Thomas Cash1, Elizabeth Fox2, Xiaowei Liu3, Charles G Minard4, Joel M Reid5, Adrienne C Scheck6, Brenda J Weigel7, Cynthia Wetmore6,8. 1. Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia. 2. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. 3. Children's Oncology Group, Monrovia, California. 4. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas. 5. Mayo Clinic, Rochester, Minnesota. 6. Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Institute for Molecular Medicine, Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona. 7. Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. 8. Exelixis, Inc., Alameda, California.
Abstract
BACKGROUND: Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors. METHODS: Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2 , were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity. RESULTS: Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2-20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80-150 mg/m2 dose range. CONCLUSIONS: Although the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28-day cycle was determined to be the RP2D.
BACKGROUND: Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors. METHODS: Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2 , were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity. RESULTS: Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2-20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80-150 mg/m2 dose range. CONCLUSIONS: Although the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28-day cycle was determined to be the RP2D.
Authors: Caitlin D Lowery; Michele Dowless; Matthew Renschler; Wayne Blosser; Alle B VanWye; Jennifer R Stephens; Philip W Iversen; Aimee Bence Lin; Richard P Beckmann; Kateryna Krytska; Kristina A Cole; John M Maris; Douglas S Hawkins; Brian P Rubin; Raushan T Kurmasheva; Peter J Houghton; Richard Gorlick; E Anders Kolb; Min H Kang; C Patrick Reynolds; Stephen W Erickson; Beverly A Teicher; Malcolm A Smith; Louis F Stancato Journal: Clin Cancer Res Date: 2018-12-18 Impact factor: 12.531
Authors: Panagiotis A Konstantinopoulos; Raphael Ceccaldi; Geoffrey I Shapiro; Alan D D'Andrea Journal: Cancer Discov Date: 2015-10-13 Impact factor: 39.397
Authors: David S Hong; Kathleen Moore; Manish Patel; Stefan C Grant; Howard A Burris; William N William; Suzanne Jones; Funda Meric-Bernstam; Jeffrey Infante; Lisa Golden; Wei Zhang; Ricardo Martinez; Sameera Wijayawardana; Richard Beckmann; Aimee Bence Lin; Cathy Eng; Johanna Bendell Journal: Clin Cancer Res Date: 2018-04-11 Impact factor: 12.531
Authors: Olivia Campagne; Abigail Davis; Anil R Maharaj; Bo Zhong; Jennifer Stripay; Dana Farmer; Martine F Roussel; Clinton F Stewart Journal: Eur J Pharm Sci Date: 2019-10-25 Impact factor: 4.384
Authors: Elisha Hayden; Holly Holliday; Rebecca Lehmann; Aaminah Khan; Maria Tsoli; Benjamin S Rayner; David S Ziegler Journal: Cancers (Basel) Date: 2021-12-13 Impact factor: 6.639