Bcl-2 Family Inhibitors / Novartis, Infinity Pharma - LARVOL DELTA

[VIRTUAL] Identification of S65487/VOB560 as a potent and selective intravenous 2nd-generation BCL-2 inhibitor active in wild-type and clinical mutants resistant to Venetoclax (AACR 2021) - P1 | "Strong and persistent tumor regression in xenograft models of lymphoid malignancies in mouse and rat were observed at well tolerated doses following weekly IV administration of S65487 in combination with the MCL-1-specific inhibitor, S64315/MIK665. Altogether, these data demonstrate that S65487/VOB560 has significant therapeutic potential against human lymphoid and myeloid malignancies as well as in patients with Venetoclax resistant leukemias. Clinical studies are currently ongoing with S65487/VOB560 (NCT03755154)."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2L1

[VIRTUAL] Evaluation of minimal residual disease in relapsed/refractory multiple myeloma patients treated with venetoclax or placebo in combination with bortezomib and dexamethasone: BELLINI study analyses. (ASCO 2020) - P3 | "Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Research Funding: AbbVie and Genentech"

Clinical • Combination therapy • IO biomarker • Residual disease • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Acquired Mutations in BAX Confer Resistance to BH3 Mimetics in Acute Myeloid Leukemia (ASH 2020) - "Background: Recent randomized trials have demonstrated improvements in overall survival (OS) for the BCL-2 inhibitor venetoclax (VEN) in combination with azacitidine and low dose cytarabine in older unfit patients with AML...S63845 and S55746 were obtained from Servier/Novartis, A1155463 from G. Lessene (WEHI), venetoclax and cytarabine from Selleckchem... We identified the presence of BAX mutations in AML samples from patients progressing on VEN-containing regimens. We show that BAX, but not BAK loss in an AML cell line is associated with resistance to BH3-mimetic drug combinations resulting in reduced survival in AML xenograft models. In contrast, BAX deficiency does not impede the cytotoxic actions of conventional chemotherapy."

IO Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • BCL2L1

A Study of Duvelisib and Venetoclax in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Indolent or Aggressive Non-Hodgkin Lymphoma, Who Have Not Previously Received a Bcl-2 or PI3K Inhibitor (clinicaltrials.gov) - P1; N=174; Recruiting; Sponsor: AbbVie; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

A Study of Duvelisib and Venetoclax in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Indolent or Aggressive Non-Hodgkin Lymphoma, Who Have Not Previously Received a Bcl-2 or PI3K Inhibitor (clinicaltrials.gov) - P1; N=174; Not yet recruiting; Sponsor: AbbVie

New P1 trial • Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Synergistic Activity of the MCL-1 Inhibitor S63845 with Midostaurin in Preclinical Human Models of FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (SOHO 2019) - "Here, we show that S63845 elicited synergistic activity with FLT3 inhibitors AC220, sorafenib and with a multi-kinase inhibitor midostaurin in pre-clinical models of AML.Results S63845 had potent single agent activity in AML cell lines and primary FLT3-ITD samples with IC50 values in low nanomolar range...Given that Mcl-1 is commonly upregulated in AML which acquired resistance to Bcl-2 inhibitor venetoclax, we also tested the efficacy of S63845/midostaurin combination in venetoclax-resistant MOLM-13 FLT3-ITD cells generated by exposure to gradually increasing doses of venetoclax in culture...We found that S63845 alone was ∼ 8 times more active in resistant cells, confirming their dependency on Mcl-1 for survival. Importantly, the S63845 and midostaurin synergy was clearly observed in venetoclax-resistant cells, which points to a novel therapeutic strategy overcoming this type of resistance.Conclusions S63845/midostaurin combination is highly effective in FLT3-ITD..."

IO Biomarker • PARP Biomarker • Preclinical