Abstract 3035: Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors

Background: Adavosertib (AD), a selective WEE1 inhibitor, may alter exposure to compounds metabolized by cytochromes P450 (CYP); this two-period open-label study (NCT03333824) assessed the effect of AD on pharmacokinetics (PK) of probe substrates for CYP1A2 (caffeine; C), CYP2C19 (omeprazole; O) and CYP3A4 (midazolam; M). Methods: In period 1, patients (pts) with locally advanced or metastatic solid tumors received a cocktail (CKT) of C 200 mg, O 20 mg, M 2 mg (single dose); in period 2, after a 7–14-day washout, pts received AD 225 mg bid on days 1–3 (5 doses), and with CKT on day 3. After CKT and AD administration, 24-hour PK sampling took place for C, O, M and their respective metabolites paraxanthine (P), 5-hydroxyomeprazole (5-HO), and 1′-hydroxymidazolam (1′-HM). Safety was assessed throughout. Results: Of 33 pts (median age, 60.0 years, range 41–83; F:M, 18:15) receiving CKT, 30 pts were given AD. AD co-administration increased C, O and M exposure by 49%, 80% and 55% (AUC), respectively; AUC0–t increased by 61%, 98% and 55%; Cmax increased by 4%, 46% and 39% (Table 1). AD addition increased 5-HO and 1′-HM exposure by 43% and 54% (AUC), respectively, and by 49% and 58% (AUC0–t) respectively; P exposure was unchanged. AD co-administration decreased Cmax for P and 5-HO by 19% and 7%, respectively, whereas Cmax increased by 33% for 1′-HM. AD addition decreased CL/F and Vz/F for all substrates and increased t1/2 and tmax for most substrates and metabolites; tmax for M and 1′-HM were unchanged. A trend of decreasing metabolite/substrate ratios for AUC, AUC0–t and Cmax was seen with AD co-administration. After receiving AD, 24 (80%) pts reported adverse events (AEs), most commonly diarrhea (16 [53%]), vomiting (9 [30%]) and nausea (8 [27%]). Nineteen (63%) pts had treatment-related AEs (6 [20%] pts with grade ≥3). Conclusions: AD (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19 and CYP3A4. No new AD-related safety concerns were identified. Citation Format: Mats Nagard, Mei-Lin Ah-See, Karen So, James Strauss, Trisha Wise-Draper, Howard Safran, Ding Wang, Laura Nadeau, William Edenfield, Lionel D. Lewis, Lone Ottesen, Yan Li, Ganesh Mugundu. Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3035.