A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study

Abstract

Background: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.

Methods: Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation.

Results: Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy.

Conclusions: This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.

Keywords: ACT III; EGFRvIII; glioblastoma; glioma; rindopepimut.

© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1.

Anti-EGFRvIII antibody titers. Antibody titers to EGFRvIII were measured by enzyme-linked immunosorbent assay as described under Methods. Each point represents an individual patient titer, while horizontal lines delineate the mean for that time point.

Fig. 2.

Kaplan–Meier estimates of PFS and OS. Survival durations are calculated from study entry, representing a median of 3.0 (range, 2.4–4.4) months from diagnosis (as shown in Table 1). Line markers represent censored data.

Fig. 3.

Kaplan–Meier estimates of PFS and OS, by MGMT promoter methylation status. (A) PFS and (B) OS are calculated from study entry, representing a median of 3.0 (range, 2.4–4.4) months from diagnosis (as shown in Table 1). Line markers represent censored data. HR, hazard ratio; NE, not estimated.

Fig. 4.

Kaplan–Meier estimates of PFS and OS for phase II rindopepimut studies. (A) PFS and (B) OS are calculated from diagnosis. Line markers represent censored data. In the 3 rindopepimut studies (ACTIVATE, ACT II, and ACT III), rindopepimut vaccinations began ∼3 mo after diagnosis.