Pediatric Phase 2 Trial Of The Wee1 Inhibitor Adavosertib (Azd1775) And Irinotecan: A Children'S Oncology Group Study (Advl1312).

Abstract Background: Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. This study reports the phase 2 expansion of the ADVL1312 phase I/II trial combining irinotecan and adavosertib in children and adolescents with relapsed/refractory solid and CNS tumors. Methods: Patients (< 21 yrs old) with measurable or MIBG-evaluable relapsed/refractory neuroblastoma (Part B), medulloblastoma/CNS embryonal tumors (Part C) or rhabdomyosarcoma (Part D) were treated with irinotecan (90 mg/m2/dose) and adavosertib (85 mg/m2/dose) orally for 5-days every 21-days. Any patient who received at least one dose was considered evaluable for response. Using a Simon's two stage design the combination was considered effective if there were three out of twenty responses in parts B and D or six out of nineteen responses in part C. Tumor tissue was analyzed for ATRX deficiency by multiplex immunofluorescence of ultrabright telomere foci and ATRX, and where available, prior tumor genomic analyses. Results: Twenty eligible patients with neuroblastoma, with a median age of nine years old (6-19) were included in Part B. They had a median of three prior chemotherapy regimens (1-7); nineteen patients (95%) had prior irinotecan and seventeen (85%) received prior radiation therapy. The combination therapy resulted in three objective responses confirmed by central review (estimated response rate of 16.7%) meeting the protocol defined efficacy endpoint for Part B. The responses included a measurable partial response (11 cycles), MIBG evaluable complete response (9 cycles) and MIBG and marrow evaluable partial response (18 cycles). In addition, there were three patients with prolonged stable disease of 8, 11 and 13 cycles. Two of the three patients with objective responses had tumors with predicted ATRX deficiency, while the third did not have available archival tumor. Of the nine neuroblastoma patient tumors with predicted ATRX deficiency, 4 (44%) had objective responses or prolonged stable disease. In part C, of 9 patients eligible for response, 1 patient with pineoblastoma had a confirmed partial response (9 cycles) and another with medulloblastoma had prolonged stable disease (11 cycles). In part D, of 10 eligible patients, 2 had stable disease of 8 and 10 cycles. Part C and D did not meet the protocol defined efficacy endpoint. The combination was well tolerated with one patient experiencing a dose limiting toxicity that resolved with dose reduction. Conclusion: This the first phase 2 clinical trial of adavosertib in pediatrics and the first in combination with irinotecan. The combination was of sufficient activity to support further study in neuroblastoma, and possibly other pediatric tumor types with recurrent ATRX mutation. Citation Format: Kristina A. Cole, Heba Ijaz, Lea Surrey, Mariarita Santi-vicini, Xiaowei Liu, Charles G. Minard, John M. Maris, Stephan Voss, Elizabeth Fox, Brenda Weigal. Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan: A Children's Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT029.