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

NCT ID: NCT04949113

Last Updated: 2024-03-08

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 423 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-08
• Study Completion Date: 2028-12-19

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A: Neoadjuvant

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.

Group Type: EXPERIMENTAL

Neoadjuvant ipilimumab + nivolumab

Intervention Type: DRUG

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

B: Adjuvant

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

Group Type: ACTIVE_COMPARATOR

Adjuvant nivolumab

Intervention Type: DRUG

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

Interventions

Neoadjuvant ipilimumab + nivolumab

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

Intervention Type: DRUG

Adjuvant nivolumab

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

Intervention Type: DRUG

Other Intervention Names

Yervoy + Opdivo; Opdivo

Eligibility 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 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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christian Blank, Prof

Role: STUDY_CHAIR

Medical oncologist/researcher

Georgina Long, Prof

Role: STUDY_CHAIR

Medical oncologist/researcher

Locations

The Angeles Clinic

Los Angeles, California, United States

MD Anderson Cancer Center

Houston, Texas, United States

Melanoma Institute Australia (MIA)

Sydney, New South Wales, Australia

Princess Alexandra Hospital

Brisbane, , Australia

Lake Macquarie Private Hospital

Gateshead, , Australia

Alfred Health

Melbourne, , Australia

Peter MacCallum Cancer Center

Melbourne, , Australia

Fiona Stanley Hospital

Murdoch, , Australia

Tasman Oncology

Southport, , Australia

Westmead Hospital

Sydney, , Australia

Netherlands Cancer Institute

Amsterdam, North Holland, Netherlands

Amsterdam University Medical Center - location VUmc

Amsterdam, , Netherlands

Amphia Ziekenhuis

Breda, , Netherlands

Maxima Medisch Centrum

Eindhoven, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Zuyderland Medisch Centrum

Heerlen, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Leiden University Medical Center

Leiden, , Netherlands

Maastricht University Medical Center

Maastricht, , Netherlands

Radboud University Medical Center

Nijmegen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Isala Hospital

Zwolle, , Netherlands

Countries

United States; Australia; Netherlands

References

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.

Reference Type: DERIVED

PMID: 38828984 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37104746 (View on PubMed)

Other Identifiers

CA209-6FR

Identifier Type: OTHER

Identifier Source: secondary_id

M21NDN

Identifier Type: -

Identifier Source: org_study_id