Fernando Carceller1, Francisco J Bautista2, Irene Jiménez3, Raquel Hladun-Álvaro4, Cécile Giraud5, Luca Bergamaschi6, Madhumita Dandapani7, Isabelle Aerts8, François Doz9, Didier Frappaz10, Michela Casanova11, Bruce Morland12, Darren R Hargrave13, Lynley V Marshall14, Gilles Vassal15, Andrew D J Pearson16, Birgit Geoerger17, Lucas Moreno18. 1. Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: Fernando.Carceller@icr.ac.uk. 2. Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: franciscojose.bautista@salud.madrid.org. 3. Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France. Electronic address: irene.jimenez@curie.fr. 4. Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: rhladun@vhebron.net. 5. Department of Paediatric Clinical Trials, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France; Department of Paediatric Neuro-Oncology, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France. Electronic address: cecile.giraud@lyon.unicancer.fr. 6. Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Luca.Bergamaschi@istitutotumori.mi.it. 7. Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK. Electronic address: Madhumita.Dandapani@bch.nhs.uk. 8. Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France. Electronic address: isabelle.aerts@curie.fr. 9. Department of Paediatric, Adolescents and Young Adults Oncology, Institut Curie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France. Electronic address: francois.doz@curie.fr. 10. Department of Paediatric Clinical Trials, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France; Department of Paediatric Neuro-Oncology, Institut Hématologique et d'Oncologie Pédiatrique, Lyon, France. Electronic address: didier.frappaz@ihope.fr. 11. Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michela.Casanova@istitutotumori.mi.it. 12. Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK. Electronic address: BRUCE.MORLAND@bch.nhs.uk. 13. Paediatric Oncology Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Electronic address: Darren.Hargrave@gosh.nhs.uk. 14. Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: LynleyVanessa.Marshall@icr.ac.uk. 15. Department of Clinical Research, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: Gilles.Vassal@gustaveroussy.fr. 16. Paediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address: andy1pearson@btinternet.com. 17. Department of Paediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Sud, Villejuif, France. Electronic address: Birgit.GEOERGER@gustaveroussy.fr. 18. Clinical Trials Unit, Paediatric Oncology Department, Hospital Niño Jesús, Madrid, Spain. Electronic address: lmorenom@ext.cnio.es.
Abstract
OBJECTIVES: Dose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in adult oncology: the Royal Marsden Hospital (RMH) and the MD Anderson Cancer Center (MDACC) scores. METHODS: Data of patients with solid tumours aged <18 years at enrolment in their first dose-finding trial between 2000 and 2014 at eight centres of the Innovative Therapies for Children with Cancer European consortium were collected. Survival distributions were compared using log-rank test and Cox regression analyses. RESULTS: Overall, 248 patients were evaluated: median age, 11.2 years (range 1.0-17.9); 46% had central nervous system (CNS) tumours and 54% extra-CNS tumours. Complete responses were observed in 2.1%, partial responses in 7.2% and stable disease in 25.9%. Median overall survival (OS) was 6.3 months (95% confidence interval, 5.2-7.4). Lansky/Karnofsky ≤80%, no school/work attendance, elevated creatinine and RMH score ≥1 correlated with worse OS in the multivariate analysis. The RMH and MDACC scores correlated with OS in adolescents (12-17 years), p = 0.002, but not in children (2-11 years). CONCLUSIONS: Performance status of 90-100% and school/work attendance at enrolment are strong indicators of longer OS in paediatric phase I trials. Adult predictive scores correlate with survival in adolescents. These findings provide a useful orientation about potential prognosis and could lead in the future to more paediatric-adapted eligibility criteria in early-phase trials.
OBJECTIVES: Dose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in adult oncology: the Royal Marsden Hospital (RMH) and the MD Anderson Cancer Center (MDACC) scores. METHODS: Data of patients with solid tumours aged <18 years at enrolment in their first dose-finding trial between 2000 and 2014 at eight centres of the Innovative Therapies for Children with Cancer European consortium were collected. Survival distributions were compared using log-rank test and Cox regression analyses. RESULTS: Overall, 248 patients were evaluated: median age, 11.2 years (range 1.0-17.9); 46% had central nervous system (CNS) tumours and 54% extra-CNS tumours. Complete responses were observed in 2.1%, partial responses in 7.2% and stable disease in 25.9%. Median overall survival (OS) was 6.3 months (95% confidence interval, 5.2-7.4). Lansky/Karnofsky ≤80%, no school/work attendance, elevated creatinine and RMH score ≥1 correlated with worse OS in the multivariate analysis. The RMH and MDACC scores correlated with OS in adolescents (12-17 years), p = 0.002, but not in children (2-11 years). CONCLUSIONS: Performance status of 90-100% and school/work attendance at enrolment are strong indicators of longer OS in paediatric phase I trials. Adult predictive scores correlate with survival in adolescents. These findings provide a useful orientation about potential prognosis and could lead in the future to more paediatric-adapted eligibility criteria in early-phase trials.
Authors: Lucas Moreno; Andrew D J Pearson; Xavier Paoletti; Irene Jimenez; Birgit Geoerger; Pamela R Kearns; C Michel Zwaan; Francois Doz; Andre Baruchel; Josef Vormoor; Michela Casanova; Stefan M Pfister; Bruce Morland; Gilles Vassal Journal: Nat Rev Clin Oncol Date: 2017-05-16 Impact factor: 66.675
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