sonrotoclax (BGB-11417)

P3, N=300, Not yet recruiting, BeiGene

P1/2, N=170, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P2, N=87, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1, N=30, Completed, BeiGene | Recruiting --> Completed

Introduction : The combination of venetoclax, the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing at approximately 230 study sites in 20 countries, including 50 sites in the US, 6 in Brazil, and 15 in Canada.

P1/2, N=56, Not yet recruiting, BeiGene

P=N/A, N=47, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P2, N=100, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

P1/2, N=260, Recruiting, BeiGene | Phase classification: P1b/2 --> P1/2 | Trial completion date: Aug 2025 --> Feb 2028 | Trial primary completion date: Dec 2023 --> Feb 2028

P1/2, N=126, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2024 --> Apr 2025

P2, N=87, Not yet recruiting, BeiGene

P1/2, N=170, Not yet recruiting, BeiGene

The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has efficacy in CLL. Other secondary endpoints include investigator (INV)-assessed PFS, CRR-INV, uMRD4 rate by flow cytometry, ORR-IRC and -INV, DOR-IRC and -INV, patient-reported outcomes, and safety and tolerability. Recruitment is ongoing.

P1, N=30, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P2, N=102, Not yet recruiting, French Innovative Leukemia Organisation

P1, N=30, Not yet recruiting, BeiGene

P2, N=47, Not yet recruiting, Shanghai Jiao Tong University School of Medicine

P2, N=30, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

P1, N=64, Active, not recruiting, BeiGene | Trial completion date: May 2024 --> Apr 2026 | Trial primary completion date: May 2024 --> Apr 2026

P2, N=97, Recruiting, BeiGene | N=72 --> 97 | Trial primary completion date: Nov 2024 --> Apr 2025

Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFSand had a more tolerable safety profile, including fewer cardiac adverse events, vs ibrutinib in a randomized,head-to-head study of patients with CLL/SLL (Brown et al. N/A

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Background: The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with CLL (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing.

P2, N=66, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=64, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

P3, N=640, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1/2, N=167, Recruiting, BeiGene | Phase classification: P1b/2 --> P1/2

P1/2, N=122, Recruiting, BeiGene | Phase classification: P2 --> P1/2

P1, N=537, Recruiting, BeiGene | Phase classification: P1a/1b --> P1

Sonrotoclax (BGB-11417) is a next-generation BH3 mimetic which binds and inhibits BCL2 with a potency >10x that of venetoclax in biochemical assays. These data confirm sonrotoclax monotherapy had a tolerable safety profile across all doses tested and encouraging antitumor activity in patients with MZL. Two patients had laboratory TLS following the initial doses that resolved. No clinical TLS were observed, indicating that TLS can be mitigated with current measures, including revised ramp-up.

We therefore aimed to investigate the prevalence and pattern of BAX-mutated CH across different hematological and non-hematological neoplasms in response to BCL2 inhibitor therapy (both venetoclax and BGB-11417)...We assessed a cohort of pts with metastatic breast cancer who received venetoclax in combination with tamoxifen (mBEP; Lok, Cancer Discover 2019), and detected BAX variants from peripheral blood samples in 5/16 (31%) pts (median age 66) after a median duration of 20 (range 13–44) months on venetoclax...In summary, the emergence of BAX-mutated CH appears to be a generalized phenomenon of adaptive hematopoiesis that occurs across both hematological and non-hematological malignancy settings as well being observed with other BCL2 inhibitors consistent with a therapeutic class effect. Further research is needed to understand the contribution of this phenomenon to the subsequent development of clinically relevant hematological abnormalities and its implications for future therapeutic resistance.

P3, N=640, Not yet recruiting, BeiGene

P2, N=85, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P2, N=85, Not yet recruiting, BeiGene

Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.

These results demonstrated that BGB-11417 monotherapy was well tolerated at all tested doses up to 640 mg/d, with no dose-dependent toxicity increase. BGB-11417 monotherapy showed promising initial efficacy results in R/R CLL/SLL, with pts achieving responses at lower dose levels. Lymphoma, Chronic lymphocytic leukemia, BCL2, Hematological malignancy

BGB-11417 is a novel Bcl-2 inhibitor that is more potent and selective than venetoclax. Initial data show an encouraging safety profile and evidence of efficacy for BGB-11417 in NHL, MCL, and WM cohorts. MTD was not reached at highest dose (640 mg QD). All low-grade TEAEs and grade ≥3 neutropenia were manageable.

Background: Bcl-2 inhibitors are effective for treating chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL); however, the emergence of resistance limits their utility. Preliminary data show BGB-11417 (monotherapy and combination with zanubrutinib) is well-tolerated. Grade ≥3 neutropenia was uncommon and manageable. TLS rates are low.

BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses ≤640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand; the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

No abstract available

P2, N=98, Recruiting, BeiGene | Not yet recruiting --> Recruiting

Preliminary findings suggest that BGB-11417 has promising efficacy and is tolerable at ≤640 mg as monotherapy and ≤160 mg combined with zanubrutinib. Dose escalation continues as MTD has not been reached. Enrollment is ongoing; data for Waldenström macroglobulinemia and treatment-naïve CLL/SLL are forthcoming.