULN (except for subjects with Gilbert syndrome who must have a total bilirubin <3.0 mg/dL);
- LDH level <1.5x ULN;
- Women of childbearing potential (WOCP) must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy during and until 23 weeks post last ipilimumab + nivolumab infusion
- Males who are sexually active with WOCP are not required to use contraception during treatment with nivolumab +/- ipilimumab, but must use appropriate method(s) of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, to avoid pregnancy during and until 17 weeks post last dabrafenib + trametinib administration
- Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, tumor biopsies and extra blood withdrawal during screening and in case of recurrence, and other requirements of the study
- Patient has signed the Informed Consent document
Exclusion Criteria
- Distantly metastasized melanoma;
- Uveal/ocular or mucosal melanoma
- In-transit metastases only (without cytological or histological proven lymph node involvement)
- Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll;
- Prior radiotherapy targeting the affected lymph node region(s);
- Subjects will be excluded if they test positive for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. Subjects treated and being at least one year free from HCV are allowed to participate;
- Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
- Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies.
- Subjects with underlying medical conditions or active infection that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events;
- Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids >10 mg prednisolone daily equivalent;
- Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion;
- Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.
- Women who are pregnant or breastfeeding;
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 08 Jul 2021 | 4 |
 Italy | Not Recruiting | 08 Jul 2021 | 3 |
 The Netherlands | Not Recruiting | 08 Jul 2021 | — |
 Poland | Not Recruiting | 08 Jul 2021 | 28 |
| Netherlands | — | — | 245 |
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 |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 240 | 6 | PRD2941372 |
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 80 | 6 | PRD2341715 |