Randomized phase III study comparing a non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor infiltrating lymphocytes and interleukine-2 to standard ipilimumab treatment in metastatic melanoma

Abstract

Background: Less than a decade ago, the prognosis of advanced melanoma was extremely poor, with a 5-year overall survival (OS) of only 9-28%. Introduction of targeted therapies and immunotherapies have significantly improved the outcome of these patients. Ipilimumab, an anti-CTLA-4 antibody, was the first to show clinical benefit in advanced melanoma patients and 20% achieved long-term survival. The PD- 1-blocking agents pembrolizumab and nivolumab further increased objective response rates (ORR) up to 40% and are now often used as first-line therapy. However, a large group of patients still does not benefit from this treatment. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) has shown promising clinical ORR of 40-70% in patients with advanced melanoma in several phase I/II trials, with durable responses in a substantial group of patients. TIL treatment consists of infusion of ex vivo expanded tumor resident T cells following non-myeloablative (NMA) chemotherapy and subsequent high-dose interleukine-2 (HD IL-2). Trial design: In this international, multicenter, open-label phase III trial, 168 patients with irresectable stage IIIc or IV melanoma, between 18 and 75 years of age, with resectable metastatic lesion(s) of at least 2-3 cm diameter and sufficient organ function, will be randomized 1:1 to either ipilimumab or TIL treatment. Patients will be stratified for BRAFV600 mutation status, treatment line (1st or 2nd) and treatment center. Patients randomized to ipilimumab (3 mg/kg i.v.) receive this once every 3 weeks, maximum of 4 doses. Patients randomized to TIL will undergo resection of a metastatic lesion for the outgrowth of TIL. Subsequently, NMA chemotherapy with cyclophosphamide (60 mg/ kg/day for 2 days i.v.) and fludarabine (25 mg/m2/day for 5 days i.v.) is administered prior to infusion of>5x109 TIL followed by HD IL-2 (600.000 IU/kg/dose every 8 hours, maximum of 15 doses). The primary endpoint is progression free survival at 6 months. Secondary endpoints are ORR, complete response rate, OS and safety.