PURPOSE: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models. METHODS: This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts. RESULTS: Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease. CONCLUSIONS: The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.
PURPOSE:AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models. METHODS: This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts. RESULTS: Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease. CONCLUSIONS: The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.
Authors: Zhaojun Qiu; Pengyan Fa; Tao Liu; Chandra B Prasad; Shanhuai Ma; Zhipeng Hong; Ernest R Chan; Hongbing Wang; Zaibo Li; Kai He; Qi-En Wang; Terence M Williams; Chunhong Yan; Steven T Sizemore; Goutham Narla; Junran Zhang Journal: Cancer Res Date: 2020-06-10 Impact factor: 12.701
Authors: Jonathan P McNally; Scott H Millen; Vandana Chaturvedi; Nora Lakes; Catherine E Terrell; Eileen E Elfers; Kaitlin R Carroll; Simon P Hogan; Paul R Andreassen; Julie Kanter; Carl E Allen; Michael M Henry; Jay N Greenberg; Stephan Ladisch; Michelle L Hermiston; Michael Joyce; David A Hildeman; Jonathan D Katz; Michael B Jordan Journal: Proc Natl Acad Sci U S A Date: 2017-05-22 Impact factor: 11.205
Authors: Yan Liu; Yuyang Li; Xiaoen Wang; Feiyang Liu; Peng Gao; Max M Quinn; Fei Li; Ashley A Merlino; Cyril Benes; Qingsong Liu; Nathanael S Gray; Kwok-Kin Wong Journal: Cancer Res Date: 2017-07-28 Impact factor: 12.701
Authors: Edward Sausville; Patricia Lorusso; Michael Carducci; Judith Carter; Mary F Quinn; Lisa Malburg; Nilofer Azad; David Cosgrove; Richard Knight; Peter Barker; Sonya Zabludoff; Felix Agbo; Patricia Oakes; Adrian Senderowicz Journal: Cancer Chemother Pharmacol Date: 2014-01-22 Impact factor: 3.333
Authors: Navnath S Gavande; Pamela S VanderVere-Carozza; Hilary D Hinshaw; Shadia I Jalal; Catherine R Sears; Katherine S Pawelczak; John J Turchi Journal: Pharmacol Ther Date: 2016-02-16 Impact factor: 12.310