Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

Abstract

BACKGROUND AND PURPOSE:

This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients.

MATERIALS AND METHODS:

The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days).

RESULTS:

The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells.

CONCLUSION:

This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

• Authors: J Biau, E Thivat, E Chautard, D Stefan, M Boone, B Chauffert, C Bourgne, D Richard, I Molnar, S Levesque, R Bellini, F Kwiatkowski, L Karayan-Tapon, P Verrelle, C Godfraind, X Durando
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 154 Pg. 227-234 (01 2021) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 32976869 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• Imidazoles
• Pyridines
• ralimetinib
• Dacarbazine
• Temozolomide

Topics

• Antineoplastic Agents, Alkylating (therapeutic use)
• Brain Neoplasms (drug therapy)
• Chemoradiotherapy
• Dacarbazine (therapeutic use)
• Glioblastoma (drug therapy)
• Humans
• Imidazoles
• Leukocytes, Mononuclear
• Pyridines
• Temozolomide (therapeutic use)