REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab (BV) in relapsed glioblastoma (GB).

Abstract

TPS2103 Background: EGFRvIII is a constitutively active tumorigenic deletion mutation of EGFR. It is expressed in ~30% of primary GB where it is linked to poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 150ug GM-CSF as an adjuvant). Remarkably consistent and promising results across 3 phase II studies in newly diagnosed, resected EGFRvIII+ GB (Lai 2011) represent a statistically significant improvement over a historical control cohort matched for major eligibility criteria (median overall survival [OS] = 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and median progression-free survival [PFS] = 12.3 - 15.3 vs. 6.4 m). ACT IV, a phase III trial in this population, is ongoing. The immunosuppressive influence of residual/advanced GB presents a challenge to activation of efficacious antitumor immune responses. Anecdotal evidence (compassionate use cases, Sampson 2008) suggests that rindopepimut may induce specific immune responses and regression in multifocal and bulky residual tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive properties (including impaired maturation of dendritic cells and disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) may further optimize EGFRvIII-specific immune response and antitumor activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in patients (pts) with 1st or 2nd relapse of EGFRvIII+ GB. BV-naïve pts will be enrolled to Group 1 (n=70: randomized 1:1 to BV plus either rindopepimut/GM-CSF or control injection [low-dose KLH]) while BV-refractory patients will enter Group 2 (n=25: to receive BV plus open-label rindopepimut/GM-CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or open-label vaccine is given in priming phase (days 1, 15 and 29), then monthly until PD. Tumor response is assessed every 8 weeks, and patients are followed for survival after PD. Objectives are PFS at 6 months (primary), objective response rate, PFS, OS, safety, immunogenicity and elimination of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328).

Current State and Future Prospects of Immunotherapy for Glioma

“…Phase III study of rindopepimut/GM-CSF with adjuvant TMZ in patients with newly diagnosed glioma (ACT IV, NCT01480479) has been discontinued as the median OS with rindopepimut was 20.4 months compared with 21.1 months in the control arm [153]. ReACT (NCT01498328) is a Phase II study of rindopepimut/GM-CSF plus bevacizumab in patients with relapsed EGFRvIII-positive glioma [154]. Interim analysis shows rindopepimut induces potent EGFRvIII-specific immune response and tumor regression, and appears to significantly prolong survival when administered with bevacizumab in patients with relapsed glioma [155].…”

Neuro-oncology: a selected review of ASCO 2012 abstracts

“…The Phase II REACT vaccine trial using the EGF receptor variant 3 vaccine, rindopepimut, is enrolling patients. Rindopepimut will be used in conjunction with bevacizumab in bevacizumab-naive patients and as add-on therapy in patients progressing on bevacizumab [21]. TOCA 511 is a novel Phase I/II trial using a retroviral replicating vector that delivers cytosine deaminase to the tumor (administered by intratumoral injection at time of reoperation) followed by oral 5-fluorocytosine that, in tumor, is converted by cytosine deaminase to 5-fluorouracil, a cytotoxic chemotherapy [22].…”