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. 2023 Aug;92(2):141-150.
doi: 10.1007/s00280-023-04555-2. Epub 2023 Jun 27.

Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study

Mats Någård  1 , Mei-Lin Ah-See  2 , James Strauss  3 , Trisha Wise-Draper  4 , Howard P Safran  5 , Laura Nadeau  6 , William J Edenfield  7 , Lionel D Lewis  8 , Dinko Rekić  9 , Corina Dota  10 , Lone H Ottesen  2 , Yan Li  11 , Ganesh M Mugundu  12
Affiliations

Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study

Mats Någård et al. Cancer Chemother Pharmacol. 2023 Aug.

Abstract

Purpose: Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.

Methods: Eligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1-2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model.

Results: Twenty-one patients received adavosertib. Concentration-QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient).

Conclusion: Adavosertib does not have a clinically important effect on QTc prolongation.

Clinicaltrials: GOV: NCT03333824.

Keywords: AZD1775; Adavosertib; Pharmacodynamics; Pharmacokinetics; QT interval; Wee1 inhibitor.

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Conflict of interest statement

LDL is a consultant to G1 Therapeutics and 7 Hills Pharma LLC. He also received, through an award to his institution, clinical trial funding for this study from AstraZeneca and other similar clinical trial funding support from the following sponsors: Bristol Myers Squibb, Bayer Pharmaceuticals, and AbbVie. WJE is a consultant for Chimerix Corp. CD, DR, MA, and MN are employees and shareholders of AstraZeneca. LHO was an employee of AstraZeneca at the time of conduct and reporting of this study. LHO is also a shareholder of AstraZeneca. All other authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
a Study design and b patient disposition flow chart. This manuscript focuses on pharmacodynamic data from part B of NCT03333824; part A is an adavosertib drug–drug interaction PK study, the results of which are reported separately. Refer to Fig. 1 for an overview of the study design of part B of the study. *Informed consent received; †A number of patients enrolled more than once; there were 49 unique enrollments; ‡Study treatment refers to treatment with either ‘cocktail’ (of caffeine, omeprazole, and midazolam) or adavosertib; §One each as a result of death (pancreatic cancer), study termination by the sponsor, and withdrawal by the patient; ‖Three each as a result of protocol-specific withdrawal and study termination by the sponsor, two because of adverse events (one was a case of diarrhea that was considered related to adavosertib), and one because of withdrawal by the patient; Two were excluded from the PK analysis in part B because of gastrectomy and small-bowel resection. bid twice daily, dECG digital electrocardiogram, PK pharmacokinetic, QTc corrected QT interval
Fig. 2
Fig. 2
Time-matched change in QTcF from baseline versus adavosertib concentration (PD analysis set). Regression line and 90% confidence bands for ΔQTcF from baseline were estimated using a linear mixed-effects model. Dashed vertical lines indicate the geometric mean Cmax of adavosertib on days 1 and 3. CI confidence interval, PD pharmacodynamic, QTcF corrected QT interval by Fridericia
Fig. 3
Fig. 3
Individual time-matched change in QTcF from baseline over time versus change in RR interval (safety analysis set). LOESS locally estimated scatter-plot smoothing, QTcF corrected QT interval by Fridericia
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