P537: SAFETY AND TOLERABILITY OF AZD0466 AS MONOTHERAPY FOR PATIENTS WITH ADVANCED HEMATOLOGICAL MALIGNANCIES - PRELIMINARY RESULTS FROM AN ONGOING PHASE I/II TRIAL (2023)

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). However, BCL2-selective inhibition can often lead to drug resistance mediated by upregulation of anti-apoptotic proteins such as BCLxl. To broaden therapeutic activity, we developed AZD0466, 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. 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. Clin Cancer Res 2020). Aims: To report preliminary data from an ongoing Phase 1/2 dose escalation and expansion study, NIMBLE - drug deNdrIMer targeting BCL2/xL in acute LEukemias (NCT04865419) - designed to evaluate preliminary safety and tolerability (primary objectives), and pharmacokinetics (PK) and preliminary efficacy (secondary objectives). Methods: Module 1, Part A dose escalation evaluated target doses of 300–3600mg, with escalation/de-escalation per a mTPI-2 design. AZD0466 is administered intravenously with a ramp-up on d1, d4, d8 in cycle 1, reaching target dose on d8, and weekly administrations thereafter. Duration of cycle 1 is 35 days; subsequent cycles are 28 days. Module 2 investigates drug-drug interactions between AZD0466 and voriconazole. Pts remain on study until progressive disease, withdrawal of consent, or unacceptable toxicity. Eligible pts are ≥18 years old with relapsed/refractory (R/R) acute leukemia without active CNS disease, or with intermediate- or high-risk myelodysplastic syndrome. We report results from Module 1, part A. Results: As of 24 Jan 2023, 24 pts (n=20 AML, n=4 ALL; median age 69.5 yrs; ECOG 1–2 in 67% of pts) had received ≥1 dose of AZD0466 (300mg, n=4; 600mg, n=4; 1200mg, n=7; 2400mg, n=4; 3600mg, n=5). Median treatment duration was 4.1 (0.9–8) weeks. No dose-limiting toxicities (DLTs) were observed in the DLT-evaluable population (n=19). Any-grade AZD0466-related adverse events (AEs) were reported for 50% of pts (n=12), with related AEs grade ≥3 in 25% (n=6) of pts and any AE leading to discontinuation in 1 pt. The most common related any-grade AEs were aspartate aminotransferase (n=5, 21%) and alanine aminotransferase level elevations (n=4, 17%), followed by febrile neutropenia (n=3, 13%) and diarrhea (n=2, 8%). Serious AZD0466-related AEs were reported in one pt (4%). One AE of intracranial bleeding deemed not related to AZD0466 was reported. As a marker of BCLxL on-target activity, transient worsening of thrombocytopenia post-dose, with rapid platelet recovery prior to the next dose, was observed. This was in line with preclinical modeling showing a decrease in platelets post-dose compared to pre-dose starting at lower doses (300/600mg), with a ceiling effect after 1200mg and little further reduction at higher doses. Among pts with ≥1 follow-up bone marrow (BM) assessment available, preliminary anti-leukemia activity based on BM blast reduction at 1200 and 2400mg was observed in 2 pts. Based on clinical and PK data, and comparison of exposures observed in the clinic and predicted from preclinical murine models, further dose escalation to 5400mg is planned to evaluate safety and clinical efficacy. Enrollment is ongoing. Summary/Conclusion: 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. Keywords: BCL-XL, ALL, BCL2, Acute myeloid leukemia