This was the reason for the choice of such a schedule for the front line phase 3 study. or in combination. Introduction CTLA-4-blocking antibodies are fully human novel monoclonal antibodies directed against CTLA-4. By targeting CTLA-4 these antibodies prevent the conversation between the costimulatory molecules B7.1 an B7.2 (CD80 and CD86) and linking to CTLA-4, thus EPZ-6438 (Tazemetostat) removing the CTLA4 inhibitory signal and releasing a brake around the immune system. This allows a natural immune response to react to malignancy cells. The mechanism of action of anti-CTLA-4 antibodies is usually therefore indirect, through EPZ-6438 (Tazemetostat) enhancing T-cell mediated immune responses. Two anti-CTLA-4 antibodies have been tested in advanced clinical trials, either in phase II and phase III: ipilimumab and tremelimumab. There is a very small difference between the two products: both are fully human monoclonal antibodies directed against CTLA-4, but ipilimumab is an immunoglobulin IgG1 isotype and tremelimumab is usually a non-complement-fixing IgG2 isotype. Ipilimumab phase II studies: the assessment of the treatment schedule Ipilimumab has being extensively analyzed in different phase II trials. In a phase II randomized study, patients with metastatic melanoma received different doses of ipilimumab (0.3 vs 3 vs 10 mg/kg) and the results indicated a statistically significant pattern of increased response rates with increased dose, suggesting a dose-effect . Overall, most promising results in terms of best overall response rate (BORR) were obtained with 10 mg/kg of EPZ-6438 (Tazemetostat) ipilimumab, every 3 weeks for TM4SF19 a total of 4 doses (induction phase) followed by maintenance period in which ipilimumab was administrated every 12 weeks (maintenance phase). This was the reason for the choice of such a routine for the front collection phase 3 study. The most common treatment-related adverse events (AEs) associated with the use of ipilimumab were immune-related and specific algorithms have been subsequently developed, showing that early acknowledgement and correct therapeutic approach with steroid therapy make most of these AEs manageable and reversible . Ipilimumab phase III studies In 2010 2010, results from the MDX010-20 clinical trial were published . This is the first randomized phase III trial to have demonstrated a benefit in overall survival (OS) in pretreated patients with metastatic melanoma. This study showed the superiority of ipilimumab arm compared to a gp100 vaccine arm: ipilimumab monotherapy experienced a median OS survival of 10.1 months whereas the OS for gp100 monotherapy was only 6.4 months. This clinical trial was EPZ-6438 (Tazemetostat) activated in 2004, before the data from your dose-ranging phase II randomized trial were available. It used an induction regimen of 3 mg/kg of ipilimumab once every 3 weeks for four administrations; patients showing disease progression after either a stable disease lasting more than 3 months after week 12 or a confirmed partial or total response were eligible for additional courses of therapy. The security profile in this study was consistent with the prior studies with ipilimumab. On June 2011, results of a second phase III trial comparing dacarbazine versus dacarbazine plus ipilimumab (CA184-024 study) in treatment na?ve patients with metastatic melanoma were published . Ipilimumab was administered at a dose of 10 mg/kg every 3 weeks for 4 doses, followed by maintenance therapy with 10 mg/kg ipilimumab for eligible patients. This study, although less than expected, supported the results of the previous phase III trial by showing an OS of 11. 2 months for patients treated with dacarbazine plus ipilimumab and an OS of 9.1 months for patients treated with dacarbazine alone. Ipilimumab efficacy: Optimal dose and schedule Even if they are not directly comparable, given the differences in study design, by looking at the survival curves of the two phase III trials [3,4] they appear to be quite comparable (Physique ?(Figure1),1), although there is usually less evidence of a tail of the curve of long term durable responses in the trial combining ipilimumab with dacarbazine. This raises some questions about which are the best dosage (3 vs 10 mg/kg), the best schedule (re-induction vs maintenance) and the combination with chemotherapy. Another question issues the role of dacarbazine regarding combination regimes and toxicity profile, since in the dacarbazine plus ipilimumab arm hepato-toxicity appeared to be higher than in the control arm (31,6% vs 2,4% of grade 3/4) and higher than with the prior experience with single agent ipilimumab at 3 or 10 mg/kg. In this regard, results from.