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Clinical Trial Results:
Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of a glioblastoma.

Summary
EudraCT number	2010-023218-30
Trial protocol	BE NL AT IT
Global end of trial date	10 Feb 2018

Results information
Results version number	v1(current)
This version publication date	29 Mar 2019
First version publication date	29 Mar 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
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Trial information

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Sponsor protocol code

26101

ISRCTN number

US NCT number

NCT01290939

WHO universal trial number (UTN)

Sponsor organisation name

EORTC

Sponsor organisation address

83 Avenue Mounier, Brussels, Belgium, 1200

Public contact

Project-Budget & Regulatory Dept, EORTC, 0032 27741047/, regulatory@eortc.be

Scientific contact

Project-Budget & Regulatory Dept, EORTC, 0032 27741047/, regulatory@eortc.be

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Dec 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jul 2015

Global end of trial reached?

Yes

Global end of trial date

10 Feb 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to investigate whether the addition of bevacizumab to lomustine improves overall survival (OS) in patients with recurrent glioblastoma compared to treatment with lomustine alone.

Protection of trial subjects

The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol was written, and the study conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation. Safety data were reviewed within the EORTC Headquarters on a regular basis as part of the Medical Review process. Problems which were identified were discussed with the Study Coordinators who took appropriate measures. Safety information were also included in trial status reports which served as a basis of discussion during EORTC Group meetings. These reports were made available to investigators participating in the study.

Background therapy

Procarbazine and nitrosoureas are modestly effective as systemic agents, although they were evaluated much before temozolomide and rigorous trials meeting current standards are absent. Concomitant and adjuvant temozolomide to radiotherapy is now the standard of care in newly diagnosed patients; however its use at the time of recurrence is debatable and in this setting nitrosoureas are currently widely used, in particular Lomustine (CCNU). A recent randomized study on recurrent glioblastoma that used lomustine noted a 19% progression free survival probability at 6 months with lomustine, similar to what had previously been observed with temozolomide in this indication . Further lomustine was used as comparator in most current trials . The REGAL trial aiming at proving superiority of a vascular endothelial receptor 2 antagonist (cediranib) alone or in combination with lomustine over lomustine alone was negative as reported at a scientific meeting. However, all data presented so far also speaked for relevant activity of lomustine in this trial, and this drug was currently widely used as a salvage regimen for recurrent glioblastoma, despite its modest activity.

Evidence for comparator

In recent years studies on anti-angiogenic agents received considerable attention because of high response rates. Trials on the above mentioned tyrosine kinase inhibitor cediranib and the humanized monoclonal antibody against circulating VEGF bevacizumab had attracted the most interest. Until now phase II trials with anti-angiogenic agents had provided promising results that required confirmation in larger and, even more important, controlled trials. Indeed, the randomized REGAL trial failed to provide evidence of better outcome in cediranib treated recurrent glioblastoma patients, despite high response rates in uncontrolled phase II studies. For bevacizumab, the promising activity observed in recurrent glioblastoma remained to be confirmed, despite the large number of uncontrolled phase II trials that had been conducted. In particular properly powered studies showing Overall Survival benefit from bevacizumab in recurrent glioblastoma were still lacking. Indeed, all but one study on bevacizumab in recurrent glioma were uncontrolled phase II studies. As of today only one randomized, non-comparative phase II study has been reported, but with an irrelevant control. This randomized phase II study observed a PFS6 of 43% after beva given as single agent and of 50% if given in combination with irinotecan. OS was very similar in both groups (approximately 9 months). Compared to the usually less than 10% obtained in recurrent glioblastoma, the observed response rates were exceptionally high (40-45% as judged by the local investigators, 28-38% after central review), and PFS6 (the agreed upon endpoint in trials on recurrent glioblastoma) was twice as high compared to trials on temozolomide and nitrosoureas. Based on the high response rates observed in this trial, in the US bevacizumab had been conditionally approved for use in recurrent glioblastoma. The registration application of bevacizumab in Europe had been been denied, because of lack appropriately controlled trials.

Actual start date of recruitment

21 Nov 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country