P579: safety, tolerability, pharmacokinetics, and preliminary antitumor activity of azd5991 in relapsed/ refractory hematologic malignancies: a phase 1 first-in-human study

Background: Myeloid cell leukemia 1 protein (MCL-1) plays an important role in tumor cell survival, progression, and resistance to therapies, including venetoclax. AZD5991 is a BH3 mimetic with a nanomolar potency against human MCL-1 and selectivity over other BCL-2 family members. Aims: The aim of this study was to assess the safety, tolerability, pharmacokinetics (PK), and antitumor activity of AZD5991 monotherapy and in combination with venetoclax in patients (pts) with relapsed or refractory (R/R) hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). Methods: This was an open-label, nonrandomized, first-in-human study. In the monotherapy cohort (dose escalation starting at 100 mg), AZD5991 was administered intravenously in escalating doses either once or twice weekly (QW or BIW), following intrapatient dose escalation on a 3-week cycle. In the combination cohort, pts with R/R AML or MDS received escalating doses of AZD5991 (starting at 150 mg QW) and venetoclax (200 or 400 mg once daily) on either a 3-week or a 4-week cycle. Primary objectives were to determine the safety and maximum tolerated dose, and secondary objectives were to assess plasma PK and antitumor activity. Informed consents were obtained from all patients. Results: As of April 26, 2022, 78 pts were treated (AZD5991 monotherapy, n=61; AZD5991 + venetoclax, n=17). 38 pts had AML, 5 MDS, 12 MM, 6 DLBCL, 5 CLL, 4 Richter’s syndrome, 4 MCL, 2 CTCL, 1 FL, and 1 WM. The most frequently reported (≥25%) treatment-emergent adverse events (TEAEs) in all enrolled pts were diarrhea (59.0%), nausea (55.1%), vomiting (47.4%), hypokalemia (29.5%), and fatigue (25.6%). Grade (G) ≥3 TEAEs occurred in 75.6% of pts; febrile neutropenia (17.9%) and anemia (15.4%) were the most common heme G ≥3 TEAEs; and sepsis (11.5%) and pneumonia (7.7%) were the most common nonheme G ≥3 TEAEs. There were 4 deaths due to TEAEs; one was G5 tumor lysis syndrome (TLS) related to AZD5991. Dose-limiting toxicities occurred in 5 pts (G3 febrile neutropenia, 250 mg QW; G3 sepsis, 400 mg QW; G5 TLS, 800 mg QW; G2 myocarditis, 600 mg BIW; G3 troponin I increased, 400 mg QW + venetoclax). Three of 5 patients with MDS achieved an objective response [complete response (CR) + hematologic improvement (HI)]: 2 (1 CR, 1 HI) in AZD5991 monotherapy, and 1 (CR) in AZD5991 + venetoclax. No objective response was observed in all other histologies. Asymptomatic elevations of conventional and high-sensitivity troponin I or T with no related ECG changes were observed in 8 (10.3%) pts. Three pts discontinued treatment due to AZD5991-related increase in troponin. Subsequently, we performed a post hoc retrospective analysis using stored plasma PK samples from 66 pts (377 samples at different time points before and after AZD5991 treatment) to better characterize the incidence of asymptomatic troponin elevations. High-sensitivity troponin T was elevated in 7/18 (39%) pts prior to any study treatment and in 54/65 (83%) of pts after any AZD5991 dose at cycle 1 and beyond. Troponin elevations were independent of age, gender, histology, and other patient characteristics, or AZD5991 exposure. In a multivariate analysis, there were no associations between elevated troponin and cardiovascular risk factors. Summary/Conclusion: Systemic administration of the MCL-1 inhibitor AZD5991 is associated with high incidence of laboratory troponin elevation while producing a low overall response rate. This unfavorable risk/benefit ratio led to study closure. Keywords: MDS/AML, Safety, Phase I, Hematological malignancy