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

Author

Listed:
  • John Hilton

    (Ottawa Hospital Research Institute)

  • Karen Gelmon

    (BC Cancer - Vancouver Centre)

  • Philippe L. Bedard

    (University Health Network
    University of Toronto)

  • 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
    University of Toronto)

  • Zachary W. Veitch

    (University Health Network
    University of Toronto)

  • 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
    Pathology and Laboratory Medicine, UBC)

  • David W. Cescon

    (University Health Network
    University of Toronto)

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.

Suggested Citation

  • 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 & L, 2022. "Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31199-2
    DOI: 10.1038/s41467-022-31199-2
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    References listed on IDEAS

    as
    1. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Stacey L. Edwards & Rachel Brough & Christopher J. Lord & Rachael Natrajan & Radost Vatcheva & Douglas A. Levine & Jeff Boyd & Jorge S. Reis-Filho & Alan Ashworth, 2008. "Resistance to therapy caused by intragenic deletion in BRCA2," Nature, Nature, vol. 451(7182), pages 1111-1115, February.
    Full references (including those not matched with items on IDEAS)

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