Phase I dose-escalation study of AZD7762 in combination with gemcitabine (gem) in patients (pts) with advanced solid tumors.

Abstract

3058 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gem in preclinical xenograft studies. Methods: This open-label, dose-escalation (3+3 design) study evaluated the safety, tolerability and PK of AZD7762 (6–40 mg iv) alone and combined with gem (750 or 1000 mg/m2 iv) (NCT00413686). Pts received AZD7762 alone on days 1 and 8 (Cycle 0) followed by 7 days’ observation, then AZD7762 + gem on days 1 and 8 of a 21-day cycle. Results: 42 pts (mean age 58 years) received AZD7762 + gem. Colorectal (n=11) and lung (n=10) were the most common primary tumor sites. Median exposure to AZD7762 was 43 days (range 1–318). Cardiac dose-limiting toxicities (DLTs) occurred in 2 pts during Cycle 0 at AZD7762 doses of 32 mg (grade [Gr] 3 asymptomatic elevated troponin I) and 40 mg (Gr 3 myocardial ischemia); both resolved following AZD7762 discontinuation. Two pts had non-cardiac DLTs in Cycle 1; 1 in the 32 mg cohort (Gr 3 vomiting/nausea) and 1 in the 40 mg cohort (Gr 4 neutropenia). Overall, fatigue (n=17) and nausea, neutropenia and pyrexia (n=11 each) were the most common AEs (no neutropenia reported in Cycle 0). In total, 26 pts had a Gr ≥3 AE (10 causally related to AZD7762 and 16 to gem), the most common being neutropenia (n=7) and hyperglycemia (n=3). AZD7762 exposure (Cmax, C24, AUC) increased in a linear and dose-proportional manner over the dose range studied. Gem did not appear to affect the PK of AZD7762. AZD7762 t½ ranged from 8–16 h for AZD7762 alone and 6–18 h for AZD7762 + gem. Plasma concentrations at doses >21 mg were consistent with those biologically effective in preclinical studies. Two pts with NSCLC (6 mg and 9 mg cohorts) had a partial response (RECIST); both were gem naive. Conclusions: The MTD of AZD7762 in combination with gem 1000 mg/m2 was 30 mg. Pts with an AE considered possibly related to AZD7762 or gem, n. AZD7762 dose (mg)/gem (mg/m2), (n) 6/750 (n=6) 6/1,000 (n=1) 6/1,000 (n=2) 9/1,000(n=3) 14/1,000 (n=6) 21/1,000(n=3) 30/1,000(n=7) 32/1,000(n=6) 40/1,000(n=8) Any grade AZD7762 causality 2 1 0 2 1 0 5 2 5 Gem causality 6 1 1 2 3 2 5 4 6 Grade ≥3 AZD7762 causality 1 1 0 0 1 0 3 0 4 Gem causality 4 1 1 1 0 1 3 1 4 SAE AZD7762 causality 0 0 0 0 0 0 1 0 2 Gem causality 0 0 0 0 0 0 1 1 2