Lucas Moreno1, Michela Casanova2, Julia C Chisholm3, Pablo Berlanga4, Pascal B Chastagner5, Sylvain Baruchel6, Loredana Amoroso7, Soledad Gallego Melcón8, Nicolas U Gerber9, Gianni Bisogno10, Franca Fagioli11, Birgit Geoerger12, Julia L Glade Bender13, Isabelle Aerts14, Christophe Bergeron15, Pooja Hingorani16, Ileana Elias17, Mathew Simcock18, Stefano Ferrara18, Yvan Le Bruchec18, Ruta Slepetis19, Nianhang Chen19, Gilles Vassal20. 1. Hospital Infantil Universitario Niño Jesús, Madrid, Spain. Electronic address: lucas.moreno@salud.madrid.org. 2. Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. 3. Royal Marsden Hospital, Sutton, UK. 4. Unidad de Oncologia Pediatrica, Hospital Universitario I Politècnic La Fe, Valencia, Spain. 5. Hôpital d'Enfants, Nancy, France. 6. The Hospital for Sick Children, Toronto, ON, Canada. 7. IRCCS Istituto Giannina Gaslini, Genova, Italy. 8. Hospital Universitario Vall d'Hebron, Barcelona, Spain. 9. University Children's Hospital, Zurich, Switzerland. 10. Department of Pediatrics, Hematology/Oncology Division, Padova, Italy. 11. Pediatric Onco-Hematology Division, Regina Margherita, Torino, Italy. 12. Gustave Roussy, Department of Pediatric and Adolescent Oncology, Villejuif, France. 13. Columbia University, New York, NY, USA. 14. Institut Curie, PSL Research University, Oncology Center SIREDO (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Paris, France. 15. Department of Pediatrics, Centre Léon Bérard, Lyon, France. 16. Phoenix Children's Hospital, Phoenix, AZ, USA. 17. Celgene Corporation, Toronto, ON, Canada. 18. Celgene International, Boudry, Switzerland. 19. Celgene Corporation, Summit, NJ, USA. 20. Gustave Roussy, Villejuif, France.
Abstract
BACKGROUND: nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. PATIENTS AND METHODS: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). RESULTS: Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. CONCLUSIONS: nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. EUDRACT: 2013-000144-26.
BACKGROUND:nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. PATIENTS AND METHODS: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). RESULTS: Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. CONCLUSIONS:nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. EUDRACT: 2013-000144-26.
Authors: Javier E Oesterheld; Damon R Reed; Bhuvana A Setty; Michael S Isakoff; Patrick Thompson; Hong Yin; Masanori Hayashi; David M Loeb; Tiffany Smith; Rikesh Makanji; Brooke L Fridley; Lars M Wagner Journal: Pediatr Blood Cancer Date: 2020-05-09 Impact factor: 3.167
Authors: Arthur Felix; Pablo Berlanga; Maud Toulmonde; Judith Landman-Parker; Sarah Dumont; Gilles Vassal; Marie-Cécile Le Deley; Nathalie Gaspar Journal: Cancer Med Date: 2021-01-15 Impact factor: 4.452