Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial (2022)

Background: Anti-apoptotic proteins of the BcL-2 family such as Bcl-2 and Bcl-xL are critical to tumor survival and are associated with resistance to anticancer therapy. 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. Dual inhibition of Bcl-2 and Bcl-xL therefore has potential for broader activity than is observed with Bcl-2-specific inhibitors such as venetoclax. AZD0466 is a drug-dendrimer conjugate in which the Bcl-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Release of AZD4320 results in lower peak plasma levels compared to direct infusion of AZD4320 at similar concentrations, reducing the potential for the on-target toxicity associated with Bcl-xL inhibition (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). AZD0466 has shown preclinical efficacy in solid (Arulananda et al. Cell Death Discov 2021) and hematological malignancies (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). Preliminary results from the first-in-human study (NCT04214093) in advanced solid malignancies indicated that AZD0466 is well tolerated; no dose-limiting toxicities (DLTs) were reported. Here, we present preliminary data from an ongoing phase I trial of AZD0466 in patients with advanced hematological malignancies (NCT04865419). Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II trial. Module 1 is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of AZD0466 as monotherapy in adults with relapsed/refractory AML, acute lymphocytic leukemia (ALL), or higher risk myelodysplastic syndrome who have received ≥1 prior line of therapy, have no standard-of-care treatment available, and have no active CNS involvement. No minimum platelet count at study entry was specified and transfusions were permitted as part of supportive care. Module 1, Part A is a dose escalation study evaluating the safety and tolerability of AZD0466 monotherapy. The selected starting dose is AZD0466 300 mg IV; decisions on escalation and de-escalation are based on a mTPI-2 design (Guo et al. Contemp Clin Trials 2017;58:23-33). AZD0466 administration starts with a dose ramp-up with administration on days 1, 4, and 8 of cycle 1, followed by weekly IV administration at the target dose. The duration of Cycle 1 is 35 days, while subsequent cycles of 28 days. All patients are treated until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary objectives of Module 1A are DLT (according to predefined criteria and occurring during cycle 1), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary objectives include assessment of PK parameters for total and released plasma AZD4320. Results: As of May 31, 2022, 9 patients had been treated (55% male; median age, 70 years). Patients received AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), or 1200 mg (n=1). The safety analysis set consists of 9 patients and the DLT-evaluable set of 7 patients. No DLTs have been observed. All patients experienced at least one adverse event (AE). Five patients experienced AEs possibly related to treatment (grade 3 febrile neutropenia event, n=1; grade 3 gamma-glutamyltransferase increase, n=1; grade 2 sinus tachycardia, n=1; grade 1 aspartate aminotransferase increase, n=3; grade 1 alanine aminotransferase increase, n=2; grade 1 abnormal coagulation test, lactate dehydrogenase increase and alkaline phosphatase increase, all n=1). Four serious AEs occurred, none of which was treatment related. No AZD0466 discontinuations due to AEs have been observed. There were no thrombocytopenia events considered related to AZD0466 at the doses given. 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. Conclusions: 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.