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

J. Biau (1, 2) , E. Thivat (1, 2) , E. Chautard (1, 2) , D. Stefan (3) , Mathieu Boone (4, 5) , Bruno Chauffert (4, 5) , C. Bourgne (6) , D. Richard (7) , I. Molna (1, 2) , S. Levesque (1, 2) , R. Bellini (1) , F. Kwiatkowski (2, 1, 8) , L Karayan-Tapon (9) , P. Verrelle (1, 10) , C. Godfraind (11, 12) , X. Durando (1, 2)

1 UNICANCER/CJP - Centre Jean Perrin [Clermont-Ferrand]
2 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
3 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
4 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
5 CHIMERE - CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516
6 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
7 Neuro-Dol - Neuro-Dol
8 CIC 1405 - Centre d'Investigation Clinique [CHU Clermont-Ferrand]
9 LNEC [Poitiers] - Laboratoire de neurosciences expérimentales et cliniques
10 Institut Curie [Paris]
11 CHU Gabriel Montpied [Clermont-Ferrand]
12 M2iSH - Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte

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.

Mots clés: Ralimetinib; Radiotherapy; Temozolomide; Glioblastoma; Phase I clinical trial

Domaines: Cancer; Hématologie; Neurobiologie; Pharmacologie

J. Biau, E. Thivat, E. Chautard, D. Stefan, Mathieu Boone, et al.. Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma. Radiotherapy & Oncology, 2021, 154 (227-234), ⟨10.1016/j.radonc.2020.09.036⟩. ⟨hal-02954534⟩