A Phase 1, Open-Label, Dose Escalation, Safety, Pk And Pd Study Of A First In Class Pol1 Inhibitor (Cx-5461) In Patients With Advanced Hematologic Malignancies (Hm).

e22212 Background: Ribosome biogenesis driven by RNA polymerase 1 (Pol1) is a fundamental cellular process increased in malignancy. We have shown that CX-5461, a small molecule inhibitor of Pol1, selectively targets AML, lymphoma and myeloma cells in preclinical in-vivomodels with minimal effects on normal hematopoietic cells (Cancer Cell 2012). Methods: Key Eligibility Criteria; Relapsed HM, u003e1 prior therapy, no standard of care therapeutic options; ECOG PS: 0-2; Adequate organ function. CX-5461 is administered by 3 weekly IV infusion over 1 hour. Based on preclinical animal testing, dosing commenced at 25mg/m2, with planned escalations up to 450mg/m2. Biomarkers of Pol1 transcription inhibition (Pol1ti) include 47S ribosome subunit pre-rRNA FISH in PBMC and tumor tissue. Results: Since July 2014, 13 patients have been treated in 4 dose cohorts (table1).To date there have been no dose-limiting toxicities (n=12). The most common drug associated toxicity was skin rash (photosensitive grade 1-2 n=4 easily m...