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.

Jonas:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kymera: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Other: Travel; Amgen: Research Funding; AROG: Research Funding; Aptose: Research Funding; Celgene: Research Funding; F. Hoffman-La Roche: Research Funding; Forma Therapeutics: Research Funding; Forty-Seven: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Loxo Oncology: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; Treadwell: Research Funding. Abedi:BMS, Autolus: Consultancy; Orca Bio: Research Funding; Autolus, BMS and Gilead Sciences: Research Funding; AbbVie, BMS and Gilead Sciences: Speakers Bureau; CytoDyn: Current holder of stock options in a privately-held company. Esteghamat:Seagen: Ended employment in the past 24 months, Speakers Bureau. Rosenberg:BMS: Consultancy; Pfizer: Consultancy; Biomea: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Kangpu Pharmaceuticals: Research Funding. Tuscano:Pharmacyclics: Research Funding; ADC therapeutics: Research Funding; Genentech: Research Funding; BMS: Research Funding; Regeneron: Research Funding; Abbvie: Research Funding.