Updated Results of a Phase I Study of Uproleselan Combined with Azacitidine and Venetoclax for the Treatment of Older or Unfit Patients with Treatment Naïve Acute Myeloid Leukemia

Introduction: Azacitidine (AZA) plus venetoclax (VEN) is standard of care for induction chemotherapy (IC) ineligible AML and leads to a complete remission (CR) rate of 38.8% and CR plus CR with incomplete count recovery (CRi) rate of 66.8% (Pratz 2024). Achieving a measurable residual disease negative (MRD-ve) CR/CRi by multiparameter flow cytometry (MFC) leads to improved outcomes; however, only 42% of CR/CRi responders are MRD-ve. AZA/VEN leads to myelosuppression and dose modifications and delays in most patients (pts). Uproleselan (UPRO) is an E-selectin antagonist that improves responses in preclinical models, including with AZA +/- VEN. A Phase I/II study of UPRO combined with IC in AML established a recommended Phase II dose (RP2D) and showed clinical activity (DeAngelo 2022). We are testing the safety and preliminary efficacy of UPRO combined with AZA/VEN in pts with untreated AML ineligible for IC. Methods: This is a single center Phase I trial of UPRO with AZA/VEN in untreated older or unfit AML pts (NCT04964505), consisting of a dose optimization portion to confirm the RP2D UPRO dose, and a dose expansion cohort. We report results of the dose optimization and ongoing expansion cohorts. Key eligibility criteria included age ≥18 years, AML diagnosis by WHO criteria, and eligibility for frontline AZA/VEN. Pts received UPRO 800 mg IV q12h (RP2D) and AZA 75 mg/m2 IV/SC q24h for 7 days, and VEN 400 mg PO daily for up to 28 days in 28-day cycles. Treatment continued until progression, intolerance, or pt or investigator decision to discontinue treatment. Pts had a VEN ramp-up in cycle 1, including tumor lysis syndrome monitoring and prophylaxis. A bone marrow biopsy was done after every cycle until achieving morphologic leukemia-free state or better response (MLFS+). UPRO was given for up to 6 cycles, decreased to daily with AZA in cycles after achieving MLFS+, and pts could continue AZA/VEN after stopping UPRO. The primary objective was to determine safety and tolerability. Adverse events (AE) were monitored throughout treatment, and dose-limited toxicities (DLT) assessed in cycle 1. The secondary objective was to evaluate preliminary efficacy, including MRD-ve CR/CRi rate, as measured by MFC with a sensitivity of at least <0.1%. Descriptive statistics were used for data analysis. Results: As of July 1, 2024, 16 pts [56% female, median age 78.5 (range 70-86)] were enrolled in dose optimization (n=6) and dose expansion (n=10) cohorts. Seven (54%) had secondary AML, including 4 (25%) with therapy-related AML. Eleven (69%) had ELN 2017 adverse risk disease; 5 (31%) had complex cytogenetics. The most common mutations identified were RUNX1 (n=5), TP53, BCOR, and DNMT3A (n=4 each), NPM1, IDH2, and ASXL1 (n=3 each), and FLT3-ITD, TET2, DDX41, and NRAS (n=2 each). All pts completed cycle 1. Median time on study was 315 days (range 31-937). Pts received a median of 3 treatment cycles (range 2-12). No DLTs were observed. Thirty- and 60-day mortality was 0% and 6%, respectively. All pts had at least one treatment-emergent AE (TEAE). The most common TEAE regardless of grade and attribution included platelet count decreased (n=14), anemia (n=12), neutropenia (n=12), nausea (n=10), anorexia (n=8), constipation (n=7), diarrhea (n=6), and febrile neutropenia (n=6). Fifteen pts (94%) experienced at least one ≥grade 3 TEAE, with platelet count decreased (n=14), anemia (n=12), neutropenia (n=12), and febrile neutropenia (n=6) most common. Ten pts (63%) experienced treatment-emergent serious AEs (SAEs), including febrile neutropenia (n=4), platelet count decreased (n=4), and lung infection (n=2). There were three grade 5 events, sepsis, death NOS, and disease progression, all unrelated to UPRO. Two pts remain on study treatment, and 14 have discontinued study therapy [pt decision (n=8), progression (n=4), and death (n=2)]. All responding pts had dose modifications and/or cycle delays. All 16 pts had a MLFS+ response. Eleven (69%) achieved CR and three CRi (19%), for a total CR/CRi rate of 88%. Eleven CR/CRi occurred with cycle 1. Nine of the CR/CRi responders were MRD-ve, for an MRD-ve CR/CRi rate of 64%. Conclusions: Ongoing results from this Phase I study demonstrate feasibility of combining UPRO with AZA/VEN in pts with untreated AML ineligible for IC. No DLTs were observed, and the most common Grade 3-4 AE and SAE were hematologic. The combination shows promising preliminary efficacy, including a 64% rate of MRD-ve CR/CRi.