Adavosertib (Azd1775) Does Not Prolong Qt Interval In Patients With Advanced Solid Tumors: A Phase I Open-Label Study Lin

Background: Adavosertib (AZD1775; AD), a highly selective inhibitor of WEE1 kinase, regulates S and G2/M cell-cycle checkpoints. This study (NCT03333824; Part B) assessed the effect of doses of AD on the QT interval in patients (pts) with advanced solid tumors. Methods: After a 7-14-day washout from prior short-term AD exposure, pts received AD 225 mg bid (five doses; combi therapy MTD/RP2D) on days 13 at 12-h intervals, under fasted conditions: 2 h pre-dose to 2 h post-dose. Pts underwent digital electrocardiogram (dECG) on day −1 (time-matched baseline), and dECG and pharmacokinetic (PK) sampling before AD administration and up to 12 h post-dose on days 1 and 3. Antiemetic(s) were given (1 mg granisetron ± 4 mg dexamethasone) on day −1 (baseline), and 30 min prior to AD (days 1-3). Pts had their final PK/dECG assessments on day 4, 24 h post-dose. Corrected QT interval by Fridericia (QTcF) outliers following dosing were defined as values \u003e450 ms or increases from baseline \u003e30 ms. Results: Of 33 enrolled pts (median age, 60.0 years, range 41-83; F:M, 18:15), 21 (64%) received AD (Part B of the study). There was no significant relationship between ΔQTcF (vs baseline) and AD concentration. The slope of the linear relationship between ΔQTcF and AD concentration was not statistically significant (P=0.27), with the 95% CI of the slope (−0.003978, 0.01351) incl 0. Model predictions of ΔQTcF at the geometric mean of AD Cmax were, on day 1 (712.8 nM) and day 3 (1462 nM), −2.4 ms (90% CI −5.9, 1.1) and −0.8 ms (90% CI −5.1, 3.6), respectively. The largest mean difference in ΔQTcF was 7.3 ms, 3 h post-dose, on day 3. On day 1, two pts had an increase in QTcF \u003e30 ms, and one of these (who took mirtazapine) had increases in QTcF \u003e30 ms on day 3. No QTcF \u003e450 ms or increase in QTcF \u003e60 ms was observed. On day 1 and day 3, there were no apparent effects of AD on mean QRS, mean PR interval or heart rate (mean change was within ± 10 bpm). Geometric mean AUC0-12 and Cmax of AD on day 1 were 4940 nM·h and 712.8 nM, respectively, vs 10810 nM·h and 1462 nM on day 3. Cmin on day 3 was 410.4 nM. Geometric least-squares mean ratios (90% CI) of AD on day 3 vs day 1 for AUC0-12 and Cmax were 231% (200, 266) and 207% (170, 251), respectively; accumulation of AD over the dosing period was ~2.3 for AUC0-12 and ~2.1 for Cmax. Median tmax of AD was 3.0 h (range 1.0-6.0) on day 1 and 2.5 h (range 1.0-3.1) on day 3. Intra-subject variability was low (5% for AUC0-12 and 9% for Cmax) on day 3. AEs were reported by 16 (76%) patients, most commonly diarrhea, nausea (each 7 [33%] pts) and vomiting (5 [24%] pts). Eleven (52%) pts had treatment-related AEs (2 [10%] pts with grade ≥3). Conclusions: No significant relationship was found between ΔQTcF and AD concentration. Modeling showed that AD does not have a clinically important effect on QT prolongation. Accumulation over the dosing period was approximately twofold, concordant with results from prior studies at this AD dose. No new safety concerns were reported. 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, Dinko Rekic, Corina Dota, Lone Ottesen, Yan Li, Ganesh Mugundu. Adavosertib (AZD1775) does not prolong QT interval in patients with advanced solid tumors: A Phase I open-label study [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 591.