Cancer chemotherapy and pharmacology · 2024
Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892).
СтатьяКлиническое исследование I фазыПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Taylor Sarah E, Behr Sarah, Cooper Kristine L, Mahdi Haider, Fabian Denise, Gallion Holly, Ueland Frederick, Vargo John, Orr Brian, Girda Eugenia, Courtney-Brooks Madeleine, Olawaiye Alexander B, Randall Leslie M, Richardson Debra L, Sullivan Stephanie A, Huang Marilyn, Christner Susan M, Beriwal Sushil, Lin Yan, Chauhan Aman, Chu Edward, Kohn Elise C, Kunos Charles, Ivy S Percy, Beumer Jan H
Аннотация
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.
CLINICAL TRIAL REGISTRATION: NCT02595879.
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.
CLINICAL TRIAL REGISTRATION: NCT02595879.