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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04949113




Registration number
NCT04949113
Ethics application status
Date submitted
16/06/2021
Date registered
2/07/2021
Date last updated
8/03/2024

Titles & IDs
Public title
Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma
Scientific title
Multicenter Phase 3 Trial Comparing Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma - NADINA
Secondary ID [1] 0 0
CA209-6FR
Secondary ID [2] 0 0
M21NDN
Universal Trial Number (UTN)
Trial acronym
NADINA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Melanoma Stage III 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Neoadjuvant ipilimumab + nivolumab
Treatment: Drugs - Adjuvant nivolumab

Experimental: 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.

Active Comparator: 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


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

Treatment: Drugs: Adjuvant nivolumab
Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Comparison of event-free survival (EFS) in the neoadjuvant and adjuvant group.
Timepoint [1] 0 0
Analysis will be performed after 132 events, though not later than after 2 years follow-up of all patients.
Secondary outcome [1] 0 0
Recurrence free survival (RFS)
Timepoint [1] 0 0
Up to 5 years after randomization
Secondary outcome [2] 0 0
Distant metastases-free survival (DMFS)
Timepoint [2] 0 0
Up to 5 years after randomization
Secondary outcome [3] 0 0
Overall survival (OS)
Timepoint [3] 0 0
Up to 5 years after randomization
Secondary outcome [4] 0 0
Pathologic response rate in the neoadjuvant arm and evaluation of association between pathologic response rate and RFS, DMFS and OS.
Timepoint [4] 0 0
Up to 5 years after randomization
Secondary outcome [5] 0 0
Rate of immune-related adverse events
Timepoint [5] 0 0
Up to 5 years after randomization
Secondary outcome [6] 0 0
Duration of immune-related adverse events
Timepoint [6] 0 0
Up to 5 years after randomization
Secondary outcome [7] 0 0
Description of type of immune-related adverse events
Timepoint [7] 0 0
Up to 5 years after randomization
Secondary outcome [8] 0 0
Description of surgical morbidity
Timepoint [8] 0 0
Up to 5 years after randomization
Secondary outcome [9] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [9] 0 0
Up to 5 years after randomization
Secondary outcome [10] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [10] 0 0
Up to 5 years after randomization
Secondary outcome [11] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [11] 0 0
Up to 5 years after randomization
Secondary outcome [12] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [12] 0 0
Up to 5 years after randomization
Secondary outcome [13] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [13] 0 0
Up to 5 years after randomization
Secondary outcome [14] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [14] 0 0
Up to 5 years after randomization
Secondary outcome [15] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [15] 0 0
Up to 5 years after randomization
Secondary outcome [16] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [16] 0 0
Up to 5 years after randomization
Secondary outcome [17] 0 0
Evaluation of health-related quality of life (HRQoL) in both treatment arms
Timepoint [17] 0 0
Up to 5 years after randomization
Secondary outcome [18] 0 0
Health technology assessments, consisting of a cost-effectiveness analysis comparing the neoadjuvant arm with the standard adjuvant arm
Timepoint [18] 0 0
Up to 5 years after randomization

Eligibility
Key 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.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/07/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
19/12/2028
Actual
Sample size
Target
Accrual to date
Final
423
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Melanoma Institute Australia (MIA) - Sydney
Recruitment hospital [2] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment hospital [3] 0 0
Lake Macquarie Private Hospital - Gateshead
Recruitment hospital [4] 0 0
Alfred Health - Melbourne
Recruitment hospital [5] 0 0
Peter MacCallum Cancer Center - Melbourne
Recruitment hospital [6] 0 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [7] 0 0
Tasman Oncology - Southport
Recruitment hospital [8] 0 0
Westmead Hospital - Sydney
Recruitment postcode(s) [1] 0 0
2060 - Sydney
Recruitment postcode(s) [2] 0 0
- Brisbane
Recruitment postcode(s) [3] 0 0
- Gateshead
Recruitment postcode(s) [4] 0 0
- Melbourne
Recruitment postcode(s) [5] 0 0
- Murdoch
Recruitment postcode(s) [6] 0 0
- Southport
Recruitment postcode(s) [7] 0 0
- Sydney
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas
Country [3] 0 0
Netherlands
State/province [3] 0 0
NH
Country [4] 0 0
Netherlands
State/province [4] 0 0
Amsterdam
Country [5] 0 0
Netherlands
State/province [5] 0 0
Breda
Country [6] 0 0
Netherlands
State/province [6] 0 0
Eindhoven
Country [7] 0 0
Netherlands
State/province [7] 0 0
Enschede
Country [8] 0 0
Netherlands
State/province [8] 0 0
Groningen
Country [9] 0 0
Netherlands
State/province [9] 0 0
Heerlen
Country [10] 0 0
Netherlands
State/province [10] 0 0
Leeuwarden
Country [11] 0 0
Netherlands
State/province [11] 0 0
Leiden
Country [12] 0 0
Netherlands
State/province [12] 0 0
Maastricht
Country [13] 0 0
Netherlands
State/province [13] 0 0
Nijmegen
Country [14] 0 0
Netherlands
State/province [14] 0 0
Rotterdam
Country [15] 0 0
Netherlands
State/province [15] 0 0
Utrecht
Country [16] 0 0
Netherlands
State/province [16] 0 0
Zwolle

Funding & Sponsors
Primary sponsor type
Other
Name
The Netherlands Cancer Institute
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Bristol-Myers Squibb
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04949113
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Christian Blank, Prof
Address 0 0
Medical oncologist/researcher
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/ct2/show/NCT04949113