A phase 1 dose‐escalation study of LY3295668 erbumine as monotherapy and in combination with topotecan and cyclophosphamide in children with relapsed/refractory neuroblastoma

拓扑替康 医学 神经母细胞瘤 联合疗法 耐火材料(行星科学) 中性粒细胞减少症 环磷酰胺 粘膜炎 队列 不利影响 肿瘤科 胃肠病学 毒性 内科学 外科 化疗 细胞培养 遗传学 天体生物学 生物 物理
作者
Steven G. DuBois,Chitose Ogawa,Lucas Moreno,Yaël P. Mossé,Matthias Fischer,Anne L. Ryan,Kieuhoa T. Vo,Bram De Wilde,Alba Rubio‐San‐Simón,Margaret E. Macy,Lisa Howell,Suzanne Shusterman,Nadège Corradini,Roberto Luksch,Isabelle Aerts,Jennifer H. Foster,Brian Weiss,C Karthik,Eunice Yuen,Emin Avşar
出处
期刊:Cancer [Wiley]
卷期号:131 (4)
标识
DOI:10.1002/cncr.35751
摘要

Abstract Background This study evaluated the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine as monotherapy and combination therapy in children with relapsed/refractory neuroblastoma. Methods Patients aged 2–21 years who had relapsed/refractory neuroblastoma were enrolled. LY3295668 erbumine was evaluated at two dose levels (12 and 15 mg/m 2 ) and administered orally twice daily continuously as monotherapy and in combination with intravenous topotecan and cyclophosphamide in 28‐day cycles. Results Twenty‐five patients were treated. No dose‐limiting toxicity occurred in monotherapy; one patient had dose‐limiting toxicities in the combination therapy cohort (grade 3 mucositis and grade 4 neutropenia). The recommended phase 2 dose for both monotherapy and combination therapy was 15 mg/m 2 . Twenty‐two patients (88%) had one or more treatment‐related adverse event(s) (TRAEs), and 18 (72%) experienced grade ≥3 TRAEs. Myelosuppression was the most common high‐grade TRAE observed in the combination therapy cohort. At both dose levels, steady‐state plasma concentrations exceeded xenograft 90% inhibitory concentration levels. In the monotherapy cohort, one patient had a minor response, and one patient had stable disease, both continuing for >12 months. In the combination therapy cohort, two patients had a partial response, two had a minor response, and six had stable disease. Overall, the response rate, according to New Approaches to Neuroblastoma Therapy version 2.0 criteria, was 8%, and the disease control rate was 52%. Conclusions LY3295668 erbumine had a manageable safety profile as monotherapy and in combination therapy. Although proof‐of‐concept clinical responses were observed, future studies with biomarker‐selected populations and/or novel combinations may yield higher response rates with Aurora kinase A inhibition.
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