AZD4320 / AstraZeneca - LARVOL DELTA

Pre-Clinical Study on the Dual BCL2/BCL-XL Inhibitor AZD0466 for the Treatment of Chronic Lymphocytic Leukemia (ASH 2023) - "To evaluate if combination treatment of AZD0466 with BTK inhibitors would improve efficacy, we transplanted murine Eµ-TCL1 tumors into syngeneic recipient mice and randomized them for treatment with vehicle, ibrutinib (30mg/kg in drinking water), acalabrutinib (25mg/kg, p.o. QD), AZD0466 (70mg/kg, i.v., QW) and combination of AZD0466 with ibrutinib or acalabrutinib. Moreover, AZD4320 was highly efficacious in MAVER-1 and MINO cell line models where resistance to venetoclax mediated by BCL-XL upregulation was modelled by an in vitro dose escalation method. In summary, our pre-clinical study shows that the dual BCL2/BCL-XL inhibitor could represent an important treatment option for venetoclax resistance mediated by specific BCL2 mutations or BCL-XL upregulation and that its efficacy could be further improved upon combination treatment with BTKi."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • ANXA5 • BCL2 • BCL2L1 • CD5 • IGH

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

Inhibition of NSD2 in t(4; 14) myeloma induces changes in mitochondrial priming (ASH 2025) - "Dynamic profilingof KMS11 indicated increased priming on BCL-XL and potentially BCL2 with delta priming of 14-21% withBAD and 14% with HRK peptides (targets BCL-XL), as well as increased sensitivity to AZD4320 and DT2216(BCL-XL PROTAC)...Additionally, we found these cells were less sensitive to AZD5991 and AZD4320 thanthe control cells, suggesting loss of NDS2 in KMS18 leads to decreased priming. Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype... Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype. Themolecular basis for these differences is under current investigation and could be related to thedifferences in genes influenced by NSD2 activity in these cells. RNAseq analysis of 3 myeloma cells..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • BCL2L1 • FGFR3 • NSD2 • TP53

Molecular subtypes and BH3 mimetic synergy with anti-leukemia agents in T-cell acute lymphoblastic leukemia (ASH 2025) - "In this study, we evaluated the ex vivo cytotoxicity of threeinvestigational BH3 mimetics, namely AZD4320 (BCL2/BCL-XL dual inhibitor), AZ'3202 (BCL-XL inhibitor),and AZD5991 (MCL1 inhibitor), using an imaging-based cell viability assay in a panel of 58 patient-derivedxenograft (PDX) models of T-ALL...These findings highlightthe interplay between molecular subtype and apoptotic signaling and their effects on BH3 mimeticsensitivity in T-ALL.Next, to investigate the therapeutic potential of BH3 mimetics in combination settings for T-ALL, weevaluated the interactions between AZD4320 and key anti-leukemic agents, i.e., asparaginase,prednisolone, nelarabine, and an LCK inhibitor, dasatinib, across 40 T-ALL PDX samples ex vivo...In three T-ALL PDX models, the combination of AZD0466 (a drug-dendrimer conjugateof AZD4320) with asparaginase consistently exhibited greater efficacy compared to monotherapy (vsAZD0466, P = 0.0007, P = 0.015, and P = 0.0006; vs asparaginase, P =..."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial (ASH 2023) - P1 | "BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1...Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al... Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated."

Clinical • IO biomarker • Metastases • Monotherapy • P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Bone Marrow Transplantation • Cerebral Hemorrhage • CNS Disorders • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor • Thrombocytopenia • Transplantation • BCL2L1 • MCL1

Identification of vulnerabilities for targeting BCL-2 family members in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "Venetoclax is a selective BCL-2 inhibitor and is successfully used in CLL and AML, but heterogeneous sensitivity to venetoclax has been described in ALL and inhibitors of other BCL-2 family members including BCL-XL-selective A-1331852 and MCL-1 selective AZD5991 have been developed. Moreover, a dual inhibitor of the anti-apoptotic BCL-2 family members BCL-2 and BCL-XL (AZD4320) with its dendrimer conjugate (AZD0466) has recently shown anti-tumor activity in hematologic cancer models with manageable toxicity...Taken together, we found vulnerabilities of T-ALL to BCL-2 family inhibition, particularly to dual BCL-2/BCL-XL inhibition by AZD4320, and we demonstrated on-target activities. Using BH3-profiling, we identified BAD-priming as a marker of response for AZD4320 and MCL-1 dependence as a resistance mechanism that can be targeted by combination treatment, suggesting further clinical evaluation."

