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

被引:18
作者
Bauer, Todd M. [1 ,2 ]
Moore, Kathleen N. [1 ,3 ]
Rader, Janet S. [4 ]
Simpkins, Fiona [5 ]
Mita, Alain C. [6 ]
Beck, J. Thaddeus [7 ]
Hart, Lowell [8 ]
Chu, Quincy [9 ]
Oza, Amit [10 ]
Tinker, Anna V. [11 ]
Imedio, Esteban Rodrigo [12 ]
Kumar, Sanjeev [12 ]
Mugundu, Ganesh [13 ]
Jenkins, Suzanne [14 ]
Chmielecki, Juliann [15 ]
Jones, Suzanne [1 ]
Spigel, David [1 ,2 ]
Fu, Siqing [16 ]
机构
[1] Sarah Cannon Res Inst, Nashville, TN USA
[2] Tennessee Oncol PLLC, Nashville, TN USA
[3] Univ Oklahoma, Stephenson Canc Ctr, Oklahoma City, OK USA
[4] Med Coll Wisconsin, Milwaukee, WI USA
[5] Univ Penn, Abramson Canc Ctr, Philadelphia, PA USA
[6] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA
[7] Highlands Oncol Grp, Springdale, AR USA
[8] Sarah Cannon Res Inst, Ft Myers, FL USA
[9] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada
[10] Princess Margaret Canc Ctr, Toronto, ON, Canada
[11] BC Canc, Vancouver, BC, Canada
[12] AstraZeneca, Oncol R&D, Cambridge, England
[13] AstraZeneca, Clin Pharmacol & Quantitat Pharmacol, Clin Pharmacol & Safety Sci, Boston, MA USA
[14] AstraZeneca, Precis Med & Biosamples, R&D, Cambridge, England
[15] AstraZeneca, Translat Med, Oncol Res & Early Dev, Boston, MA USA
[16] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
关键词
OVARIAN-CANCER; PLATINUM-RESISTANT; ANTITUMOR-ACTIVITY; OPEN-LABEL; MK-1775; KINASE; COMBINATION; CHEMOTHERAPY; GEMCITABINE; CARBOPLATIN;
D O I
10.1007/s11523-023-00965-7
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundAdavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.ObjectiveThe safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.Patients and MethodsEligible 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.ResultsEighty 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).ConclusionAdavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors.
引用
收藏
页码:517 / 530
页数:14
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