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

Malignant Melanoma Stage III Clinical Trial

— NADINA  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04949113
• Other study ID #: M21NDN
• Secondary ID: CA209-6FR
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 8, 2021
• Est. completion date: December 19, 2028

Study information

• Verified date: March 2024
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 423
• Est. completion date: December 19, 2028
• Est. primary completion date: January 12, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Malignant Melanoma Stage III
• Melanoma

Intervention

Drug:
• Neoadjuvant ipilimumab + nivolumab
2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection
• Adjuvant nivolumab
Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.

Locations

Country	Name	City	State
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	Melanoma Institute Australia (MIA)	Sydney	New South Wales
Australia	Westmead Hospital	Sydney
Netherlands	Amsterdam University Medical Center - location VUmc	Amsterdam
Netherlands	Netherlands Cancer Institute	Amsterdam	NH
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
United States	MD Anderson Cancer Center	Houston	Texas
United States	The Angeles Clinic	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	Overall survival (OS)	OS is defined as time between date of randomization and date of death.	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	Rate of immune-related adverse events	Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.	Up to 5 years after randomization
Secondary	Duration of immune-related adverse events	Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	Description of surgical morbidity	Surgical complication rates according to Clavien-Dindo surgical classification.	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	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).	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	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.	Up to 5 years after randomization
Secondary	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).	Up to 5 years after randomization
Secondary	Evaluation of health-related quality of life (HRQoL) in both treatment arms	Quality of life as measured by an immunotherapy-specific questionnaire.	Up to 5 years after randomization
Secondary	Evaluation of health-related quality of life (HRQoL) in both treatment arms	Quality of life as measured by an assessment of work performance.	Up to 5 years after randomization
Secondary	Evaluation of health-related quality of life (HRQoL) in both treatment arms	Quality of life as measured by a questionnaire on sexual health.	Up to 5 years after randomization
Secondary	Evaluation of health-related quality of life (HRQoL) in both treatment arms	Quality of life as measured by the Amsterdam Cognition Scale.	Up to 5 years after randomization
Secondary	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).	Up to 5 years after randomization