Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor 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 II 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. Patients and Methods: Using a 3þ3 escalation design, five 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 gH2AX was performed. Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (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. Conclusions: Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
Bibliographical noteFunding Information:
The research reported above is supported by the Children's Oncology Group, the NCI of the NIH under award number UM1CA228823, R01 CA214912, as well as Solving Kids Cancer and the Cookies for Kids’ Cancer Foundations. We would like to
The research reported above is supported by the Children's Oncology Group, the NCI of the NIH under award number UM1CA228823, R01 CA214912, as well as Solving Kids Cancer and the Cookies for Kids' Cancer Foundations. We would like to acknowledge Astra Zeneca for supply of adavosertib and support of pharmacokinetic analysis; the Children's Oncology Group Phase I Consortium Operations Team; the institutional principal investigators and clinical coordinators; and the patients and their families who participated on the ADVL1312 trial.
© 2019 American Association for Cancer Research.