First-in-human study of AZD5153, a small molecule inhibitor of bromodomain protein 4 (BRD4), in patients (pts) with relapsed/refractory (RR) malignant solid tumor and lymphoma: Preliminary data.

Abstract

3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

Alternative approaches to target Myc for cancer treatment

“…28 Thus, BET inhibitors, like AZD5153 and GSK525762, could be promising candidates for further clinical usage in Myc-deregulated cancer. 29 Besides, a strategy or technology termed as proteolysis targeting chimera (PROTAC) has been developed recently to hijack the Cereblon E3 ubiquitin ligase for degrading specific oncoproteins, such as BRD4, potently and constantly. 30 PROTAC was first used as a chemical knock-down approach with reversibility and has been recently explored to satisfy additional needs, including drug discovery.…”

“… 28 Thus, BET inhibitors, like AZD5153 and GSK525762, could be promising candidates for further clinical usage in Myc-deregulated cancer. 29 …”

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

“…In addition, this combo was relatively well-tolerated, likely because the adverse effects of mTORi and BETi affect different organ systems. In contrast, the AKTi and BETi combo had poor tolerability in vivo despite being synergistic in vitro, probably because of overlapping adverse effects (e.g., diarrhea) of AKTi and BETi (42,43). These results stress the need to select the drugs with non-overlapping toxicities to increase antitumor activity and minimize adverse effects.…”

BET Proteins as Attractive Targets for Cancer Therapeutics

“…Importantly, AZD5153 demonstrated a cytotoxic effect at a concentration 100 nM and tumour regression at concentrations 2.5-10 mg/kg for AML and prostate cancer xenografted tumours [57][58][59]. AZD5153 progressed to clinical trial, which reported similar DLTs as for OTX015, indicating that although BETis' chemical structure is diverse, toxicities may be shared across BETis [60]. A dose escalation study of a new BETi, BAY1238097, in eight patients with solid cancers was prematurely terminated due to DLTs [61].…”