Nadina

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Jul 2021 → ongoing

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513519-28-00

EudraCT number

2021-001492-16

ClinicalTrials.gov

NCT04949113

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare the event-free survival (EFS) of neoadjuvant ipilimumab + nivolumab (followed by adjuvant nivolumab or dabrafenib + trametinib in patients not achieving a pathologic response) versus standard adjuvant nivolumab

Secondary objectives 8

1. To describe the Overall Survival (OS) in both arms
2. To describe the RFS and distant metastases-free survival (DMFS) in both arms
3. To describe the EFS including a new primary melanoma (excluding melanoma in situ) as an event in both arms;
4. To evaluate the association between pathologic response and RFS, DMFS and OS, including analyses of the pathologic response subgroups (pCR, near pCR, pPR) and a subgroup analyses in BRAF wildtype and BRAFV600 mutated patients
5. To describe the rate and type of immune-related adverse events
6. To describe surgical morbidity
7. To evaluate health-related quality of life (HRQoL) in both treatment arms
8. To perform health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm

Conditions and MedDRA coding

Stage III melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Men and women, at least 16 years of age
2. World Health Organization (WHO) Performance Status 0 or 1
3. 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 one: o a palpable node, confirmed as melanoma by pathology; o a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology; o a PET scan positive lymph node of any size confirmed as melanoma by pathology;
4. No other malignancies, except adequately treated and with a cancer-related lifeexpectancy of more than 5 years
5. No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3
6. No prior targeted therapy targeting BRAF and/or MEK
7. No immunosuppressive medications within 6 months prior study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed);
8. 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);
9. LDH level <1.5x ULN;
10. 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 during and until 23 weeks post last ipilimumab + nivolumab infusion
11. Males who are sexually active with WOCP are not required to use contraception during treatment with nivolumab +/- ipilimumab, but 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 during and until 17 weeks post last dabrafenib + trametinib administration
12. 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
13. Patient has signed the Informed Consent document

Exclusion criteria 13

1. Distantly metastasized melanoma;
2. Uveal/ocular or mucosal melanoma
3. In-transit metastases only (without cytological or histological proven lymph node involvement)
4. 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;
5. Prior radiotherapy targeting the affected lymph node region(s);
6. 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;
7. Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
8. Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies.
9. 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;
10. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids >10 mg prednisolone daily equivalent;
11. Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion;
12. 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.
13. Women who are pregnant or breastfeeding;

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. EFS, 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.

Secondary endpoints 10

1. OS, defined as time between date of randomization and date of death from any cause;
2. RFS, defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first;
3. DMFS, defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first;
4. EFS including new primary melanoma, defined as time from randomization to a new primary melanoma (excluding melanoma in situ), melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first;
5. Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria70, see 7.1.1) in the neoadjuvant arm;
6. Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS;
7. Frequency and duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0;
8. Surgical complication rates according to Clavien-Dindo surgical classification;
9. Quality of life as measured by EORTC QLQ C30, the Melanoma Subscale and Melanoma Surgery Subscale of FACT-M, the Cancer Worry Scale, HADS questionnaire, EQ-5D-5L, the immunotherapy-specific questionnaire, an assessment of work performance, sexual health, and Amsterdam Cognition Scan;
10. Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

C.Blank

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

C.Blank

Locations

4 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications