Abstract CT022: A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors
Authors: Falchook Gerald S. , Sachdev Jasgit , Imedio Esteban Rodrigo , Kumar Sanjeev , Mugundu Ganesh , Chmielecki Juliann , Jones Suzanne , Spigel David R. , Johnson Melissa 
Published: August 2019

Abstract
Background: Adavosertib is a highly selective inhibitor of Wee1, a crucial regulator of intra-S and G2/M cell cycle checkpoints. This Phase Ib study (NCT02610075) investigated dosing and schedule for adavosertib monotherapy and determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors.
Methods: Pts received adavosertib orally once (QD) or twice daily (BID) on a 5/9 schedule (5 days on treatment followed by 9 days off) in 14-day cycles, or one of two 5/2 dosing schedules (5 days on followed by 2 days off; weekly or 2 out of 3 weeks) in 21-day cycles. MTD was determined using a 3+3 dose-escalation cohort design. DLTs were defined as toxicities related to adavosertib, occurring during the first cycle. PK and biomarker analyses were performed on blood samples. Pts’ response to treatment was assessed using RECIST v1.1.
Results: 62 pts (female, 64.5%; median age, 61.5 years; most common primary tumor sites: lung [24.2%] and ovary [21.0%]) received treatment (QD schedule, n=50; BID schedule, n=12) (Table 1). Median treatment duration was 1.77 months. Adavosertib was steadily absorbed (median time to max concentration: 2.0-4.15 h) and slowly eliminated (mean half-life: 5-12 h). AEs leading to dose reductions, interruptions and discontinuations were reported by 17 (27.4%), 25 (40.3%) and 4 (6.5%) pts, respectively. The most common grade ≥3 AEs were anemia, neutropenia (both n=9, 14.5%) and diarrhea (n=8, 12.9%). The overall response rate was 3.4% (n=2 [thymoma; anal]), disease control rate 48.4% (n=30) and median progression-free survival 2.7 months. Circulating-tumor-derived DNA pharmacodynamic analyses will be presented.
Conclusions: The MTD was determined to be 125 mg (BID 5/9) and 300 mg (QD 5/2 and 5/9) for 2/3 weeks, with 300 mg (QD 5/2) being the RP2D. The safety/tolerability profile was considered acceptable. Adavosertib monotherapy showed preliminary evidence of antitumor activity in a heavily pretreated patient population.
Table 1CohortAdavosertib dose (schedule)N evaluableAny AE Grade ≥3, n (%)DLTs, n (%)DLTs:* AE preferred term/CTCAE gradeBID 1125 mg (5/9)64 (66.7)0–BID 2150 mg (5/9)65 (83.3)2 (33.3)Diarrhea/3 and nausea/2 Dehydration/3QD 1.1200 mg (5/9)51 (20.0)0–QD 1.2200 mg (5/2)53 (50.0)0–QD 2.1250 mg (5/9)42 (50.0)0–QD 2.2250 mg (5/2)33 (100.0)0–QD 2.3250 mg (5/2 weekly)95 (50.0)2 (22.2)Thrombocytopenia/3 and neutropenia/3 Thrombocytopenia/2QD 3.1300 mg (5/9)43 (75.0)0–QD 3.2300 mg (5/2)1512 (75.0)2 (13.3)Nausea/2 and weight decreased/1 Pneumonia/3QD 3.3300 mg (5/2 weekly)21 (50.0)2 (100.0)Thrombocytopenia/4 Nausea/2 and vomiting/2Total5939 (62.9)8125/2: doses given on days 1–5 and 8–12 per 21-day cycle; 5/2 weekly schedule: doses given on days 1–5, 8–12 and 15–19 per 21-day cycle; 5/9: doses given on days 1–5 per 14-day cycle. *Some patients experienced &gt;1 DLT. CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicity
Citation Format: Gerald S. Falchook, Jasgit Sachdev, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Melissa Johnson. A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT022.