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)

• Published in: Clinical cancer research 2020-03, Vol.26 (6), p.1213-1219
• Main Authors: Cole, Kristina A, Pal, Sharmistha, Kudgus, Rachel A, Ijaz, Heba, Liu, Xiaowei, Minard, Charles G, Pawel, Bruce R, Maris, John M, Haas-Kogan, Daphne A, Voss, Stephan D, Berg, Stacey L, Reid, Joel M, Fox, Elizabeth, Weigel, Brenda J
• Format: Article
• Language: English
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Cell Cycle Proteins - antagonists & inhibitors; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - pathology; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Humans; Irinotecan - administration & dosage; Male; Maximum Tolerated Dose; Neoplasms - drug therapy; Neoplasms - pathology; Neuroblastoma - drug therapy; Neuroblastoma - pathology; Patient Safety; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - administration & dosage; Pyrimidinones - administration & dosage; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - pathology; Tissue Distribution; Treatment Outcome; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-3470

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. Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m /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; 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 ) in combination with irinotecan (90 mg/m ) 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/m ) in combination with irinotecan (90 mg/m ) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.