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 hours, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12h. 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 to 200 mg/m² on days 1 to 5 every 28 days).Results: The MTD of ralimetinib was 100 mg/12h with chemoradiotherapy. The three patients treated at 200 mg/12h 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/12h. The most frequent doselimiting toxicities were hepatic cytolysis and rash.

p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer

“…In a randomized phase 1b/2 trial in recurrent ovarian cancer, patients that received the p38 MAPK inhibitor ralimetinib in addition to gemcitabine and carboplatin, had a modest improvement in progression free survival [32]. Ralimetinib is also being explored in other disease sites with other combination therapies [33,34]. Given the specific potential for p38 MAPK inhibition to affect androgen signaling shown here and elsewhere, there may be an opportunity to explore this drug for the treatment of prostate cancer.…”

Silencing of the lncRNA H19 enhances sensitivity to X-ray and carbon-ions through the miR-130a-3p /WNK3 signaling axis in NSCLC cells

“…A randomized controlled trial with 118 patients revealed that ralimetinib in combination with gemcitabine and carboplatin could improve the progression-free survival (PFS) of patients with recurrent ovarian cancer [ 42 ]. Moreover, encouraging results were obtained, including for ralimetinib combined with radiotherapy plus temozolomide, in the treatment of glioblastoma [ 43 ], and for ralimetinib combined with tamoxifen to treat advanced breast cancer [ 44 ]. Combined with these results, our study indicates that radiotherapy combined with ralimetinib could be considered a modality for NSCLC in future clinical trials.…”

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

“…Cancer Cell International *Correspondence: brain_lab@suda.edu.cn; johnhyl@163.com † Tingzheng Pan and Xuetao Li contributed equally to this work 1 Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou, People's Republic of China Full list of author information is available at the end of the article quality of life [3,4]. The GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic [5].…”