Stuart L. Cramer, Alyssa Terry Reddy, Charles Gene Minard, Stephan Voss, Elizabeth Fox, Xiaowei Liu, Kristina Denic, Joel M. Reid, Brenda J. Weigel
{"title":"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。","authors":"Stuart L. Cramer, Alyssa Terry Reddy, Charles Gene Minard, Stephan Voss, Elizabeth Fox, Xiaowei Liu, Kristina Denic, Joel M. Reid, Brenda J. Weigel","doi":"10.1002/cam4.70376","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p><i>Nab</i>-sirolimus (ABI-009, <i>nab</i>-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 <i>Nab</i>-sirolimus in combination with temozolomide and irinotecan.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Using a rolling 6 design, <i>Nab</i>-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, <i>Nab</i>-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m<sup>2</sup>/dose, maximum 250 mg/dose) and irinotecan (90 mg/m<sup>2</sup>/dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of <i>Nab</i>-sirolimus were investigated (DL1: 35 mg/m<sup>2</sup>/dose, DL-1: 20 mg/m<sup>2</sup>/dose, and DL-2: 15 mg/m<sup>2</sup>/dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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 <i>Nab</i>-sirolimus.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>The MTD for <i>Nab</i>-sirolimus was 15 mg/m<sup>2</sup>/dose IV on D1 and D8 in combination with temozolomide 125 mg/m<sup>2</sup>/dose and oral irinotecan 90 mg/m<sup>2</sup>/dose daily for 5 days during 21D cycles.</p>\n </section>\n \n <section>\n \n <h3> Trial Registration</h3>\n \n <p>ClinicalTrials.gov identifier NCT02975882</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.70376","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Stuart L. Cramer, Alyssa Terry Reddy, Charles Gene Minard, Stephan Voss, Elizabeth Fox, Xiaowei Liu, Kristina Denic, Joel M. Reid, Brenda J. Weigel\",\"doi\":\"10.1002/cam4.70376\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p><i>Nab</i>-sirolimus (ABI-009, <i>nab</i>-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 <i>Nab</i>-sirolimus in combination with temozolomide and irinotecan.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Using a rolling 6 design, <i>Nab</i>-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, <i>Nab</i>-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m<sup>2</sup>/dose, maximum 250 mg/dose) and irinotecan (90 mg/m<sup>2</sup>/dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of <i>Nab</i>-sirolimus were investigated (DL1: 35 mg/m<sup>2</sup>/dose, DL-1: 20 mg/m<sup>2</sup>/dose, and DL-2: 15 mg/m<sup>2</sup>/dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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 <i>Nab</i>-sirolimus.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>The MTD for <i>Nab</i>-sirolimus was 15 mg/m<sup>2</sup>/dose IV on D1 and D8 in combination with temozolomide 125 mg/m<sup>2</sup>/dose and oral irinotecan 90 mg/m<sup>2</sup>/dose daily for 5 days during 21D cycles.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Trial Registration</h3>\\n \\n <p>ClinicalTrials.gov identifier NCT02975882</p>\\n </section>\\n </div>\",\"PeriodicalId\":139,\"journal\":{\"name\":\"Cancer Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.70376\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cam4.70376\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cam4.70376","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
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.
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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