Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies. (August 2021)

• Record Type: Journal Article
• Authors: Geoerger, Birgit; Morland, Bruce; Jiménez, Irene; Frappaz, Didier; Pearson, Andrew D.J.; Vassal, Gilles; Maeda, Patricia; Kincaide, Jasmine; Mueller, Udo; Schlief, Sarah; Teufel, Michael; Ploeger, Bart A.; Cleton, Adriaan; Agostinho, Andrea C.; Marshall, Lynley V.
• Is Part Of: European journal of cancer. Volume 153(2021)
• Page Start: 142
• Page End: 152
• Publication Date: 2021-08
• Subjects: Regorafenib -- Solid tumour -- Paediatric -- Phase 1 -- Pharmacokinetics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.05.023
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m 2 ) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model. Results: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60–93 mg/m 2 ). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m 2 . The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand–foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. Conclusions: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m 2 . Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. Clinical trial number: NCT02085148. Highlights: Regorafenib had acceptable tolerability in paediatric patients. The recommended phase 2 dose (RP2D) in paediatric patients was 82 mg/m 2 . Exposure at the RP2D was comparable with adult exposure at the standard 160 mg/day. Preliminary antitumour activity supports further studies in paediatric patients. Regorafenib treatment downregulated circulating target proteins c-KIT and VEGFR2.