Dovepress with GM-CSF was performed on day 21 of each 28-day temozolomide cycle. The mean cohort age was 57 years, with most patients (64%) having a KPS of 100. There was minimal toxicity, with no significant elevations in autoimmunity markers and no development of new T2 abnormalities. All immunized patients developed EGFRvIII-specific humoral responses, with only patients in the DI group having DTH responses. Interestingly, despite inducing more severe lymphopenia, treatment with DI temozolomide enhanced humoral and cellular immune responses following vaccination compared to STD temozolomide. As previously seen, 91.6% of recurrent tumors had lost expression of EGFRvIII. The median PFS was 15.2 months, with patients having a median OS of 23.6 months. These outcomes were significantly better than historical controls, with survival significantly exceeding the survival expectations of Curran’s recursive partitioning analysis (P , 0.0001) and the EORTC 26981/22981-NCIC CE3 Phase III randomized trial (P = 0.008) (Figure 3). Another Phase II trial (ACTIII) to study the eff icacy of PEPvIII-KLH/rindopepimut in a larger population of newly diagnosed GBMs was then initiated.95 This study enrolled 65 patients, with therapy including temozolomide maintenance therapy (150–200 mg/m2 for 5/28 days) and three vaccinations every 2 weeks and then on the 21st day of each temozolomide cycle monthly (Figure 4). The median age was 56 years, with studied patients having a median KPS of 90. Toxicity in this trial included grade I–II injection site reactions, a grade II hypersensitivity reaction, and a case with grade III toxic epidermal necrolysis. The median PFS was 12.3 months and OS was 24.6 months, both of which were signif icantly higher than historical controls (P = 0.0088 Newly diagnosed GBM gross total resection EGFRvIII expressing tumors no progression during TMZ/RT XRT (~60 Gy) TMZ (75 mg/m2/d) Rindopepimut for the treatment of glioblastoma and ,0.0001, respectively) (Figure 3). As expected, patients with methylated MGMT had a signif icantly higher PFS (17.5 vs 11.2 months; P = 0.0057) and OS (32.3 vs 20.9 months; P = 0.0067). Ongoing clinical trials Currently there are two active trials investigating the use of rindopepimut in GBM. A Phase III trial (ACT IV) has been initiated to investigate the safety and efficacy of rindopepimut in newly diagnosed GBM (Figure 3). This international trial is being conducted at over 100 centers and will include ∼374 patients with a gross total resection. Additionally, patients having incomplete resections will be enrolled, allowing for the evaluation of rindopepimut efficacy in patients with residual tumor burden. All patients will only receive two priming vaccines (compared to three in previous trials). The estimated completion date is November 2016. Another Phase II trial (ReACT) is investigating the efficacy of rindopepimut in combination with bevacizumab in patients with relapsed EGFRvIII-positive GBM. Patients will be enrolled into two groups: Group 1 patients will be randomly assigned to receive either rindopepimut or KLH, each with bevacizumab; Group 2 patients will all be treated with rindopepimut in combination with bevacizumab and consists of those refractory to bevacizumab. The primary outcome measure is PFS rate at 6 months, with secondary outcomes being safety and tolerability, antitumor activity, and EGFRvIII-specific immune response. As tumor volume is not an exclusion criterion in this trial, the efficacy of rindo- pepimut in cases with significant tumor burden will also be evaluated. This study will seek to enroll 95 patients and has an estimated primary completion date of March 2014. TMZ therapy (150 to 200 mg/m2) for days 1–5 of each 28 day cycle (up to 12 cycles) 0 y a D 4 1 y a D 4 2 y a D On the 21st day of each TMZ cycle, then monthly until progression or intolerance Intradermal administration of rindopepimut (~500 µg) with GM-CSF (~150 µg) Figure 4 Timeline demonstrating the schedule of treatment for glioblastoma patients undergoing immunotherapy with rindopepimut. Abbreviation: GBM, glioblastoma multiforme. Core Evidence 2012:7 submit your manuscript | www.dovepress.com Dovepress 99