First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

Linda M Liau, Keyoumars Ashkan, David D Tran, Jian L Campian, John E Trusheim, Charles S Cobbs, Jason A Heth, Michael Salacz, Sarah Taylor, Stacy D D'Andre, Fabio M Iwamoto, Edward J Dropcho, Yaron A Moshel, Kevin A Walter, Clement P Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A Toms, Kevin O Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R Abram, Andrew J Brenner, Steven Brem, Matthew G Ewend, Simon Khagi, Jana Portnow, Lyndon J Kim, William G Loudon, Reid C Thompson, David E Avigan, Karen L Fink, Francois J Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S Baskin, Pamela Z New, Michel Lacroix, Sven-Axel May, Timothy J Pluard, Victor Tse, Richard M Green, John L Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E Maida, Robert M Prins, Timothy F Cloughesy, Paul Mulholland, Marnix L Bosch, Linda M Liau, Keyoumars Ashkan, David D Tran, Jian L Campian, John E Trusheim, Charles S Cobbs, Jason A Heth, Michael Salacz, Sarah Taylor, Stacy D D'Andre, Fabio M Iwamoto, Edward J Dropcho, Yaron A Moshel, Kevin A Walter, Clement P Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A Toms, Kevin O Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R Abram, Andrew J Brenner, Steven Brem, Matthew G Ewend, Simon Khagi, Jana Portnow, Lyndon J Kim, William G Loudon, Reid C Thompson, David E Avigan, Karen L Fink, Francois J Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S Baskin, Pamela Z New, Michel Lacroix, Sven-Axel May, Timothy J Pluard, Victor Tse, Richard M Green, John L Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E Maida, Robert M Prins, Timothy F Cloughesy, Paul Mulholland, Marnix L Bosch

Abstract

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-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://ichgcp.net/clinical-trials-registry/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Keywords: Dendritic cell; Glioblastoma; Immunotherapy; Vaccine.

Figures

Fig. 1
Fig. 1
Recruitment, inclusion, and randomization of patients in the study. (1) Patients are screened prior to surgery, so glioblastoma (GBM) determination is made from pathological diagnosis after surgery. (2) Insufficient tumor lysate generated to meet threshold. (3) Progressive disease or pseudo-progression (which are indistinguishable at this point) based on central review of MRI imaging at baseline post-chemoradiation. (4) Patients who consented to tumor donation but then declined participation in trial prior to leukapheresis. (5) Includes deviations from standard chemoradiation protocol, history of prior malignancy, inadequate renal or bone marrow function, etc. (6) Includes drug product failure or insufficient drug or placebo manufactured to meet release criteria. (7) Includes clinical deterioration, declining Karnofsky performance status, or patient deaths. (8) Includes biopsy only, surgery canceled, or tumor tissue not processed after surgery
Fig. 2
Fig. 2
Overall survival curves for patients in the intent-to-treat population. Overall survival analyses of time from date of surgery until death or last follow-up according to the Kaplan–Meier method for all patients in the intent-to-treat (ITT) population (a), and the ITT population stratified by MGMT gene promoter methylation status (b). Censored patients are annotated by a small vertical line

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