ABI-009(奈博-西罗莫司)联合替莫唑胺和伊立替康治疗复发性或难治性实体瘤(包括中枢神经系统肿瘤)儿科患者的1期研究--儿童肿瘤组织儿科早期临床试验网络研究ADVL1514。

IF 2.9 2区 医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2024-11-02 DOI:10.1002/cam4.70376
Stuart L. Cramer, Alyssa Terry Reddy, Charles Gene Minard, Stephan Voss, Elizabeth Fox, Xiaowei Liu, Kristina Denic, Joel M. Reid, Brenda J. Weigel
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引用次数: 0

摘要

背景:Nab-西罗莫司(ABI-009,nab-rapamycin;Aadi Bioscience Inc. [Aadi])是一种与人体白蛋白结合的西罗莫司纳米颗粒,是一种强效的mTOR抑制剂。该 I 期试验旨在确定 Nab-sirolimus 与替莫唑胺和伊立替康联合用药的剂量限制性毒性(DLT)、最大耐受剂量或 II 期推荐剂量(MTD/RP2D)以及药代动力学:在随后的周期中,纳布-西罗莫司与替莫唑胺(125 毫克/平方米/剂量,最大剂量 250 毫克/平方米/剂量)和伊立替康(90 毫克/平方米/剂量)在 D1 和 D8 日联合口服。周期为 21 天。研究了纳布-西罗莫司的三个剂量水平(DL)(DL1:35 毫克/平方米/剂量、DL-1:20 毫克/平方米/剂量和 DL-2:15 毫克/平方米/剂量)。用于估算MTD/RP2D的观察期定义为周期1和周期2:结果:33 名患者入组,32 名符合条件。剂量确定包括 17 名可评估患者,中位(范围)年龄为 12(2-20)岁,另有 6 名患者加入药代动力学队列(4 名可评估毒性)。C1 或 C2 DLT 主要是血小板减少,包括 2/5 名 DL1 患者、2/6 名 DL-1 患者和 1/6 名 DL-2 患者。一名尤文肉瘤患者(DL1)出现部分反应,并继续接受了35个周期的治疗。雷帕霉素的清除率与剂量有关。伊立替康的清除率及其活性代谢物SN-38的暴露量不受与纳布-西罗莫司联合用药的影响:结论:Nab-西罗莫司的MTD为15 mg/m2/dose,D1和D8静脉滴注,联合替莫唑胺125 mg/m2/dose和口服伊立替康90 mg/m2/dose,每天5天,21D周期:试验注册:ClinicalTrials.gov标识符NCT02975882。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A Phase 1 Study of ABI-009 (Nab-sirolimus) in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors—A Children's Oncology Group Pediatric Early Phase Clinical Trial Network Study ADVL1514

Background

Nab-sirolimus (ABI-009, nab-rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin-bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose-limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab-sirolimus in combination with temozolomide and irinotecan.

Methods

Using a rolling 6 design, Nab-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) and irinotecan (90 mg/m2/dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of Nab-sirolimus were investigated (DL1: 35 mg/m2/dose, DL-1: 20 mg/m2/dose, and DL-2: 15 mg/m2/dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2.

Results

Thirty-three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2–20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL-1, and 1/6 patients at DL-2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN-38 exposure were not affected by coadministration with Nab-sirolimus.

Conclusion

The MTD for Nab-sirolimus was 15 mg/m2/dose IV on D1 and D8 in combination with temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose daily for 5 days during 21D cycles.

Trial Registration

ClinicalTrials.gov identifier NCT02975882

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来源期刊
Cancer Medicine
Cancer Medicine ONCOLOGY-
CiteScore
5.50
自引率
2.50%
发文量
907
审稿时长
19 weeks
期刊介绍: Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
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