NIVOLUMAB for Stage III melanoma

Inclusion criteria

• {"criterion_text":"- Men and women, at least 16 years of age\n- 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\n- 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\n- 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\n- Patient has signed the Informed Consent document\n- World Health Organization (WHO) Performance Status 0 or 1\n- 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;\n- No other malignancies, except adequately treated and with a cancer-related lifeexpectancy of more than 5 years\n- No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3\n- No prior targeted therapy targeting BRAF and/or MEK\n- No immunosuppressive medications within 6 months prior study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed);\n- 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);\n- LDH level <1.5x ULN;"}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"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

• {"endpoint_text":"- OS, defined as time between date of randomization and date of death from any cause;\n- RFS, defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first;\n- DMFS, defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first;\n- 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;\n- Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria70, see 7.1.1) in the neoadjuvant arm;\n- Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS;\n- Frequency and duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0;\n- Surgical complication rates according to Clavien-Dindo surgical classification;\n- 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;\n- Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.","definition_or_measurement_approach":"OS defined as time between date of randomization and date of death from any cause; RFS defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death; DMFS defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death; EFS including new primary melanoma defined as time from randomization to a new primary melanoma (excluding melanoma in situ), melanoma progression, recurrence, treatment-related death, or melanoma-related death. Other endpoints measured as specified (pathologic response categorized per INMC criteria; adverse events per CTCAE 5.0; surgical complications per Clavien-Dindo; HRQoL by listed instruments)."}

Netherlands

Earliest CTIS Part Ii Submission Date

13-06-2024

Latest Decision Or Authorization Date

26-03-2026

Processing Time Days

651

Number Of Sites

14

Number Of Participants

245

Italy

Earliest CTIS Part Ii Submission Date

13-06-2024

Latest Decision Or Authorization Date

25-06-2024

Processing Time Days

12

Number Of Sites

1

Number Of Participants

3

France

Earliest CTIS Part Ii Submission Date

13-06-2024

Latest Decision Or Authorization Date

24-06-2024

Processing Time Days

11

Number Of Sites

4

Number Of Participants

4

Poland

Earliest CTIS Part Ii Submission Date

01-10-2024

Latest Decision Or Authorization Date

21-10-2024

Processing Time Days

20

Number Of Sites

1

Number Of Participants

28

Primary sponsor

Full Name

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands