First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study
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
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2019
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 rDN..View full abstract
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Awarded by National Health and Medical Research Council (NHMRC) of Australia Development grant
Awarded by Cancer Council Victoria (CCV)
We thank the patients and their families for their participation in the study. We also thank the Peter MacCallum Cancer Centre Research Nursing Team. We thank Dr. Megan Bywater and Dr. Stephen Lade for advising on assays used in this study. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia Development grant (#1038852), Cancer Council Victoria (CCV) grants-in-aid (#1084545 and #1100892) and the Peter MacCallum Cancer Foundation. Senhwa Biosciences provided financial support with respect to drug supply and pharmacokinetic studies. Researchers were funded by NHMRC Fellowships (to G.A. McArthur, R.B. Pearson, R.D. Hannan) and the Snowdome Foundation fellowship funding (to A. Khot).