Patients with stage III melanoma
Conditions
Interventions
Trade Name: OPDIVO
Product Name: Nivolumab
Product Code: BMS-936558
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Nivolumab
Other descriptive name: NIVOLUMAB
Concentr
Sponsors
NKI-AVL
Eligibility
Sex/Gender
All
Inclusion 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 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; - 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, PD-L1 or LAG-3; - 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 =65 years) yes F.1.3.1 Number of subjects for this age range 198
Exclusion criteria
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; targeting the affected lymph node region(s); - 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 Objective: Key secondary objective - To describe the Overall Survival (OS) in both arms; Secondary objectives - To describe the RFS and distant metastases-free survival (DMFS) in both arms; - To describe the EFS including a new primary melanoma as an event in both arms; - To describe the (major) pathologic response rate in the neoadjuvant arm; - To evaluate the association between pathologic response and RFS, DMFS and OS, including analysis of the pathologic response subgroups (pCR, near pCR, pPR) and a subgroup analyses in BRAF wildtype and BRAFV600 mutated patients; - To describe the rate and type of immune-related adverse events; - To describe surgical morbidity; - To evaluate health-related quality of life (HRQoL) in both treatment arms; - To perform health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm.;Primary end point(s): 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.;Timepoint(s) of evaluation of this end point: Every 12 weeks, starting from week 12. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint - 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, whichever occurs first; - DMFS, defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first; - EFS including new primary melanoma, defined as time from randomization to a new primary melanoma, melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first; - Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR, according to INMC criteria69, see 7.1.1) in the neoadjuvant arm; - Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and OS; - Frequency and duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0; - Surgical complication rates according to Clavien-Dindo surgical classification; - 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; - Performing health technology assessments comparing the neoadjuvant arm with the standard adjuvant arm. ;Timepoint(s) of evaluation of this end point: Every 12 weeks, starting from week 12. Adverse events are monitored continuously. Questionairs: At baseline, week 6 week 12, and every 12 weeks until week 60, then then at month 18, 24, 30, and 36. Continously ePRO collection using KAIKU app. | — |
Countries
Australia, France, Italy, Netherlands, Poland, United States
Contacts
Public ContactClinical Projects Manager
NKI-AVL
Outcome results
None listed