A PHASE 1 STUDY OF BET INHIBITION USING RG6146 IN RELAPSED/REFRACTORY (R/R) MYC‐EXPRESSING DIFFUSE LARGE B CELL LYMPHOMA (DLBCL)

Abstract

Introduction: Bromodomain and extraterminal (BET) proteins are transcription cofactors that participate in several oncogenic processes in DLBCL, including MYC regulation. BET inhibitors (BETi) have demonstrated activity in DLBCL preclinically, in part by disrupting BET binding to super‐enhancer sites of several cell‐essential genes, including MYC. BET inhibition may therefore be a therapeutic strategy in DLBCL, including MYC‐expressing disease. RG6146 is a novel, noncovalent subcutaneous (sc) BETi in early clinical development. We report safety, pharmacokinetics (PK), pharmacodynamics (PD), (Figure Presented) and preliminary clinical response data for a cohort of DLBCL patients enrolled within a larger phase I study (NCT01967362). Methods: DLBCL patients with R/R disease after >=2 lines of therapy and abnormal MYC expression (IHC or FISH) were eligible. RG6146 was given as 0.3 or 0.45 mg/kg daily sc on either 3 of 4 or 2 of 3 week schedules. Disease assessment followed the Lugano criteria. CD11b expression on monocytes was assessed as a PD biomarker by flow cytometry. Results: A total of 19 patients received RG6146 sc 0.30 mg/kg x 21d q4wks (n = 2), 0.45 mg/kg x 21d q4wks (n = 2), or 0.45 mg/kg x 14d q3wks (n = 15). Median age was 67 years (range 49‐82); median number of prior treatments was 3 (range 2‐6). Grade (G) 3/4 treatmentrelated toxicities included thrombocytopenia (n = 2, both G4), neutropenia (n = 1, G4), fatigue (n = 1, G3), hyperglycemia (n = 1, G4), hyperbilirubinemia (n = 1, G3), and hyperuricemia (n = 1, G3). At 0.45 mg/kg x 14d q3wks, 2 patients had objective PR. Seven patients came off study for disease progression within the first cycle. The intent to treat ORR was 11%, and 17% in the evaluable population (Figure 1). PK measurements showed that RG6146 half‐life was approximately 10 hr with low‐to‐moderate variability for Cmax and AUC (Table ). CD11b expression showed ~50% reduction by day 15; SD or PR patients displayed significant reductions, with greatest decrease ~70%. Conclusions: RG6146 has an acceptable safety profile in patients with R/R MYC‐expressing DLBCL. Its ability to down‐regulate CD11b on monocytes supports the putative mechanism of action that RG6146 prevents BET co‐activator loading at super‐enhancers, and may provide a PD marker to guide dose and schedule optimization. RG6146 can induce objective responses and tumor shrinkage in chemorefractory patients, suggesting disruption of super‐enhancer loading of BETs with RG6146 may be a viable therapeutic strategy in DLBCL. Combination studies are planned.