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

NCT04949113 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: M21NDNCA209-6FR
• Study Type: interventional
• Target: 423
• Locations: 3 countries
• Sites: 24

Brief Summary

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.

Conditions

Malignant Melanoma Stage III

Keywords

Checkpoint inhibition; Checkpoint inhibitor; Immunotherapy; PD-1 inhibitor; CTLA-4 inhibitor; Ipilimumab; Nivolumab; Neoadjuvant; Adjuvant; Resectable melanoma; NADINA; M21NDN; Checkpoint blockade

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• Recurrence free survival (RFS)

  Up to 5 years after randomization

• Distant metastases-free survival (DMFS)

  Up to 5 years after randomization

• Overall survival (OS)

  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.

  Up to 5 years after randomization

• Rate of immune-related adverse events

  Up to 5 years after randomization

Study Arms (2)

A: Neoadjuvant

EXPERIMENTAL

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

B: Adjuvant

ACTIVE COMPARATOR

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

Interventions

Neoadjuvant ipilimumab + nivolumab DRUG

2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection

Also known as: Yervoy + Opdivo

A: Neoadjuvant

Adjuvant nivolumab DRUG

Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.

Also known as: Opdivo

B: Adjuvant

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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.

You may not qualify if:

• 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;
• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (24)

The Angeles Clinic

Los Angeles, California, 90025, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Melanoma Institute Australia (MIA)

Sydney, New South Wales, 2060, Australia

Location

Princess Alexandra Hospital

Brisbane, Australia

Location

Lake Macquarie Private Hospital

Gateshead, Australia

Location

Alfred Health

Melbourne, Australia

Location

Peter MacCallum Cancer Center

Melbourne, Australia

Location

Fiona Stanley Hospital

Murdoch, Australia

Location

Tasman Oncology

Southport, Australia

Location

Westmead Hospital

Sydney, Australia

Location

Netherlands Cancer Institute

Amsterdam, North Holland, 1066CX, Netherlands

Location

Amsterdam University Medical Center - location VUmc

Amsterdam, Netherlands

Location

Amphia Ziekenhuis

Breda, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Zuyderland Medisch Centrum

Heerlen, Netherlands

Location

Medisch Centrum Leeuwarden

Leeuwarden, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

Isala Hospital

Zwolle, Netherlands

Location

Related Publications (2)

• Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, Hoeijmakers LL, Saw RPM, Lijnsvelt JM, Maher NG, Pulleman SM, Gonzalez M, Torres Acosta A, van Houdt WJ, Lo SN, Kuijpers AMJ, Spillane A, Klop WMC, Pennington TE, Zuur CL, Shannon KF, Seinstra BA, Rawson RV, Haanen JBAG, Ch'ng S, Naipal KAT, Stretch J, van Thienen JV, Rtshiladze MA, Wilgenhof S, Kapoor R, Meerveld-Eggink A, Grijpink-Ongering LG, van Akkooi ACJ, Reijers ILM, Gyorki DE, Grunhagen DJ, Speetjens FM, Vliek SB, Placzke J, Spain L, Stassen RC, Amini-Adle M, Lebbe C, Faries MB, Robert C, Ascierto PA, van Rijn R, van den Berkmortel FWPJ, Piersma D, van der Westhuizen A, Vreugdenhil G, Aarts MJB, Stevense-den Boer MAM, Atkinson V, Khattak M, Andrews MC, van den Eertwegh AJM, Boers-Sonderen MJ, Hospers GAP, Carlino MS, de Groot JB, Kapiteijn E, Suijkerbuijk KPM, Rutkowski P, Sandhu S, van der Veldt AAM, Long GV. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. N Engl J Med. 2024 Nov 7;391(18):1696-1708. doi: 10.1056/NEJMoa2402604. Epub 2024 Jun 2.

  PMID: 38828984 DERIVED

• Long GV, Menzies AM, Scolyer RA. Neoadjuvant Checkpoint Immunotherapy and Melanoma: The Time Is Now. J Clin Oncol. 2023 Jun 10;41(17):3236-3248. doi: 10.1200/JCO.22.02575. Epub 2023 Apr 27.

  PMID: 37104746 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Christian Blank, Prof

  Medical oncologist/researcher

  STUDY CHAIR

• Georgina Long, Prof

  Medical oncologist/researcher

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label two-arm randomized phase 3 trial

Study Record Dates

• First Submitted: June 16, 2021
• First Posted: July 2, 2021
• Study Start: July 8, 2021
• Primary Completion: January 12, 2024
• Study Completion (Estimated): December 19, 2028
• Last Updated: March 8, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); AU (8); NL (14)