A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha 2b in patients with recurrent epithelial ovarian cancer

Background: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R; tocilizumab), and immune enhancer interferon-alpha (Peg-Intron) is feasible, safe, and able to enhance immunity in patients with recurrent EOC.Patients and methods: In this dose-escalation study, patients received tocilizumab 1, 2, 4, or 8 mg/kg i.v., q4 weeks during the first three cycles of carboplatin (AUC5) plus doxorubicin [pegylated liposomal doxorubicin (PLD) 30 mg/m(2) or doxorubicin 50 mg/m(2) i.v., day 1, q4 weeks, for six cycles]. At the highest tocilizumab dose (8 mg/kg), Peg-Intron (1 mu g/kg s.c.) was added. Peripheral blood mononuclear cells were collected for immunomonitoring at baseline, after three and six cycles. Dose-limiting toxicity (DLT), CA-125, and radiologic response were evaluated.Results: In the 23 patients enrolled, no DLT was established. The most frequent grade 3/4 adverse events (CTCAE v4.03) were neutropenia (23%), febrile neutropenia (19%), and ileus (19%). No treatment-related deaths occurred. Using CT evaluation, 11 of 21 assessable patients responded, 6 had stable disease and 3 progressive disease. Patients receiving highest dose tocilizumab showed a functional blockade of IL-6R with increased levels of serum IL-6 (P = 0.02) and soluble IL-6R (P = 0.008). Consequently, immune cells displayed decreased levels of pSTAT3, myeloid cells produced more IL-12 and IL-1 beta while T cells were more activated and secreted higher amounts of effector cytokines interferon-gamma and tumor necrosis factor-alpha. An increase in sIL-6R was potentially associated with a survival benefit (P = 0.03).Conclusions: Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal) doxorubicin, using 8 mg/kg tocilizumab. This combination is recommended for phase II evaluation based on immune parameters.