Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma

Study Overview
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Brief Summary
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This is an international (Australia, Europe, and USA) open-label two-arm randomized phase 3 trial including 420 stage III (≤3 resectable in-transit metastases allowed) cutaneous or unknown primary melanoma patients. Patients will be randomized 1:1 to receive either 2 cycles of neoadjuvant ipilimumab 80 mg + nivolumab 240 mg every 3 weeks followed by a total lymph node dissection (TLND) and, if applicable, resection of in-transit metastases (arm A) versus standard upfront TLND +/- resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks (arm B). Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks for 46 weeks (11 cycles). In case of BRAF V600E/K mutation-positivity, patients from arm A with a pathologic partial or non-response (>10% viable tumor) will be treated with adjuvant dabrafenib plus trametinib for 46 weeks. Patients will be treated in the study in both arms until melanoma progression to irresectable stage III or stage IV disease, disease recurrence, unacceptable toxicity, subject withdrawal of consent or until end of study treatment. An interim analysis will be performed after 60 events have occurred. The data safety monitory board (DSMB) will be ad hoc consulted when unexpected toxicities are reported. Patients will be followed by 12 weekly CT scans until end of year 3 and then until year 5 according to the institute's standards.

Official Title
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Multicenter Phase 3 Trial Comparing Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma - NADINA

Conditions
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Malignant Melanoma Stage III

Intervention / Treatment
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* Drug: Neoadjuvant ipilimumab + nivolumab
* Drug: Adjuvant nivolumab


Participation Criteria
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Eligibility Criteria
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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 a palpable node, confirmed as melanoma by pathology, or a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology, or 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 life-expectancy of more than 5 years; No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1; 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 for 23 weeks post last ipilimumab + nivolumab infusion; Males who are sexually active with 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 for 31 weeks post last ipilimumab + nivolumab infusion; 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; 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; Women who are pregnant or breastfeeding; 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label two-arm randomized phase 3 trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Neoadjuvant<br>2 cycles of neoadjuvant ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by a total lymph node dissection (TLND) and if applicable, resection of in-transit metastases. Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks 11 cycles. In case of BRAF V600E/K mutation-positivity, patients will be treated with adjuvant dabrafenib plus trametinib for 46 weeks instead. | Drug: Neoadjuvant ipilimumab + nivolumab<br>* 2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection<br>* Other names: Yervoy + Opdivo;|
| Active Comparator: B: Adjuvant<br>Standard upfront total lymph node dissection (TLND) and if applicable, resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks | Drug: Adjuvant nivolumab<br>* Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of event-free survival (EFS) in the neoadjuvant and adjuvant group. | EFS is defined as 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. Occurrence of a new primary melanoma during treatment/follow-up is also regarded as an event. Presurgical resectable progression to stage III disease in arm A is not defined as an event, even as death to another reason than melanoma or the study treatment. | Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival (RFS) | RFS is defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first. | Up to 5 years after randomization | 
| Distant metastases-free survival (DMFS) | DMFS is defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first. | Up to 5 years after randomization | 
| Overall survival (OS) | OS is defined as time between date of randomization and date of death. | Up to 5 years after randomization | 
| Pathologic response rate in the neoadjuvant arm and evaluation of association between pathologic response rate and RFS, DMFS and OS. | The pathologic response rate will be categorized into pathologic complete response (pCR), near-pCR, major pathologic response (MPR), pathologic partial response (pPR), pathologic no response (pNR), according to International Neoadjuvant Melanoma Consortium (INMC) criteria. | Up to 5 years after randomization | 
| Rate of immune-related adverse events | Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. | Up to 5 years after randomization | 
| Duration of immune-related adverse events | Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. | Up to 5 years after randomization | 
| Description of type of immune-related adverse events | Type of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0. | Up to 5 years after randomization | 
| Description of surgical morbidity | Surgical complication rates according to Clavien-Dindo surgical classification. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by EORTC Quality of Life Questionnaire-core 30 (QLQ C30). The QLQ-C30 is scored on 4 point Likert-scales: Not at all, A little, Quite a bit, and Very much. and is composed of both multi-item scales and single-item measures. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by the Melanoma Subscale and Melanoma Surgery Subscale of Functional Assessment of Cancer Therapy - Melanoma (FACT-M). The FACT-M is scored on a 5 point Likert-scale: Not at all, A little bit, Somewhat, Quite a bit, and Very much.. A Higher score represents higher Health Related Quality of Life (HRQoL). | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by the Cancer Worry Scale. The Cancer Worry Scale is scored on a 4 point Likert-scale: Almost never, Sometimes, Often, and Almost always. Higher scores indicate more worrying about cancer. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by the Hospital Anxiety and Depression Scale (HADS) questionnaire. The HADS is a questionnaire that is scored on several 4 point Likert-scales. Higher score on the HADS questionnaire indicates more hospital-related anxiety and depression. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by the 5-level EuroQOL-5D questionnaire (EQ-5D-5L). | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by an immunotherapy-specific questionnaire. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by an assessment of work performance. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by a questionnaire on sexual health. | Up to 5 years after randomization | 
| Evaluation of health-related quality of life (HRQoL) in both treatment arms | Quality of life as measured by the Amsterdam Cognition Scale. | Up to 5 years after randomization | 
| Health technology assessments, consisting of a cost-effectiveness analysis comparing the neoadjuvant arm with the standard adjuvant arm | Cost-effectiveness measured by an incremental cost-effectiveness ratio (ICER) (e.g., incremental cost per quality-adjusted life-year (QALY) gained). | Up to 5 years after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Checkpoint inhibition, Checkpoint inhibitor, Immunotherapy, PD-1 inhibitor, CTLA-4 inhibitor, Ipilimumab, Nivolumab, Neoadjuvant, Adjuvant, Resectable melanoma, NADINA, M21NDN, Checkpoint blockade