American Association for Cancer Research
21598290cd181455-sup-213713_2_supp_5497462_pqwxm7.pdf (115.85 kB)

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

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journal contribution
posted on 2023-04-03, 22:48 authored by Amit Khot, Natalie Brajanovski, Donald P. Cameron, Nadine Hein, Kylee H. Maclachlan, Elaine Sanij, John Lim, John Soong, Emma Link, Piers Blombery, Ella R. Thompson, Andrew Fellowes, Karen E. Sheppard, Grant A. McArthur, Richard B. Pearson, Ross D. Hannan, Gretchen Poortinga, Simon J. Harrison

All Supplementary Methods and associated references


National Health and Medical Research Council (NHMRC) of Australia

Cancer Council Victoria (CCV)

Peter MacCallum Cancer Foundation


Snowdome Foundation



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. 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