AZD0466 / AstraZeneca, Starpharma - LARVOL DELTA

A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: AstraZeneca | Phase classification: P1/2 ➔ P1

Phase classification • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1

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

NIMBLE: Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies (clinicaltrials.gov) - P1 | N=46 | Terminated | Sponsor: AstraZeneca | Phase classification: P1/2 ➔ P1

Phase classification • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

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

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer. (PubMed, Cell Death Dis) - "While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • BCL2 • BCL2L1 • BCL2L11 • MCL1

BCL-X_L inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV^600E colorectal cancer (Nature, Cell Death Dis) - "Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone."

Preclinical

BCL-X_L inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV^600E colorectal cancer (Nature, Cell Death Dis) - "Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone."

Preclinical

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 • Transplantation • ANXA5 • BCL2 • BCL2L1 • CD5 • IGH

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial (ASH 2023) - P1, P1/2 | "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 • 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 • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1

Emerging BCL 2 Inhibitors (SOHO 2023) - P1, P1/2, P1a/1b, P1b/2, P2 | "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..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia • Waldenstrom Macroglobulinemia • BCL2L1

A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=7 | Terminated | Sponsor: AstraZeneca | N=50 ➔ 7 | Trial completion date: May 2025 ➔ Aug 2023 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2024 ➔ Aug 2023; Due to safety reasons.

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1

NIMBLE: Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies (clinicaltrials.gov) - P1/2 | N=42 | Terminated | Sponsor: AstraZeneca | N=133 ➔ 42 | Suspended ➔ Terminated; Trial terminated based on benefit-risk profile assessment

Enrollment change • Metastases • Monotherapy • Trial termination • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

NIMBLE: Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies (clinicaltrials.gov) - P1/2 | N=133 | Suspended | Sponsor: AstraZeneca | Trial completion date: Oct 2024 ➔ Aug 2023 | Recruiting ➔ Suspended | Trial primary completion date: Oct 2024 ➔ Aug 2023

Metastases • Monotherapy • Trial completion date • Trial primary completion date • Trial suspension • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

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

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

In depth characterization of physicochemical Critical Quality Attributes of a clinical drug-dendrimer conjugate. (PubMed, Int J Pharm) - "In order to fully characterize AZD0466, a drug-dendrimer conjugate currently under clinical development by AstraZeneca, a collaboration was initiated with the European Nanomedicine Characterisation Laboratory to deploy a state-of-the-art multi-step approach to measure physicochemical properties...Thus, the aim of this work is to guide in depth characterization efforts in the analysis of drug-dendrimer conjugates. Additionally, it serves to highlight the importance of using the adequate complementary techniques to measure physical and chemical stability in both simple and biological media, to drive a complex drug-dendrimer conjugate product from discovery to clinical development."

Journal

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

A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=50 | Recruiting | Sponsor: AstraZeneca | Trial primary completion date: May 2025 ➔ Oct 2024

Combination therapy • Metastases • Monotherapy • Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1

A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=50 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Nov 2024 ➔ May 2025 | Trial primary completion date: Nov 2024 ➔ May 2025

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1

The global characterisation of a drug-dendrimer conjugate - PEGylated poly-lysine dendrimer. (PubMed, J Pharm Sci) - "Here we report the first example of a global characterisation of a drug-dendrimer conjugate - PEGylated poly-lysine dendrimer currently under development (AZD0466). The impact of the wide variety of analytical and measurement techniques on the overall understanding of this complex molecular entity is discussed, with the relative capabilities of the various approaches compared. The results of this study are an essential platform for the research and development of the future generations of related dendrimer-based medicines."

Journal

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

"@AstraZeneca #Oncology #EarlyClinicalDevelepment The most anticipated drugs🤔 ➡️#AZD0466: #Dendrimer(@Starpharma_ASX)-conjugated dual #Bcl2/#BclxL inhibitor ➡️#AZD8701: #FOXP3 #ASO, #Tregs depletion💘 ➡️#AZD8205: #B7H4 #TOP1i #ADC, Synergy with #PARP1 selective inhibitor👌" (@gasingiltv)

Oncology • BCL2 • BCL2L1 • FOXP3 • VTCN1

A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=50 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting | Initiation date: Feb 2022 ➔ Jul 2022

Combination therapy • Enrollment open • Monotherapy • Trial initiation date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1

THE DUAL BCL-2 AND BCL-XL INHIBITOR AZD4320 SHOWS ON-TARGET ACTIVITY IN ALL AND ACTS SYNERGISTICALLY WITH MCL-1 INHIBITION (EHA 2022) - "AZD4320 was developed as a dual inhibitor of BCL-2 and BCL-XL, and its dendrimer conjugate (AZD0466) was recently reported to demonstrate anti-tumor activity in hematological cancer models, while showing only a transient thrombocytopenia. Aims In this study, the anti-leukemia activities of the dual BCL-2 and BCL-XL inhibitor AZD4320 and of MCL-1-selective AZD5991 were evaluated and compared to the effects of other BH3-mimetics (BCL-2-selective venetoclax, BCL-XL-selective A-1331852 and MCL-1-selective S63845)...Importantly, the highest synergism was found at low concentrations of both inhibitors, suggesting efficacy at moderate concentrations, which could potentially be achieved in vivo . Conclusion In summary, our study demonstrates sensitivity, on-target activity and synergism of the dual BCL-2 and BCL-XL inhibitor AZD4320 with inhibition of MCL-1, thereby providing strong evidence for further clinical evaluation in ALL."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • BCL2 • BCL2L1