Clinical Trials /

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

NCT04949113

Description:

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 not achieving a pathologic 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 not achieving a pathologic response (>50% 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.

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma of Unknown Primary
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: M21NDN
  • NCT ID: NCT04949113

Conditions

  • Malignant Melanoma Stage III

Interventions

DrugSynonymsArms
Neoadjuvant ipilimumab + nivolumabYervoy + OpdivoA: Neoadjuvant
Adjuvant nivolumabOpdivoB: Adjuvant

Purpose

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 not achieving a pathologic 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 not achieving a pathologic response (>50% 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.

Trial Arms

NameTypeDescriptionInterventions
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 not achieving a pathologic 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.
  • 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
  • Adjuvant nivolumab

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Recurrence free survival (RFS)
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:RFS is defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first.
Measure:Distant metastases-free survival (DMFS)
Time Frame:Up to 5 years after randomization
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:OS is defined as time between date of randomization and date of death.
Measure:Pathologic response rate in the neoadjuvant arm and evaluation of association between pathologic response rate and RFS, DMFS and OS.
Time Frame:Up to 5 years after randomization
Safety Issue:
Description: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.
Measure:Rate of immune-related adverse events
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.
Measure:Duration of immune-related adverse events
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.
Measure:Description of type of immune-related adverse events
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Type of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.
Measure:Description of surgical morbidity
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Surgical complication rates according to Clavien-Dindo surgical classification.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by EORTC Quality of Life Questionnaire-core 30 (QLQ C30).
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by the Melanoma Subscale and Melanoma Surgery Subscale of Functional Assessment of Cancer Therapy - Melanoma (FACT-M).
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by the Cancer Worry Scale.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by the Hospital Anxiety and Depression Scale (HADS) questionnaire.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by the 5-level EuroQOL-5D questionnaire (EQ-5D-5L).
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by an immunotherapy-specific questionnaire.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by an assessment of work performance.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by a questionnaire on sexual health.
Measure:Evaluation of health-related quality of life (HRQoL) in both treatment arms
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Quality of life as measured by the Amsterdam Cognition Scale.
Measure:Health technology assessments, consisting of a cost-effectiveness analysis comparing the neoadjuvant arm with the standard adjuvant arm
Time Frame:Up to 5 years after randomization
Safety Issue:
Description:Cost-effectiveness measured by an incremental cost-effectiveness ratio (ICER) (e.g., incremental cost per quality-adjusted life-year (QALY) gained).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:The Netherlands Cancer Institute

Trial Keywords

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

Last Updated

July 2, 2021