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)

Abstract

◥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/m 2 /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/m 2 ) in combination with irinotecan (90 mg/m 2 ) 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/m 2 ) in combination with irinotecan (90 mg/m 2 ) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.

WEE1 Inhibition in Combination With Targeted Agents and Standard Chemotherapy in Preclinical Models of Pancreatic Ductal Adenocarcinoma

“…In our in vivo cohorts, the combination of AZD1775 with irinotecan or capecitabine had anti-tumor effects on the p53 mutant models while no significant differences were noted for the p53 wild type models. These results are consistent with published reports of synergy in the combination of AZD1775 with capecitabine or irinotecan in solid tumors ( 18 , 19 , 31 ). Interestingly, there were no significant differences in tumor development from the combination of AZD1775 and navitoclax, though both PDX models tested were mutant p53.…”

Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling

“…There has been increasing interest in the use of AZD-1775 in various cancer settings, with several early phase clinical trials showing a favorable toxicity profile in a number of different cancers [ 29 , 34 , 45 , 46 , 47 , 48 ]. Wee1 is a protein kinase that acts as an inhibitor of the cell cycle through phosphorylation of the CDK1/cyclin B complex resulting in G2 cell cycle arrest [ 49 ].…”

A resource for exploring the understudied human kinome for research and therapeutic opportunities

“…WEE1 has also been targeted recently by investigational anti-cancer therapeutics (e.g. adavosertib) 85 . WEE1 and PKMYT1 are not functionally redundant since both are essential in over 90% of DepMap cell lines and they are known to have different activities against T14 and Y15 of CDK1.…”