TY - JOUR
T1 - A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
AU - Bauer, Todd M.
AU - Moore, Kathleen N.
AU - Rader, Janet S.
AU - Simpkins, Fiona
AU - Mita, Alain C.
AU - Beck, J. Thaddeus
AU - Hart, Lowell
AU - Chu, Quincy
AU - Oza, Amit
AU - Tinker, Anna V.
AU - Imedio, Esteban Rodrigo
AU - Kumar, Sanjeev
AU - Mugundu, Ganesh
AU - Jenkins, Suzanne
AU - Chmielecki, Juliann
AU - Jones, Suzanne
AU - Spigel, David
AU - Fu, Siqing
N1 - Funding Information:
We thank the patients who participated in this trial and their families. Medical writing assistance, in the form of the preparation and revision of this article, was supported financially by AstraZeneca and provided by C.L. Attwell Ph.D. of AMICULUM Limited.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7
Y1 - 2023/7
N2 - Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. Patients and Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1–3 and 8–10 of a 21-day treatment cycle. Results: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). Conclusion: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. Trial Registration: ClinicalTrials.gov identifier NCT02482311; registered June 2015.
AB - Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. Patients and Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1–3 and 8–10 of a 21-day treatment cycle. Results: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). Conclusion: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. Trial Registration: ClinicalTrials.gov identifier NCT02482311; registered June 2015.
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U2 - 10.1007/s11523-023-00965-7
DO - 10.1007/s11523-023-00965-7
M3 - Article
C2 - 37278879
AN - SCOPUS:85161298600
SN - 1776-2596
VL - 18
SP - 517
EP - 530
JO - Targeted oncology
JF - Targeted oncology
IS - 4
ER -