IO biomarker • Acute Lymphocytic Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (ASH 2024) - "Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • BCL2L1 • CASP3 • CDK1 • CDK9 • MCL1

Mitochondrial Priming Is Heterogenous in t(4; 14) Multiple Myeloma and Can be Induced By Inhibition of NSD2 (ASH 2024) - "Consistent with these findings, TKO cells were found to be more sensitive to venetoclax, the BCL2/BCLXL inhibitor AZD4320 and the BCLXL PROTAC DT2216. Conclusions : Mitochondrial priming is heterogenous in t(4; 14) MM which likely explains the lack of responses to venetoclax. However, inhibition or loss of NSD2 results in increased priming and sensitivity to BCLXL and possibly BCL2 inhibition raising the possibility of combination therapy for targeting this high-risk form of myeloma."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ANXA5 • BCL2L1 • MCL1 • NSD2 • PTPRC

m6a and NuRD complexes regulate monocytic differentiation and resistance to BCL2/BCL2L1 inhibitors in acute myeloid leukemia. (PubMed, Haematologica) - "Using CRISPR-based genome-wide perturbation screens, we investigated the genetic dependencies of venetoclax and the BCL2/BCL2L1 dual inhibitor AZD4320. Accordingly, in AML patient samples we found reduced expression of the respective m6a or NuRD complexes was significantly associated with monocytic differentiation and ex vivo resistance to the same drugs. These findings provide critical insights into previously undescribed mechanisms of BCL2 family inhibitor resistance in AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • MCL1 • RBM15 • ZMYND8

ASSESSING THE EFFICACY OF NK CELLS IN COMBINATION WITH BH3-MIMETICS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2025) - "To assess sensitivity of T-ALL for BH3-mimetics, we performed EC50 measurements for the BH3-mimetics venetoclax (BCL-2), A1331852 (BCL-XL), AZD4320 (BCL-2/BCL-XL) and AZD5991 (MCL-1). Taken together, we found heterogeneous sensitivity of T-ALL to NK cells and BH3-mimetics. These sensitivities were reflected in BH3-profiling assays, providing a potential marker of response. Combining NK cells with BH3-mimetics improved cell killing efficacy, suggesting further preclinical and potential clinical evaluation."

Clinical • Combination therapy • IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • Thrombocytopenia • BCL2 • BCL2L1 • IL15 • MCL1

Novel CDK12/13 inhibitor CTX-439 downregulates MCL1 via transcriptional mRNA read-through and synergistically acts with BCL-XL inhibitors for cancer therapy (AACR 2025) - "Moreover, dual inhibition of CTX-439 and AZD4320, which targets BCL-XL, synergistically induced rapid apoptosis in vitro and significantly suppressed tumor growth in vivo. Interestingly, our study revealed a novel CDK12/13 inhibition mechanism targeting short mRNAs, such as MCL1, that can be used to establish new therapeutic combination strategies with BCL-XL inhibitors. Additionally, our study provides a new avenue to improve cancer therapy outcomes."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • BRCA1 • BRCA2 • CDK12 • MCL1

Anti-leukemia efficacy of the dual BCL2/BCL-XL inhibitor AZD0466 in acute lymphoblastic leukemia preclinical models. (PubMed, Blood Adv) - "We also evaluated the therapeutic potential of targeting these proteins with AZD0466, a novel drug-dendrimer conjugate of the BCL2/-XL inhibitor AZD4320, and with BCL2 inhibitor venetoclax (ABT-199). Our findings therefore suggest that the novel dual BCL2/-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL. These findings facilitate the translation of dual BCL2/-XL inhibitors into ALL clinical trials, either alone or in combination with standard- of- care chemotherapy and immune therapies."

IO biomarker • Journal • Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1

CELL-FREE DNA AS A BIOMARKER FOR CELL DEATH AND TREATMENT RESPONSE IN ON-CHIP THREE-DIMENSIONAL SARCOMA TUMOR MODELS (CTOS 2024) - "Treatments for spheroids and mouse xenografts included staurosporine (cytotoxic alkaloid chemotherapy), radiotherapy, and/or AZD4320 anti-Bcl2/xL senolytic to assess the correlation between cfDNA levels and cell death (Figure 1.D and 2A)... Our study demonstrated a strong correlation between cfDNA release and cell viability, highlighting cfDNA as a reliable biomarker for monitoring cell death and treatment response in various 3D tumor models. The variability in cfDNA response to different treatments underscores the importance of context-specific analyses for accurate biomarker assessment. Future studies should explore the mechanisms behind cfDNA release discrepancies and differentiate between tumor and non-tumor cfDNA to estimate therapeutic windows."

