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

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 ad...

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Published in:Cancer chemotherapy and pharmacology 2023-08, Vol.92 (2), p.141-150
Main Authors: Någård, Mats, Ah-See, Mei-Lin, Strauss, James, Wise-Draper, Trisha, Safran, Howard P., Nadeau, Laura, Edenfield, William J., Lewis, Lionel D., Rekić, Dinko, Dota, Corina, Ottesen, Lone H., Li, Yan, Mugundu, Ganesh M.
Format: Article
Language:English
Subjects:
Anemia
Appetite loss
Assessments
Cancer Research
Cancer therapies
Cardiac arrhythmia
Cardiovascular diseases
Cell cycle
Chemotherapy
Constipation
Diarrhea
DNA damage
Drug dosages
EKG
Electrocardiography
Health risks
Kinases
Medical research
Medicine
Medicine & Public Health
Oncology
Original
Original Article
Patients
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Prolongation
Solid tumors
Tumors
Vomiting
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Summary: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 (C max ) 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 C max 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.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-023-04555-2