A Phase Ii Study (Nct01883323) Evaluating the Infusion of Autologous Tumor-Infiltrating Lymphocytes (Til) and Low-Dose Interleukin-2 (Il-2) Therapy Following Non-Myeloablative Lymphodepletion Using Cyclophosphamide and Fludarabine in Patients with Metastatic Melanoma

Abstract

ABSTRACT Background: The Immune Therapy Program at the Princess Margaret Cancer Centre, Toronto, is the first adoptive cell therapy (ACT) program in Canada. Current TIL protocols aim to achieve anti-tumor responses by using minimally cultured TIL, pretreating with high dose lymphodepleting chemotherapy and IV administration of high dose IL-2, a T cell growth factor. High dose IL-2 can result in significant treatment-limiting toxicity and suitable patients must be highly selected. Our group has modified this approach to expand TIL using a rapid expansion protocol (REP) in moderate dose IL-2 (Nguyen 2010), thus enabling moderate dose IL-2 administration post TIL infusion. Trial design: A single arm phase II trial in metastatic melanoma was designed to assess safety and response of our modified TIL protocol. TIL in vitro expansion and function is assessed by flow cytometry for CD3, CD4, and CD8 phenotype, and, in response to autologous tumor, cytotoxicity and IFN-γ production. TIL are then prepared for autologous infusion using a REP. Eligible patients must have measureable stage IV melanoma or unresectable stage III disease with a lesion suitable for TIL production, a life expectancy of > 3 months, ECOG ≤1 and stable brain metastases for ≥3 months from time of definitive treatment. Patients are admitted on day -5 for preconditioning with cyclophosphamide (60mg/kg for 2 days) and fludarabine (25mg/m2 for 5 days). TIL infusion (1x10^10–1.6x10^11 cells) occurs on day 0 and moderate dose daily IL-2 (125,000 IU/kg subcutaneous injection) commences three hours after TIL infusion, for 10 days with 2 days rest after 5 days; toxicity allowing. The first radiological assessment of response is at 4 weeks post TIL infusion and q3 monthly thereafter. Ex vivo immune monitoring is ongoing to assess persistence and function of infused T cells. This study has opened, and patients are actively undergoing treatment. The trial follows a two-stage Simon design that allows for early stopping for futility. A response rate of 5% or lower is considered too low to be of interest (p0 = 0.05), while if the treatment has a response rate of 30% or more it will be considered to be effective (pA = 0.3). If there is ≥1 responder documented in the first 5 subjects treated, the study will continue to a target of 12 patients (type I error rate of 0.084). Disclosure: All authors have declared no conflicts of interest.