Cell-free DNA • IO biomarker • Preclinical • Fibrosarcoma • Leiomyosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

The dual BCL-2 and BCL-XL inhibitor AZD4320 acts on-target and synergizes with MCL-1 inhibition in B-cell precursor ALL. (PubMed, Blood Adv) - No abstract available

Journal • BCL2 • BCL2L1

SINGLE CELL RNA SEQUENCING PROFILING OF ADULT T-CELL LEUKEMIA AND MOLECULAR MECHANISM OF GENE RGS13 INVOLVING IN DEVELOPMENT OF ATLL (EHA 2024) - "Single-cell sequencing data from 9 samples yielded 82,977 high-quality cells, divided into three groups: patientgroup, HTLV-1 carrier group, and healthy donor group. Using the Seurat method for clustering anddimensionality reduction, a total of 35 cell clusters were identified for each sample. Analysis revealed significantenrichment of CD4+ central memory T-cell subgroups (clusters 4, 8, 10, 11, 13, and 15) in the patient group,with higher proportions than HTLV-1 carriers and healthy donors, suggesting tumor-associated CD4+ T cells."

Clinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD4

AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial (AACR 2024) - P1/2 | "AZD0466 is a drug-dendrimer conjugate consisting of the dual Bcl-2/Bcl-xL inhibitor AZD4320 covalently conjugated to a pegylated poly-L-lysine dendrimer, which allows for gradual release by hydrolysis. The study was terminated due to similar findings in a concurrent trial (D8241C00001; NIMBLE). With an objective response observed at the 1200 mg dose level, further development of agents targeting Bcl-2/xL in NHL is warranted with efforts to reduce the cardiotoxicity profile."

Clinical • IO biomarker • Metastases • P1 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • CASP3

SAFETY AND TOLERABILITY OF AZD0466 AS MONOTHERAPY FOR PATIENTS WITH ADVANCED HEMATOLOGICAL MALIGNANCIES - PRELIMINARY RESULTS FROM AN ONGOING PHASE I/II TRIAL (EHA 2023) - P1/2 | "Background: The BCL2 family of proteins induce apoptosis via caspase activation and are being increasingly targeted in hematologic malignancies by small molecules such as venetoclax (VEN)...Preclinically, AZD4320 showed activity in patient (pt)-derived AML xenografts and superior tumor growth inhibition to VEN and navitoclax in VEN-resistant xenograft models (Balachander et al...Module 2 investigates drug-drug interactions between AZD0466 and voriconazole... Treatment with AZD0466 is well tolerated in pts with R/R acute leukemia, with AEs matching expected toxicity from preclinical data. Preclinical efficacy modeling and clinical PK data suggest further dose escalation is warranted to explore clinical activity."

Clinical • IO biomarker • Metastases • Monotherapy • P1/2 data • Acute Myelogenous Leukemia • CNS Disorders • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • BCL2 • BCL2L1

Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR. (PubMed, J Ovarian Res) - "In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC."

Journal • Endometriosis • Gynecology • Oncology • Ovarian Cancer • Solid Tumor • Women's Health • ARID1A

AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models (AACR 2023) - P1, P1/2 | "The active moiety, AZD4320, is a potent dual inhibitor of BCL-2 and BCL-XL...AZD0466 outperformed the selective BCL-2 inhibitor venetoclax in 6/10 models. Notably, AZD0466 was active in models resistant to platinum/etoposide chemotherapy, the standard-of-care for SCLC...AZD0466 exhibits linear PK, consistent across solid tumor and leukemia patients. The doses tested are in line with preclinical studies in SCLC."

IO biomarker • Preclinical • Hematological Malignancies • Leukemia • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • BCL2 • BCL2L1 • CASP3 • NEUROD1 • NEUROD1 • YAP1

[VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) (SOHO 2021) - P1/2 | "AZD5991 is a highly selective BH3-mimetic that demonstrates high in vitro potency in MCL1-dependent cell lines with an IC50 <1 nM.7 We have demonstrated that direct MCL1 inhibition with AZD5991 disrupts survival of neoplastic B-cells in lymph-node mimicking conditions, induces mitochondrial dysfunction and cooperates with BCL2/X inhibitors in vitro and in vivo.8 A phase 1 clinical trial of AZD5991 alone or in combination with venetoclax in hematologic malignancies is ongoing (NCT03218683)...AMG-176 demonstrated synergy with venetoclax in AML models; however, it also caused cytopenias.9 AMG-176 was shown to induce apoptosis of CLL cells independent of prognostic markers and overcame the protective effect of stromal microenvironment.10 However, suppressive effects on hematopoiesis will likely become the dose- limiting factor in clinical trials of MCL1-targeting agents. The effect of MCL1 inhibition on cord blood-derived CD34+ cells was studied using a..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CD19 • CD34 • CDK7 • ROR1 • SYK

