BR101801

P1, N=30, Active, not recruiting, Boryung Pharmaceutical Co., Ltd | Recruiting --> Active, not recruiting

Moreover, BR101801 exerted robust synergistic effects on IR-induced cell cycle arrest, apoptosis, and tumor growth inhibition, even in radioresistant HCT116 p53 cells. Overall, these findings provide a scientific rationale for combining BR101801 with IR as a new therapeutic strategy to overcome radioresistance induced by p53 deficiency.

Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.

The results for the phase 1a study evaluated the safety, efficacy results and pharmacokinetic characteristics, 200 mg QD was shown to provide target exposure for clinical efficacy with the tolerable and safe profile. BR101801 showed of antitumor activity, especially in R/R PTCL patients. Hence, the phase 1b study of BR101801 is warranted in R/R PTCL patients and we expect BR101801 would become a promising therapeutic option for these patients.

In phase 1a clinical study; 200mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 showed signs of preliminary activity; especially in relapsed or refractory(R/R) PTCL patients. Hence we expect BR101801 would become a promising therapeutic option for R/R PTCL patients.

Our study demonstrates that BR101801, an oral triple inhibitor of PI3Kδ/γ and DNA-PK, effectively elicited anticancer immune responses within the TME and potently inhibited tumor progression in combination with immune checkpoint blockade.

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.

Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

In addition, combination BR101801 and IR suppressed tumor growth compared with IR alone by reducing phosphorylation of DNA-PK in human solid cancer xenografts. Our findings suggested that BR101801 is a selective DNA-PK inhibitor with a synergistic radiosensitizing effect in human solid cancers, providing evidence for clinical applications.

200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL.

A tumor mouse xenograft model was established by subcutaneously implanting human derived B-cell lymphoma cell line, SU-DHL-10 (Bendamustine, Rituximab) or DOHH-2 (Venetoclax) into female SCID mice. In vitro selectivity and target potency of BR101801 on different PI3K subtypes including DNA-PK were studied in cell-free systems in which the biochemical IC50 values of BR101801 for PI3K-α, -β, -γ, -δ and DNA-PK were 106 nM, 171 nM, 15 nM, 2 nM and 6 nM, respectively. BR101801 is a first-in-class triple inhibitor of PI3K γ/δ and DNA-PK, and has shown highly potent effects to block cellular proliferation of NHL cell lines including both the indolent and aggressive subtypes. Therefore, the strategy of triple targeting against PI3K γ/δ and DNA-PK suggests rationale for BR101801 as innovative therapeutics for NHL patients.

Recent studies have reported anti-cancer immunity by use of PI3K-δ inhibitor (Idelalisib), PI3K-γ inhibitor (IPI-549) and DNA-PK inhibitor (NU7441). The immunosuppressive effect of BR101801 changing the tumor microenvironment was verified without cancer cells. It is demonstrated that anticancer immunity by decreasing Tregs and increasing CD8. Anti-tumor immunity was enhanced by decreasing the expression of PD1, TIM3, LAG3 and TIGIT in CD8 + cells.