Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma

Abstract

Bromodomain and extra-terminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL (NCT03255096). RO was delivered for 14 days of a 21-day cycle, while venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO + venetoclax doublet, rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO + 600 mg venetoclax; for RO + venetoclax + rituximab the MTDs were 0.45 mg/kg, 600 mg and 375 mg/m2, respectively. The most frequent grade 3/4 adverse events were neutropenia (28%), anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%, 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use.

Triple combination of BET plus PI3K and NF-κB inhibitors exhibit synergistic activity in adult T-cell leukemia/lymphoma

“…Single-agent therapy demonstrated some partial responses with limited dose escalation 13,21,50 . Thus, recent studies [51][52][53][54] have been focused on using these agents in combination therapy for recurrent/relapsed diseases. The triple combination therapy is promising and recommended for acute ATL patients with advanced and aggressive disease.…”

Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

“…4 ) [ 83 – 86 ]. Phase I clinical trials of the combination of venetoclax and the BET inhibitor R06870810 or the dual HDAC and PI3K inhibitor fimepinostat (CUDC-907) in R/R DLBCL showed manageable safety profiles and durable anti-tumor activities [ 87 , 88 ], but in MCL no clinical trials have been initiated yet.…”

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…In a phase 1 study of BETi RO6870810 monotherapy in patients with DLBCL, objective responses were observed in 11% [ 115 ]. A combination study with venetoclax and rituximab in R/R DLBCL demonstrated ORR of 38.5%, including 20.5% CR [ 116 ]. However, despite the promising rationale, there was no convincing synergy between concurrent BET and BCL2 inhibition.…”