Cole KA, Pal S, Kudgus RA, Ijaz H, Liu X, Minard CG, Pawel BR, Maris JM, Haas-Kogan DA, Voss SD, Berg SL, Reid JM, Fox E, Weigel BJ. Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312). Clin Cancer Res. 2020 Mar 15;26(6):1213-1219. doi: 10.1158/1078-0432.CCR-19-3470. Epub 2019 Dec 19. PMID: 31857431; PMCID: PMC7073289.
Publication Citation
Abstract
Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Anti-tumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D) and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors. Using a 3+3 escalation design, 5 dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day), delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed. Thirty-seven patients were enrolled; twenty-seven were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, 3 regimens) and 21 (78%) received prior radiation therapy. Eleven patients had a primary CNS malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose limiting grade 3 dehydration. A patient with Ewing Sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients. Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the maximum tolerated dose in children and adolescents with solid and CNS tumors.