Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies

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 e93 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 Z 1]). The MTD was defined as 82 mg/m 2 . The most common Grade !3 drugrelated TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and handefoot 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.

Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis

“…After screening, six additional clinical studies with results on clinicaltrials.gov were included in the analysis. In total, 70 records (64 published articles and 6 clinical trials with published results retrieved from clinicaltrials.gov) reporting AEs of anti-angiogenic drugs in pediatric patients with solid tumors were included in the systematic review [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ,…”

“…Most of the studies evaluated AEs of anti-angiogenic drugs in patients with central nervous system tumors (sixteen various glioma [ 24 , 25 , 29 , 32 , 43 , 44 , 45 , 46 , 65 , 75 , 76 , 80 , 81 , 82 , 83 , 84 ], eight various brain tumors [ 28 , 33 , 54 , 59 , 61 , 64 , 72 , 88 ], three ependymoma [ 30 , 70 , 79 ], two medulloblastoma [ 23 , 51 ], one astrocytoma [ 47 ], and two neuroblastoma [ 56 , 78 ]). Twenty-three studies referred to a cohort of patients with various solid tumors [ 27 , 31 , 34 , 37 , 38 , 39 , 40 , 41 , 50 , 53 , 55 , 58 , 60 , 63 , 66 , 68 , 71 , 73 , 74 ,…”

“…Twenty studies reported the number of AEs of anti-angiogenic drugs used as monotherapy (three for bevacizumab [ 40 , 43 , 72 ], four for sorafenib [ 47 , 71 , 90 , 91 ], three for sunitinib [ 31 , 67 , 70 ], two for pazopanib [ 41 , 73 ], two for vandetanib [ 42 , 49 ], one for aflibercept [ 39 ], one for axitinib [ 37 ], one for cabozatinib [ 27 ], one for trebananib [ 50 ], one for lenvatinib [ 35 ], one for regorafenib [ 38 ], and one for ramucirumab [ 74 ]), thirty-six reported anti-angiogenic drugs used in combination with standard chemotherapy (twenty-nine for bevacizumab [ 23 , 26 , 28 , 29 , 33 , 44 , 45 , 46 , 51 , 52 , 54 , 55 , 56 , 57 , 58 , 64 , 66 , 68 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ], four for sorafenib [ …”

Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas

“…Regorafenib has been evaluated by the ITCC as single agent and subsequently in combination with chemotherapy in paediatric patients with recurrent or refractory solid malignancies (NCT02085148) [51]. It has been shown that regorafenib can be combined with standard dose vincristine and irinotecan in a sequential dosing schedule [52,53].…”

Safety and efficacy of multiple tyrosine kinase inhibitors in pediatric/adolescent and young adult patients with relapsed or refractory osteosarcomas: A single‐institution retrospective analysis

“…Phase I studies on sorafenib, 14 everolimus, 15 or regorafenib 16 for pediatric relapsed or refractory solid tumors, including osteosarcoma, have been conducted, and the safety of these drugs in children has been established. Furthermore, a phase I/II study reported that lenvatinib has a median PFS of 3.0 months and an objective response rate of 6.7% 17 .…”