Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors

Abstract

AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750-1,000 mg/m(2) on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m(2) and AZD7762 9 mg cohort). The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.