Clinical trial NCT04949113: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
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
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2021-07-02
Enrollment: 423
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label two-arm randomized phase 3 trial
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Comparison of event-free survival (EFS) in the neoadjuvant and adjuvant group.
timeFrame: Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients.
Secondary outcomes:
measure: Recurrence free survival (RFS)
timeFrame: Up to 5 years after randomization
measure: Distant metastases-free survival (DMFS)
timeFrame: Up to 5 years after randomization
measure: Overall survival (OS)
timeFrame: Up to 5 years after randomization
measure: Pathologic response rate in the neoadjuvant arm and evaluation of association between pathologic response rate and RFS, DMFS and OS.
timeFrame: Up to 5 years after randomization
measure: Rate of immune-related adverse events
timeFrame: Up to 5 years after randomization
measure: Duration of immune-related adverse events
timeFrame: Up to 5 years after randomization
measure: Description of type of immune-related adverse events
timeFrame: Up to 5 years after randomization
measure: Description of surgical morbidity
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Evaluation of health-related quality of life (HRQoL) in both treatment arms
timeFrame: Up to 5 years after randomization
measure: Health technology assessments, consisting of a cost-effectiveness analysis comparing the neoadjuvant arm with the standard adjuvant arm
timeFrame: Up to 5 years after randomization
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic
state: California
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Sydney
country: Australia
facility: Melanoma Institute Australia (MIA)
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
city: Gateshead
country: Australia
facility: Lake Macquarie Private Hospital
city: Melbourne
country: Australia
facility: Alfred Health
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Southport
country: Australia
facility: Tasman Oncology
city: Sydney
country: Australia
facility: Westmead Hospital
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
state: NH
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center - location VUmc
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Zwolle
country: Netherlands
facility: Isala Hospital
Study officials:
affiliation: Medical oncologist/researcher
name: Christian Blank, Prof
role: STUDY_CHAIR
affiliation: Medical oncologist/researcher
name: Georgina Long, Prof
role: STUDY_CHAIR
References: