Phase I/II Study of the PARP Inhibitor Olaparib and Irinotecan in Children and Young Adults with Recurrent/Refractory Malignancies: Arm D of the AcSé-ESMART Trial.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Gatz Susanne A, Berlanga Pablo, Le Teuff Gwénaël, Valiev Ivan, Leruste Amaury, André Nicolas, Bluteau Dominique, Corradini Nadege, Rubino Jonathan, Thomas Fabienne, Nebchi Souad, Karamouza Eleni, Petit Jeanne, Thebaud Estelle, Rubio-San-Simón Alba, van Eijkelenburg Natasha K A, Marshall Lynley V, Raimbault Sandra, Canete Adela, Ducassou Stephane, Makin Guy, Casanova Michela, De Carli Emilie, Petit Arnaud, Cardon Melis, Lacroix Ludovic, Pierron Gaelle, Schleiermacher Gudrun, Hubank Michael J F, Soriano Fernandez Aroa, Langenberg Karin P S, Castel David, Adam-de Beaumais Tiphaine, Paoletti Xavier, Lukka Pradeep B, Baldry Richard, Mortimer Peter G S, Nikolaev Sergey I, Geoerger Birgit
Аннотация
PATIENTS AND METHODS: Olaparib was administered orally twice daily on days 1 to 10 and irinotecan intravenously on days 4 to 8 of a 21-day cycle. Dose escalation followed the continuous reassessment method; activity was assessed in diverse tumor types (cohort 1) and Ewing sarcoma (cohort 2) according to a minimax Simon 2-stage design. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways.
RESULTS: Seventy patients (median age, 14.9 years; range, 5.0-23.8) were included, 34 with diverse tumor types (25 with HRR gene alterations) and 36 with Ewing sarcoma. Sixty-six patients received 348 treatment cycles (median, 2; range, 1-51) over four dose levels. Main toxicities were gastrointestinal and myelosuppression; the RP2D was olaparib 90 mg/m2 twice daily and irinotecan 20 mg/m2/day. Olaparib exposure in children was equivalent to that in adults. The overall response rate was 9.1% (cohort 1, 11.8%; cohort 2, 6.3%). Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for nine to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest a high aneuploidy score possibly associated with objective response and prolonged stable disease.
CONCLUSIONS: Olaparib combined with irinotecan demonstrated activity in pediatric tumors, which was enriched among tumors that exhibited aneuploidy.