melanoma skin cancer
Conditions
Interventions
Resectable stage III melanoma patients with palpable lymph nodes, naïve for
CTLA-4/PD-1/PD-L1 immunotherapy, will be treated either post-surgery for 12
weeks with the combination of ipilimumab+nivol
Sponsors
Nederlands Kanker Instituut
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: • Adults at least 18 years of age • World Health Organization (WHO) Performance Status 0 or 1 • Histologically confirmed resectable stage III melanoma with palpable lymph node metastases and no history or active in-transit metastases within the last 6 months • Patient willing to undergo triple tumor biopsies during screening and in case of disease progression • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 • No immunosuppressive medications within 6 months prior study inclusion • Presence of at least two of the defined HLA alleles • Screening laboratory values must meet the following criteria: WBC >= 2.0x109/L, Neutrophils >=1.5x109/L, Platelets >=100 x109/L, Hemoglobin >=5.5 mmol/L, Creatinine
Exclusion criteria
Exclusion criteria: • Distantly metastasized melanoma • Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy • Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy • Radiotherapy prior or post surgery within this trial • Patients will be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection • Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) • Allergies and Adverse Drug Reaction - History of allergy to study drug components - History of severe hypersensitivity reaction to any monoclonal antibody • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events; • Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; • Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion • Pregnant or nursing
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary readout will be the alteration in magnitude or breadth of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood. To this purpose the immunogenic mutational load of each patient*s melanoma will be determined by DNA and RNA sequencing from baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide presentation in HLA will be predicted in silico. MHC-tetramer staining containing the predicted peptides will be done as described before. In addition, we will analyze the effect of therapy on intratumoral T cell responses to obtain better insight into the mode of action of therapy. Identified neo-antigen specific T cells will be analyzed with respect to their phenotype and immunologic function (intracellular cytokine staining, lytic function as determined by CD107 staining, and coculture with APC presenting the cognate antigen). Safety and feasibility as measured by SUSARs and adherence to the timelines in the study protocol. | — |
Secondary
| Measure | Time frame |
|---|---|
| RFS, as determined according to RECIST 1.1 criteria. Rate and type of adverse events and late adverse events Correlation between RFS and the delta of magnitude and/or breadth of neo-antigen T cell population Pharmacokinetics and pharmacodynamics of nivolumab and ipilimumab comparing the two different treatment arms | — |
Countries
Netherlands
Outcome results
None listed