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Malignant Melanoma Stage IIIPhase 3NADINANCT04949113

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

A Phase 3 study testing Neoadjuvant ipilimumab + nivolumab and Adjuvant nivolumab in people with Malignant Melanoma Stage III, run by The Netherlands Cancer Institute at 24 sites in 3 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 16 years and older
Conditions the study is for
Malignant Melanoma Stage III
What is being tested?
Neoadjuvant ipilimumab + nivolumab and Adjuvant nivolumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
423 participants
Where
24 sitesin 3 countries
Study dates
8 Jul 2021to 19 Dec 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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;
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  • 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.

Who cannot join

  • 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;
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  • 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.

Trial locations and contacts

24 sites in 3 countries.

24 sites in 3 countries

Netherlands14 sites

  • Netherlands Cancer Institute

    Amsterdam, North Holland, 1066CX

  • Amsterdam University Medical Center - location VUmc

    Amsterdam

  • Amphia Ziekenhuis

    Breda

  • Maxima Medisch Centrum

    Eindhoven

  • Medisch Spectrum Twente

    Enschede

  • University Medical Center Groningen

    Groningen

  • Zuyderland Medisch Centrum

    Heerlen

  • Medisch Centrum Leeuwarden

    Leeuwarden

  • Leiden University Medical Center

    Leiden

  • Maastricht University Medical Center

    Maastricht

  • Radboud University Medical Center

    Nijmegen

  • Erasmus Medical Center

    Rotterdam

  • University Medical Center Utrecht

    Utrecht

  • Isala Hospital

    Zwolle

Other trials in Netherlands

Australia8 sites

  • Princess Alexandra Hospital

    Brisbane

  • Lake Macquarie Private Hospital

    Gateshead

  • Alfred Health

    Melbourne

  • Peter MacCallum Cancer Center

    Melbourne

  • Fiona Stanley Hospital

    Murdoch

  • Tasman Oncology

    Southport

  • Melanoma Institute Australia (MIA)

    Sydney, New South Wales, 2060

  • Westmead Hospital

    Sydney

Other trials in Australia

United States2 sites

  • MD Anderson Cancer Center

    Houston, Texas, 77030

  • The Angeles Clinic

    Los Angeles, California, 90025

Other trials in United States

About this study

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

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.

Being tested
Neoadjuvant ipilimumab + nivolumab, Adjuvant nivolumab
Keywords
Checkpoint inhibition, Checkpoint inhibitor, Immunotherapy, PD-1 inhibitor, CTLA-4 inhibitor, Ipilimumab, Nivolumab, Neoadjuvant, Adjuvant, Resectable melanoma, NADINA, M21NDN, Checkpoint blockade
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Neoadjuvant ipilimumab + nivolumabDrug

    Also called Yervoy + Opdivo

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

  • Adjuvant nivolumabDrug

    Also called Opdivo

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

Study groups in NCT04949113
Study groupRoleWhat they receive
A: NeoadjuvantExperimental2 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.
Receives: Drug: Neoadjuvant ipilimumab + nivolumab
B: AdjuvantActive comparatorStandard 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
Receives: Drug: Adjuvant nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients.

Secondary outcomes (18)

  1. 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.

    Measured: Up to 5 years after randomization

  2. 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.

    Measured: Up to 5 years after randomization

  3. Overall survival (OS)

    OS is defined as time between date of randomization and date of death.

    Measured: Up to 5 years after randomization

  4. 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.

    Measured: Up to 5 years after randomization

  5. Rate of immune-related adverse events

    Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

    Measured: Up to 5 years after randomization

  6. Duration of immune-related adverse events

    Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

    Measured: Up to 5 years after randomization

  7. 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.

    Measured: Up to 5 years after randomization

  8. Description of surgical morbidity

    Surgical complication rates according to Clavien-Dindo surgical classification.

    Measured: Up to 5 years after randomization

  9. 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.

    Measured: Up to 5 years after randomization

  10. 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).

    Measured: Up to 5 years after randomization

  11. 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.

    Measured: Up to 5 years after randomization

  12. 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.

    Measured: Up to 5 years after randomization

  13. 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).

    Measured: Up to 5 years after randomization

  14. Evaluation of health-related quality of life (HRQoL) in both treatment arms

    Quality of life as measured by an immunotherapy-specific questionnaire.

    Measured: Up to 5 years after randomization

  15. Evaluation of health-related quality of life (HRQoL) in both treatment arms

    Quality of life as measured by an assessment of work performance.

    Measured: Up to 5 years after randomization

  16. Evaluation of health-related quality of life (HRQoL) in both treatment arms

    Quality of life as measured by a questionnaire on sexual health.

    Measured: Up to 5 years after randomization

  17. Evaluation of health-related quality of life (HRQoL) in both treatment arms

    Quality of life as measured by the Amsterdam Cognition Scale.

    Measured: Up to 5 years after randomization

  18. 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).

    Measured: Up to 5 years after randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jul 2021
  2. Study start8 Jul 2021
  3. Primary completion12 Jan 2024
  4. Study completion19 Dec 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Open-label two-arm randomized phase 3 trial
Masking
None (open label)
Enrolment
423 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04949113
Sponsor's protocol ID
M21NDN
Other IDs
CA209-6FR
Acronym
NADINA
Status last verified
Mar 2024
First submitted
16 Jun 2021
Last updated
8 Mar 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 38828984

  • 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.

    PubMed 37104746

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Neoadjuvant ipilimumab + nivolumab and Adjuvant nivolumab in people with Malignant Melanoma Stage III, run by The Netherlands Cancer Institute at 24 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 8 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in Netherlands, Australia, United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Comparison of event-free survival (EFS) in the neoadjuvant and adjuvant group. (time frame: Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04949113, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Mar 2024.

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