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

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 hematological cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined a maximum tolerated dose 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.