NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2353-2353
• Main Authors: Konopleva, Marina, Jain, Nitin, Andersen, Courtney L, Couto Francisco, Natalia, Elgeioushi, Nairouz, Hobson, Rosalind, Scott, Martin, Stone, John, Sharma, Shringi, Morentin Gutierrez, Pablo, Tibes, Raoul, Davies, Barry, Winkler, Thomas, Fabbri, Giulia, Zumla Cader, Fathima, McNeer, Nicole
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-147482

Introduction: While BCL2 inhibition benefits many patients with acute myeloid leukemia (AML), resistance often occurs due to upregulation of other anti-apoptotic proteins such as MCL and BCLxL. Dual BCL2/xL inhibition with AZD4320 has potential for broader activity than BCL2-specific inhibition with venetoclax (Balachander et al, Clinical Cancer Research 2020). AZD0466 is a drug-dendrimer conjugate in which AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and where, following IV infusion, AZD4320 is gradually released by hydrolysis. The dendrimer construct allows for efficient delivery of the highly potent but poorly soluble active drug, and this release profile was designed to mitigate potential maximum concentration (Cmax)-dependent BCLxL mediated effects (Patterson et al, Nature Communications Biology 2021). AZD0466 has shown antitumor activity in a range of preclinical models of hematological malignancy, including cell-line derived and patient-derived xenograft models of acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-cell acute lymphoblastic leukemia (T-ALL - Kannan et al AACR 2020 Abstract 3075). AZD0466 has previously been administered to 9 patients with advanced solid malignancies at doses declared tolerable through 200 mg in the first-time-in-human study (NCT04214093), and a physiologically based PK model validated across nonclinical species was used to predict human doses and exposures expected to drive tumor regression in hematologic malignancy. These studies provide rationale for testing AZD0466 in refractory AML and ALL patients in this phase I/II dose escalation and monotherapy expansion and drug-drug interaction study (NCT04865419). Study Design and Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II dose escalation and expansion study. Module 1 will evaluate safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD0466 as monotherapy in patients with relapsed/refractory AML or ALL. Patients are eligible if ≥ 18 years of age with any subtypes of relapsed/refractory AML or ALL without active CNS involvement and after at least one prior line of therapy. Treatment with hydroxyurea during screening and cycle 1 is permitted to control white blood cell count. Patients with extramedullary disease are also eligible. Primary endpoints are safety and tolerability of AZD0466 in patients with acute leukemia. In dose escalation,