Phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follicular lymphoma.

Abstract

TPS305 Background: Follicular lymphoma (FL) is one of the most immune-responsive of all cancers. However, immunosuppressive mechanisms in the tumor microenvironment may impair the efficacy of antitumor immune responses. We have recently identified the programmed death (PD)- 1/PD-ligand pathway as an important immunosuppressive mechanism in the FL tumor microenvironment. Expression of the coinhibitory PD-1 receptor was markedly increased on intratumoral T cells and associated with decreased reactivity to autologous FL tumor cells. Blocking PD-1/PD-ligand pathway with CT-011 enhanced the proliferation of antitumor T cells and augmented the expression of activating receptors on human NK cells. Administration of CT-011 delayed tumor growth and improved survival of mice in lymphoma xenograft models and combination with rituximab further improved survival compared with rituximab alone (Chu et al, Blood, Nov 2009; 114: 724.). In a phase I clinical trial, CT-011 was safe, induced sustained elevations of CD4+ T cells, and the sole patient with FL on the trial, who had large tumor masses, achieved a durable complete remission lasting >14 months (Berger et al, Clin Cancer Res, 2008). Based on these data, we are now conducting a single-arm phase II trial with CT-011 and rituximab in relapsed FL patients (n = 30). The rationale is that the combination is likely to activate both innate (NK cells) and adaptive (T cells) arms of the immune system and thereby enhance the clinical efficacy without increasing toxicity. The primary endpoint is overall response rate. Methods: Patients with FL, relapsing after at least 1 but not more than 4 prior therapies, with rituximab-sensitive disease will be eligible. Patients must be ≥ 18 years, have measurable disease, adequate organ function, and absolute lymphocyte count of ≥ 0.6×109/L. Patients with HIV, hepatitis B or C, and autoimmune diseases are excluded. CT-011 will be administered IV every 4 weeks for 4 infusions and rituximab will be administered IV weekly for 4 weeks. The trial was activated in January 2010 and one patient has been enrolled. Blood and tumor samples will be collected to assess the effect of CT-011 on T cells and NK cells. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CureTech