Journal Article

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies

Cheng, Brian Y. C., Soong, John, Gelmon, Karen, Renouf, Daniel J., Cescon, David W., Jonker, Derek, Kono, Takako, Chen, Eric, Chen, Bingshu, Li, Irene, Rushton, Moira, Goodwin, Rachel, Soria-Bretones, Isabel, Beatty, Sean, Tinker, Anna V., Aparicio, Samuel, Hansen, Aaron R., Hagerman, Linda, Tu, Dongsheng, Laurie, Scott A., Pritchard, Kathleen I., Hilton, John, Xu, Hong, Veitch, Zachary W., Lui, Hongbo, Bedard, Philippe L., Yap, Damian, Lee, Sung-Eun, Seymour, Lesley, Kellar, Deb, Lai, Daniel, Feilotter, Harriet

2022

Overview

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/m 2 ) 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/m 2 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. G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/1059/602 / 692/308/2779/109/1940 / 692/4028/67/1059 / Biomarkers / BRCA1 protein / BRCA2 protein / Breast cancer / Cancer therapies / Deoxyribonucleic acid / DNA / DNA repair / Drug dosages / Homologous recombination / Homology / Humanities and Social Sciences / Lethality / Medical research / multidisciplinary / Mutation / Ovaries / Patients / Pharmacokinetics / Phototoxicity / Repair / Reversion / RNA polymerase / Science / Science (multidisciplinary) / Solid tumors / Toxicity / Tumors