melanoma skin cancer
Conditions
Interventions
In OpACIN-neo patients will be treated pre-surgically for 6 weeks with the
combination of ipilimumab + nivolumab at three different combination schemes
(30 patients per arm).
Medicine tested: 2 cour
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 • Cytologically and histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months • No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years • Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 • No immunosuppressive medications within 6 months prior study inclusion • 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 • Brain metastases • History of in-transit metastases within the last 6 months • No measurable lesion according to RECIST 1.1 • 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 (except for non-responders in PRADO extension cohort; in this group is adjuvant radiotherapy allowed) • Patients who test positive for hepatitis B or C or HIV.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| OpACIN-neo - Safety as measured by the frequency of grade 3/4 immune-related adverse events (during the first 12 weeks). - Response rate according to RECIST 1.1 at week 6 - Pathologic response according to central revision (pathology of NKI). An interim analysis will be performed after 13 patients have been included in each arm (see 4.5), thus in total 39 patients have been included. PRADO extension cohort: - Pathologic response rate according to central revision (by a pathologist of the NKI or MIA) of the marked index lymph node - RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node. - RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab plus optional radiotherapy (or dabrafenib/trametinib if BRAFV600E positive and treatment is approved). RFS will be calculated from day of resection of marked lymph node. | — |
Secondary
| Measure | Time frame |
|---|---|
| Opacin neo - Recurrence Free Survival (RFS) - Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03 - Description of associations of mutational load, RNA tumor signatures, and surface marker expression with tumor immune infiltrates and response - Alteration in magnitude or breadth of the neo-antigen specific T cell responses in peripheral blood from baseline to surgery at week 6 in each 10 randomly chosen patients per arm. Prado - Response rate according to RECIST 1.1 at week 6 - RFS at 2, 3 and 5 years - DMFS at 2, 3 and 5 years - OS at 2, 3 and 5 years - Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks - Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND - Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03 - Description of associations of mutational load, RNA tumor signatures (e.g. T cell, TiS, and IFN), and surface marker expression with tumor immune infiltrates and pathologic response - Alteration in expansion/induction of tumor-resident TCR clones in peripheral blood from baseline to surgery at week. - Quality of life as measured by EORTC QLQ C30 and the melanoma and the surgery subscale of FACT-M | — |
Countries
Netherlands
Outcome results
None listed