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, >1 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 managed by sun avoidance and erythroderma grade 3 in one CTCL patient). Other adverse events (AEs) have been mild cytopenias related to underlying disease. 3 patients, 2 (MM) and 1 (DLBCL), have shown prolonged disease stabilisation receiving 6, 3 and 15 cycles of drug. The latter remains on drug after 10 months. PK analyses showed favorable and linear exposure with dose. Treatment with CX-5461 causes robust and significant Pol1ti 1hr post-infusion. Median Pol1ti 49.0% (Range:22.9- 69.9%, n=3), 51.1% (34.4 - 64.4%, n=4), 19.6% (-72.0 – 69.7%, n=4) and 46.5% (n=1) for cohorts 1-4 respectively. At 24hrs, Pol1 transcription levels rebound and return to baseline levels. Conclusions: CX-5461 is well tolerated with low grade manageable AEs to date. Inhibition of Pol1 transcription in PBMC indicated on-target drug activity in these initial dose cohorts. The trial continues in dose escalation. Clinical trial information: ACTRN12613001061729. Pt ID Age Sex Diagnosis Dose level mg/m2 No. of doses Best Response 1 73 M MM 25 6 SD 2 47 F MM 25 3 SD 3 54 F DLBCL 25 1 PD 4 79 F CTCL 50 2 mixed 5 26 F HD 50 1 PD 6 74 M CLL 50 1 Early PD 7 70 F DLBCL 50 15 SD 8 47 M MM 100 1 PD 9 78 M TPLL 100 1 Early PD 10 21 F DLBCL 100 2 PD 11 34 M HD 100 2 PD 12 74 F MM 170 1 NA 13 56 M MM 170 1 NA