A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.

Abstract

BACKGROUND:

The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.

METHODS:

Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity.

RESULTS:

One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS.

CONCLUSIONS:

Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.

CLINICAL TRIAL REGISTRATION:

NCT01582269, ClinicalTrials.gov.

• Authors: Alba A Brandes, Antoine F Carpentier, Santosh Kesari, Juan M Sepulveda-Sanchez, Helen R Wheeler, Olivier Chinot, Lawrence Cher, Joachim P Steinbach, David Capper, Pol Specenier, Jordi Rodon, Ann Cleverly, Claire Smith, Ivelina Gueorguieva, Colin Miles, Susan C Guba, Durisala Desaiah, Michael M Lahn, Wolfgang Wick
• Journal: Neuro-oncology (Neuro Oncol) Vol. 18 Issue 8 Pg. 1146-56 (08 2016) ISSN: 1523-5866 [Electronic] England
• PMID: 26902851 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents, Alkylating
• Pyrazoles
• Quinolines
• LY-2157299
• Lomustine

Topics

• Antineoplastic Agents, Alkylating (adverse effects, therapeutic use)
• Brain Neoplasms (drug therapy)
• Disease-Free Survival
• Drug Therapy, Combination (adverse effects, methods)
• Female
• Glioblastoma (drug therapy)
• Humans
• Kaplan-Meier Estimate
• Lomustine (adverse effects, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Pyrazoles (adverse effects, pharmacokinetics, therapeutic use)
• Quinolines (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome