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

John Hilton, Karen Gelmon, Philippe L. Bedard, Dongsheng Tu, Hong Xu, Anna V. Tinker, Rachel Goodwin, Scott A. Laurie, Derek Jonker, Aaron R. Hansen, Zachary W. Veitch, Daniel J. Renouf, Linda Hagerman, Hongbo Lui, Bingshu Chen, Deb Kellar, Irene Li, Sung-Eun Lee, Takako Kono, Brian Y. C. Cheng, Damian Yap, Daniel Lai, Sean Beatty, John Soong, Kathleen I. Pritchard, Isabel Soria-Bretones, Eric Chen, Harriet Feilotter, Moira Rushton, Lesley Seymour (), Samuel Aparicio and David W. Cescon
Additional contact information
John Hilton: Ottawa Hospital Research Institute
Karen Gelmon: BC Cancer - Vancouver Centre
Philippe L. Bedard: University Health Network
Dongsheng Tu: Canadian Cancer Trials Group
Hong Xu: Molecular Oncology, BC Cancer Research Institute
Anna V. Tinker: BC Cancer - Vancouver Centre
Rachel Goodwin: Ottawa Hospital Research Institute
Scott A. Laurie: Ottawa Hospital Research Institute
Derek Jonker: Ottawa Hospital Research Institute
Aaron R. Hansen: University Health Network
Zachary W. Veitch: University Health Network
Daniel J. Renouf: BC Cancer - Vancouver Centre
Linda Hagerman: Canadian Cancer Trials Group
Hongbo Lui: Canadian Cancer Trials Group
Bingshu Chen: Canadian Cancer Trials Group
Deb Kellar: Ottawa Hospital Research Institute
Irene Li: University Health Network
Sung-Eun Lee: BC Cancer - Vancouver Centre
Takako Kono: Molecular Oncology, BC Cancer Research Institute
Brian Y. C. Cheng: Molecular Oncology, BC Cancer Research Institute
Damian Yap: Molecular Oncology, BC Cancer Research Institute
Daniel Lai: Molecular Oncology, BC Cancer Research Institute
Sean Beatty: Molecular Oncology, BC Cancer Research Institute
John Soong: Senhwa Biosciences, Inc
Kathleen I. Pritchard: Sunnybrook Health Sciences Centre
Isabel Soria-Bretones: University Health Network
Eric Chen: University Health Network
Harriet Feilotter: Canadian Cancer Trials Group
Moira Rushton: Canadian Cancer Trials Group
Lesley Seymour: Canadian Cancer Trials Group
Samuel Aparicio: Molecular Oncology, BC Cancer Research Institute
David W. Cescon: University Health Network

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-31199-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31199-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-31199-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().