Lyndon J. Kim

BACKGROUND: -L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

2005 Background: The trial investigated whether adding tumor-antigen-loaded DC vaccine to surgery and chemoradiation would improve overall survival (OS) or progression free survival (PFS). Methods: HLA-A1+ and/or -A2+ resected patients with residual tumor <1 cm3 received 6 weeks of concurrent temozolomide (TMZ) and radiation. 124 patients were randomized 2:1 to receive ICT-107 (autologous PBMC-derived DC pulsed with 6 synthetic peptide CTL epitopes targeting the GBM tumor and tumor stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Rα2) or its matching control (unpulsed DC). Patients then received induction ICT-107 or control QWx4 followed by maintenance TMZ, 5 days/mo for 12 mos. Booster vaccinations occurred at 1, 3, and 6 mos after induction, and every 6 mos thereafter. The trial concluded and data were evaluated at 67 events. Results: ICT-107 was generally safe and well tolerated, with no imbalance in AEs between the treated and control groups. PFS improved by 2 mos in the ICT-107 ITT group (p=0.02 two-sided, hazard ratio (HR)=0.56). In the per-protocol (PP) group (117 patients receiving all 4 induction vaccinations), p=0.01 two-sided, HR=0.53, and the difference in median PFS increased to 3 mos. The median OS favored ICT-107 by 2 mos in the ITT and 3 mos in the PP groups. However, the number of events was small and OS did not reach statistical significance (p=0.58 two-sided, HR=0.87, and p=0.40 two-sided, HR=0.79, respectively). Median follow-up from randomization was 13.6 mos. In the ICT-107 group, vaccine activation markers IL12 and HLA-DR were predictive of OS (p-values < 0.05). There were no correlations in the placebo group. Conclusions: This is the first randomized, placebo-controlled immunotherapy trial in GBM to positively affect a clinical outcome, PFS. Although OS improvement was not statistically significant at the 67/124 event point, patients continue to be followed for OS, allowing periodic updating of the primary endpoint and assessment of long-term survival. Analysis of QOL, and correlation of both tumor antigen expression and vaccine immunologic response with OS are in process.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.