Anne-Sophie Defachelles1, Emilie Bogart2, Michela Casanova3, Johannes H M Merks4, Gianni Bisogno5, Giuseppina Calareso3, Soledad Gallego Melcon6, Susanne Andrea Gatz7, Marie-Cécile Le Deley2, Kieran McHugh8, Alicia Probst2, Nathalie Rocourt2, Rick R van Rijn9, Keith Wheatley10, Véronique Minard-Colin1, Julia C Chisholm11. 1. Department of Pediatric and Adolescent Oncology, INSERM U1015, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 2. Centre Oscar Lambret, Lille, France. 3. Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 4. Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. 5. Department of Women and Children Health, University Hospital of Padova, Padova, Italy. 6. University Hospital Vall d'Hebron, Barcelona, Spain. 7. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. 8. Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 9. Amsterdam University Medical Centers, Amsterdam, the Netherlands. 10. University of Birmingham, Birmingham, United Kingdom. 11. Children and Young People's Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom.
Abstract
PURPOSE: The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). METHODS: In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m2 once a day on day 1 and day 8) and irinotecan (50 mg/m2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m2 once a day from day 1 to day 5 and 150 mg/m2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445). RESULTS: Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). CONCLUSION: The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.
PURPOSE: The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). METHODS: In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m2 once a day on day 1 and day 8) and irinotecan (50 mg/m2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m2 once a day from day 1 to day 5 and 150 mg/m2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445). RESULTS: Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). CONCLUSION: The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.
Authors: Christopher I Milton; Joanna Selfe; Ewa Aladowicz; Stella Y K Man; Carolina Bernauer; Edoardo Missiaglia; Zoë S Walters; Susanne A Gatz; Anna Kelsey; Melanie Generali; Gary Box; Melanie Valenti; Alexis de Haven-Brandon; David Galiwango; Angela Hayes; Matthew Clarke; Elisa Izquierdo; David Gonzalez De Castro; Florence I Raynaud; Vladimir Kirkin; Janet M Shipley Journal: Mol Oncol Date: 2021-12-18 Impact factor: 6.603
Authors: Michael T Meister; Marian J A Groot Koerkamp; Terezinha de Souza; Willemijn B Breunis; Ewa Frazer-Mendelewska; Mariël Brok; Jeff DeMartino; Freek Manders; Camilla Calandrini; Hinri H D Kerstens; Alex Janse; M Emmy M Dolman; Selma Eising; Karin P S Langenberg; Marc van Tuil; Rutger R G Knops; Sheila Terwisscha van Scheltinga; Laura S Hiemcke-Jiwa; Uta Flucke; Johannes H M Merks; Max M van Noesel; Bastiaan B J Tops; Jayne Y Hehir-Kwa; Patrick Kemmeren; Jan J Molenaar; Marc van de Wetering; Ruben van Boxtel; Jarno Drost; Frank C P Holstege Journal: EMBO Mol Med Date: 2022-08-02 Impact factor: 14.260