Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors.

Abstract

3033 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has shown synergistic activity with irino in xenograft models. Methods: A 3+3 design evaluated the safety and PK of AZD7762 (6–144 mg iv) ± irino (100 or 125 mg/m2 iv) (NCT00473616). AZD7762 was given alone on days 1 and 8 (Cycle 0); after 7 days’ observation, AZD7762 was given after irino on days 1 and 8 of 21-day cycles until disease progression/discontinuation for any reason. To further confirm safety, an expansion phase was conducted at the MTD. Results: 68 pts received AZD7762 (6 mg [n=11]; 9 mg [3]; 14 mg [9]; 21 mg [4]; 32 mg [5]; 48 mg [7]; 64 mg [5]; 96 mg [19]; 144 mg [5]). Colorectal (n=29) was the most common tumor site. Median exposure to AZD7762 was 43 days (range 1–520). During dose escalation, 1 pt had DLTs of myocardial infarction with Gr 4 ventricular dysfunction during AZD7762 144 mg monotherapy. Three pts had non-cardiac DLTs during Cycle 1: 6 mg (Gr 3 diarrhea/decreased appetite/dehydration); 14 mg (Gr 3 increased alanine aminotransferase); 48 mg (Gr 4 febrile neutropenia). In the expansion phase (AZD7762 96 mg + irino 100 mg/m2), 3/11 evaluable pts had DLTs (Gr 2 left ventricular systolic dysfunction/Gr 4 troponin increase; Gr 3 troponin increase; Gr 3 cardiomyopathy) – all occurred during AZD7762 monotherapy. Overall, the most common AEs were diarrhea, fatigue and nausea. AZD7762 Cmax, C24h, and AUC increased in a linear and dose-proportional manner. Plasma concentrations at doses >21 mg were consistent with those biologically effective in preclinical studies. Irino did not affect AZD7762 PK. By RECIST, 1 CR (48 mg; small cell carcinoma of the ureter; duration ~18 months) and 1 PR (144 mg; colon with prior irino treatment) were observed. Conclusions: During dose escalation, the AZD7762 MTD was 96 mg with irino 100 mg/m2. However, recruitment to the 96 mg safety expansion phase was stopped due to cardiac DLTs during Cycle 0 (AZD7762 monotherapy). DLTs during combination therapy were consistent with those reported with irino alone.