Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.

An early feasibility study of the Nativis Voyager® device in patients with recurrent glioblastoma: first cohort in US.

AIM: Evaluation of the Nativis Voyager® device in patients with recurrent glioblastoma (rGBM). MATERIALS & METHODS: Voyager is a noninvasive, nonthermal, nonionizing and portable investigational device which delivers ultra-low radio frequency energy (ulRFE®) that uses a magnetic field to penetrate tissues to alter specific biologic functions within cells. Patients with rGBM were treated with Voyager alone (V) or Voyager in combination with standard of care (V + SoC). Safety and clinical utility were assessed every 2-4 months. RESULTS: Data from the first 11 patients treated are reported here. Median progression-free survival was 10 weeks in the V arm and 16 weeks in the V + SoC arm. Median overall survival was 16 months in V arm and 11 months in the V + SoC arm. No serious adverse events associated with the device were reported. CONCLUSION: These data suggest that the Voyager is safe and feasible for the treatment of rGBM.

Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas.

BACKGROUND: : Glioma cells secrete glutamate and also express alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionate (AMPA) glutamate receptors, which contribute to the proliferation, migration, and neurotoxicity of malignant gliomas. Talampanel is an oral AMPA receptor inhibitor with excellent central nervous system penetration and good tolerability in clinical trials for epilepsy and other neurologic disorders. METHODS: : A phase 2 trial was conducted to evaluate the efficacy of talampanel in patients with recurrent malignant glioma as measured by 6-month progression-free survival (PFS6). RESULTS: : Thirty patients (22 with glioblastomas [GBMs] and 8 with anaplastic gliomas [AGs]; 63% men) with median age of 51 years (range, 20-67 years) and a median Karnofsky performance scale of 80 were included. Patients tolerated treatment well, and most adverse events were mild and reversible; the most common toxicities were fatigue (27%), dizziness (23%), and ataxia (17%). There was only 1 partial response (5%) reported in the GBM stratum and none among AG patients. At a median follow-up of 13 months, 28 patients (93%) had died. The PFS6 was 4.6% for the initial 22 GBM patients, and the study was terminated early due to treatment futility; the PFS6 was 0% for 8 AG patients. The median PFS was 5.9 weeks for GBM and 8.9 weeks for AG patients. The median overall survival was 13 weeks for GBM patients and 14 months for AG patients. CONCLUSIONS: : Talampanel was well-tolerated but had no significant activity as a single agent in unselected recurrent malignant gliomas. Cancer 2010. Published 2010 by the American Cancer Society.

A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors.

PURPOSE: Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors. EXPERIMENTAL DESIGN: A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted. RESULTS: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m(2), with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months. CONCLUSION: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2). Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.