Phase I dose-escalation and pharmacokinetic (PK) study of regorafenib in pediatric patients with recurrent or refractory solid malignancies.

Geoerger, Birgit; Morland, Bruce; Jiménez, Irène; Frappaz, Didier; Pearson, Andrew D.J.; Vassal, Gilles; Maeda, Patricia; Kincaide, Jasmine; Mueller, Udo; Schlief, Sarah; Cleton, Adriaan; Chassot-Agostinho, Andrea; Marshall, Lynley V.

doi:10.1200/jco.2016.34.15_suppl.10542

Cited by 5 publications

(4 citation statements)

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“…The drug dosage and administration schedules were determined based on previous studies 16,18,19 . Details of the maintenance dosage are provided in Table 2.…”

Section: Resultsmentioning

confidence: 99%

“…The drug dosage and administration schedules were determined based on previous studies. 16,18,19 Details of the maintenance dosage are provided in Table 2. In the sorafenib monotherapy and sorafenib with everolimus groups, the patients were given 400-mg tablets of regorafenib and 3-mg or 5-mg tablets of everolimus.…”

Section: Drug Dosage and Administration Schedulementioning

confidence: 99%

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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

Sugiyama¹,

Arakawa²,

Shirakawa³

et al. 2023

Pediatric Blood & Cancer

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Background The prognosis of relapsed or refractory osteosarcoma remains poor. Recent reports have stated that molecular targeting agents, including multiple tyrosine kinase inhibitors (MTKIs), are effective against adult osteosarcoma. To determine the safety and efficacy of MTKI therapy in children, adolescents and young adults (AYAs), we conducted a retrospective study on adverse events and treatment outcomes. Methods We retrospectively reviewed the medical records of patients with relapsed or refractory osteosarcoma who received MTKI therapy at the Department of Pediatric Oncology, National Cancer Center Hospital, from December 2013 to May 2021. Results The study included 31 patients (15 males and 16 females) who received MTKIs, including sorafenib monotherapy (seven patients), sorafenib and everolimus (14 patients), and regorafenib monotherapy (10 patients). Their median age was 17 years (range: 11–22 years). The incidence of treatment‐related grade 3 nonhematological adverse events was 14.3% in the sorafenib monotherapy group, 21.4% in the sorafenib with everolimus group, and 20.0% in the regorafenib monotherapy group. No grade 4 nonhematological adverse events were observed. The median progression‐free survival (PFS) was 51 days in the sorafenib monotherapy group, 101 days in the sorafenib with everolimus group, and 167 days in the regorafenib monotherapy group. Conclusion The safety profile of MTKI therapies in pediatric and AYA patients was comparable to that in adult patients. MTKI therapies, particularly regorafenib, against pediatric relapsed osteosarcoma can suppress tumor growth and prolong PFS with tolerable adverse events.

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“…The drug dosage and administration schedules were determined based on previous studies 16,18,19 . Details of the maintenance dosage are provided in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Section: Drug Dosage and Administration Schedulementioning

confidence: 99%

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

Sugiyama¹,

Arakawa²,

Shirakawa³

et al. 2023

Pediatric Blood & Cancer

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“…Hematologic toxicity was seen at a higher rate in heavily pretreated pediatric patients than in adults. 67 Observed exposure of regorafenib and active metabolites was similar to the adult exposure in the therapeutic dose range, although details were not yet reported. Furthermore, using a physiology-based PK model, the RP2D of 72 mg/m 2 was predicted to result in 100% of adult exposure.…”

Section: Regorafenibmentioning

confidence: 88%

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

Janssen

Dorlo

Steeghs

et al. 2020

Clin Pharma and Therapeutics

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In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure–efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.

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“…For evaluating the predictive performance in children, the PopPK model–based results were applied, by aggregation of the calculated geometric mean of the individual simulated exposure (AUC from time 0 to 24 hours after the last dose in steady state [AUC 24,ss ]) estimates 13 from the individual patients for each age group 47 . The PBPK predictions for each individual matched to the demographics of the individual patients were aggregated by calculating the geometric mean of the individual AUC 24,ss for each predefined age group.…”

Section: Methodsmentioning

confidence: 99%

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

Ince

Dallmann

Frechen

et al. 2021

The Journal of Clinical Pharma

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Development and guidance of dosing schemes in children have been supported by physiology‐based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound‐ and system‐specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small‐molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK‐predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2‐fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted‐to‐observed PK ratios were within a 2‐fold error range (n = 27), with two‐thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.

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Phase I dose-escalation and pharmacokinetic (PK) study of regorafenib in pediatric patients with recurrent or refractory solid malignancies.

Cited by 5 publications

References 0 publications

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

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

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

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