Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892).
Sarah E Taylor, Sarah Behr, Kristine L Cooper, Haider Mahdi, Denise Fabian, Holly Gallion, Frederick Ueland, John Vargo, Brian Orr, Eugenia Girda, Madeleine Courtney-Brooks, Alexander B Olawaiye, Leslie M Randall, Debra L Richardson, Stephanie A Sullivan, Marilyn Huang, Susan M Christner, Sushil Beriwal, Yan Lin, Aman Chauhan, Edward Chu, Elise C Kohn, Charles Kunos, S Percy Ivy, Jan H Beumer
{"title":"Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892).","authors":"Sarah E Taylor, Sarah Behr, Kristine L Cooper, Haider Mahdi, Denise Fabian, Holly Gallion, Frederick Ueland, John Vargo, Brian Orr, Eugenia Girda, Madeleine Courtney-Brooks, Alexander B Olawaiye, Leslie M Randall, Debra L Richardson, Stephanie A Sullivan, Marilyn Huang, Susan M Christner, Sushil Beriwal, Yan Lin, Aman Chauhan, Edward Chu, Elise C Kohn, Charles Kunos, S Percy Ivy, Jan H Beumer","doi":"10.1007/s00280-024-04720-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.</p><p><strong>Methods: </strong>We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed.</p><p><strong>Results: </strong>19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance.</p><p><strong>Conclusions: </strong>Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.</p><p><strong>Clinical trial registration: </strong>NCT02595879.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"4"},"PeriodicalIF":2.7000,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-024-04720-1","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.
Methods: We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed.
Results: 19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance.
Conclusions: Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