Novel Agents in Chronic Lymphocytic Leukemia (CLL) (SOHO 2022) - "The subsequent key areas hold promise: Alternative Inhibitors of BTK Here, non-covalent BTK inhibitors, such as pirtobrutinib (LOXO- 305) and nemtabrutinib (ARQ-531), have shown effi cacy in CLL resistant to covalent BTK inhibitors...AZD5991 is a highly selective BH3-mimetic that demonstrates high potency in MCL1-dependent cell lines.9 Our group has shown that selective targeting Mcl-1 induced metabolic dysfunction and abrogated survival of lymphoid cells in vitro and in vivo.10 Other BH3- mimetics targeting Mcl-1 include AMG-176 and S63845.11,12 However, Mcl-1 targeting agents may be associated with toxicities, including against the hematopoietic stem and progenitor cells, potentially leading to cytopenias in the clinic.13 The therapeutic window for these agents needs to be defi ned. BH3-mimetics which target Bcl-xL, such as navitoclax, are not being developed in CLL due to concerns of thrombocytopenia.14 However, AZD4320, an alternative Bcl-2/xL inhibitor, is being..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • CD19 • ROR1 • TP53

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial (ASH 2022) - P1, P1/2 | "Specific Bcl-2 inhibition using venetoclax is beneficial in patients with acute myeloid leukemia (AML), but resistance often develops due to upregulation of anti-apoptotic proteins such as Bcl-xL and Mcl-1...Following IV infusion, released AZD4320 exhibited a dose-proportional increase in area under the concentration time curve (AUC) and maximum serum concentration (Cmax), moderate PK variability (≈50% coefficient of variation), and a half-life of ≈18 hours. AZD0466 has been well tolerated, with no DLTs to date and no discontinuations due to treatment-related AEs. The trial continues to enroll, further dose escalation is planned, and updated data will be presented."

Clinical • Monotherapy • P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Cardiovascular • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • BCL2L1

Combined Inhibition of MCL1 By AZD5991 and BCL2/Bclxl By AZD4320 As Promising Strategies to Overcome Acute Leukemia Tumor Burden and Niche Chemoresistance (ASH 2022) - "To investigate the in vitro, ex vivo and in vivo effects of AZD5991 (AstraZeneca), a novel MCL1 inhibitor compound, alone or in combination with AZD4320 (BCL-2/BCL-XL inhibitor compound), venetoclax, cytarabine and doxorubicin. MCL1 overexpression in mononuclear cells from patients with acute leukemia and that present or not resistance to venetoclax treatment, is associated with poor prognosis and relapse disease. Our results demonstrated that co-targeting MCL-1, BCL-2 and BCL-xL, through the AZD5991 and AZD4320 compounds in the treatment of acute leukemias, may enhance therapeutic specificity, overcome chemoresistance and contribute with the cure of these aggressive malignant disorders."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • ANXA5 • BCL2 • BCL2L1 • CD34

BCL-XL Blockage with A1155463 Significantly Increases Efficacy of Venetoclax in Mantle Cell Lymphoma in Vitro and In Vivo (ASH 2022) - "Mantle cell lymphoma (MCL) is a rare chronically relapsing subtype of aggressive B-cell non-Hodgkin lymphoma characterized by the canonical chromosomal translocation t (11; 14) and other molecular cytogenetic aberrations including overexpression of BCL2 protein. We demonstrated that the thrombocytopenia associated with continued therapy with A1155463 could be managed by 4 days on / 3 days off treatment strategy, which cannot be applied in case of fixed dual BCL2/BCL-XL inhibitors like navitoclax, or AZD4320. In summary, the combined inhibition of BCL2 and BCL-XL with VEN and A1155463 is a highly effective experimental treatment strategy for R/R MCL with a potential translation to the clinical grounds."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • Transplantation • BCL2L1 • CD40 • MCL1

NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies (ASH 2021) - P1, P1/2 | "Dual BCL2/xL inhibition with AZD4320 has potential for broader activity than BCL2-specific inhibition with venetoclax (Balachander et al, Clinical Cancer Research 2020)...Treatment with hydroxyurea during screening and cycle 1 is permitted to control white blood cell count...Module 2 is a drug-drug interaction (DDI) study that will investigate the safety and establish the sensitivity of AZD0466 to voriconazole, a strong inhibitor of CYP3A4...This study is actively enrolling patients at sites in the USA, and will be opening at multiple sites in Australia, Europe and South Korea. An update of preliminary safety and pharmacokinetics will be presented."

Clinical • IO biomarker • Monotherapy • P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • BCL2L1 • CYP3A4 • TP53