Nature communications · 2022
Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.
СтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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.
Hilton John, Gelmon Karen, Bedard Philippe L, Tu Dongsheng, Xu Hong, Tinker Anna V, Goodwin Rachel, Laurie Scott A, Jonker Derek, Hansen Aaron R, Veitch Zachary W, Renouf Daniel J, Hagerman Linda, Lui Hongbo, Chen Bingshu, Kellar Deb, Li Irene, Lee Sung-Eun, Kono Takako, Cheng Brian Y C, Yap Damian, Lai Daniel, Beatty Sean, Soong John, Pritchard Kathleen I, Soria-Bretones Isabel, Chen Eric, Feilotter Harriet, Rushton Moira, Seymour Lesley, Aparicio Samuel, Cescon David W
Аннотация
CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.