Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study

Author:

Casanova Michela1ORCID,Bautista Francisco2ORCID,Campbell-Hewson Quentin3ORCID,Makin Guy4ORCID,Marshall Lynley V.5ORCID,Verschuur Arnauld C.6ORCID,Cañete Nieto Adela7ORCID,Corradini Nadège8ORCID,Ploeger Bart A.9ORCID,Brennan Barbara J.9ORCID,Mueller Udo10ORCID,Zebger-Gong Hong11ORCID,Chung John W.12ORCID,Geoerger Birgit13ORCID

Affiliation:

1. 1Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

2. 2Department of Paediatric Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

3. 3Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.

4. 4Division of Cancer Sciences, School of Medical Sciences, University of Manchester and Royal Manchester Children's Hospital, Manchester, United Kingdom.

5. 5Paediatric and Adolescent Oncology Drug Development Team, The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom.

6. 6Department of Pediatric Haematology-Oncology, La Timone Children's Hospital, AP-HM, Marseille, France.

7. 7Unidad de Oncología Pediátrica, Hospital Universitario y Politecnico La Fe, Valencia, Spain.

8. 8Hematology and Oncology Pediatric Institute, Léon Bérard Center, Lyon, France.

9. 9Pharmacometrics/Modelling and Simulation, Bayer AG, Berlin, Germany.

10. 10Department of Statistics, ClinStat GmbH, Cologne, Germany.

11. 11Medical Affairs and Pharmacovigilance, Bayer AG, Berlin, Germany.

12. 12Clinical Development Oncology, Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.

13. 13Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, INSERM U1015, Université Paris-Saclay, Villejuif, France.

Abstract

Abstract Purpose: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. Patients and Methods: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1–5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. Results: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9–14.8] and median overall survival was 8.7 months (95% CI, 5.5–16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). Conclusions: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).

Funder

n/a

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference50 articles.

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