Format

Send to

Choose Destination
Cancer Discov. 2019 Aug;9(8):1036-1049. doi: 10.1158/2159-8290.CD-18-1455. Epub 2019 May 15.

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study.

Khot A#1, Brajanovski N#2, Cameron DP3,4, Hein N3, Maclachlan KH1,2,4, Sanij E2,4,5, Lim J6, Soong J6, Link E4,7, Blombery P1,4,8, Thompson ER4,8, Fellowes A2,8, Sheppard KE2,4,9, McArthur GA2,4,10, Pearson RB2,4,9,11, Hannan RD2,3,4,9,11,12, Poortinga G13,4,10, Harrison SJ14,4.

Author information

1
Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
2
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
3
The ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.
4
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
5
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
6
Senhwa Biosciences, Inc., New Taipei City, Taiwan, Republic of China.
7
Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
8
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
9
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
10
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Parkville, Victoria, Australia.
11
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
12
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
13
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. gretchen.poortinga@petermac.org Simon.Harrison@petermac.org.
14
Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. gretchen.poortinga@petermac.org Simon.Harrison@petermac.org.
#
Contributed equally

Abstract

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center