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

Background
- VIALE-A established azacitidine (AZA) with venetoclax (VEN) as a standard of care for AML ineligible for induction chemotherapy (IC).
- Patients (Pts) who achieved a measurable residual disease (MRD) negative complete remission (CR) or CR with incomplete count recovery (CRi) by multiparameter flow cytometry (MFC) had improved outcomes; however, only 41% of CR/CRi responders achieved MRD negativity.
- Uproleselan (UPRO) is a novel E-selectin antagonist that disrupts cell survival pathways and improves chemotherapy responses in preclinical models, including in combination with AZA +/- VEN.
- A phase 1/2 study of UPRO combining with IC in AML pts established a recommended phase 2 dose (RP2D).
- UPRO was associated with higher CR/CRi and MRD negative (MRD-ve) rates, lower induction mortality, and less severe mucositis compared to historical controls.
- We are exploring the combination of UPRO with AZA/VEN to improve outcomes in pts with untreated AML ineligible for standard IC.

Methods
- This ongoing single center phase 1 trial of frontline UPRO in combination with AZA/VEN in older or unfit AML pts (NCT04964505) consists of a dose optimization portion, using a modified 3+3 dose optimization design to confirm the RP2D UPRO dose level (800 mg IV q12h for 7 days), and a dose expansion cohort.
- We report results of the dose optimization portion and initial expansion phase subjects. 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 and AZA 75 mg/m2 IV/SC q24h for 7 days, and VEN 400 mg PO daily for 28 days in 28-day cycles.
- Treatment continued until progression, intolerance, or patient decision to stop.
- 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 morphologic leukemia-free state or better response (MLFS+). UPRO was given for up to 6 cycles with dosing decreased to daily after achieving MLFS+.
- 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, notably MRD-ve CR/CRi rate, as measured by MFC.

Results

- As of June 26, 2022, 8 pts [75% female, median age 78 (range 70-81)] were enrolled in the dose optimization (n=6) and dose expansion (n=2) portions of the study.
- Four (50%) had de novo AML and 4 (50%) had secondary AML, including 3 (38%) with therapy-related AML. Six (75%) had ELN 2017 adverse risk disease; 3 (38%) had complex cytogenetics.
- The most common mutations identified were RUNX1 (n=4), BCOR (n=2) and TET2 (n=2), and 1 patient each had TP53, NPM1, FLT3-ITD, or IDH2 mutations.
- All pts completed cycle 1. Median time on study is currently 126 days (range 32-179). Pts received a median of 3 treatment cycles (range 1-6). No DLTs were observed.
- There were no deaths in the first 30 days from treatment initiation; there was 1 death from sepsis in the first 60 days.
- All pts had at least 1 treatment-emergent AE (TEAE). The most common TEAE, regardless of grade and attribution, included anemia (n=6), thrombocytopenia (n=6), anorexia (n=4), nausea (n=4), neutropenia (n=4), fatigue (n=3), hypocalcemia (n=3), and hyponatremia (n=3). All pts experienced at least 1 ≥grade 3 TEAE, with anemia (n=6), thrombocytopenia (n=6), neutropenia (n=4), and febrile neutropenia (n=2) most common. Four pts (50%) experienced 9 total serious AEs (SAEs), including thrombocytopenia (n=2).
- There were 2 grade 5 events, sepsis and AML disease progression, both unrelated to UPRO.
- Two pts remain on study treatment, and 6 have discontinued study therapy [patient decision (n=4) and death (n=2)]. All pts with an MLFS+ had dose modifications and/or cycle delays.
- All 8 pts had a MLFS+ response. Five (63%) achieved CR and 1 CRi, for a total CR/CRi rate of 75%, and 2 achieved MLFS. Five CR/CRi responses occurred with cycle 1. Four of the CR/CRi responses were MFC MRD-ve, for an overall MRD-ve CR/CRi rate of 50% and 67% among the CR/CRi responders.

Conclusions

- Preliminary results from this phase 1 study reveal a tolerable safety profile of 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 50% rate of MRD-ve CR/CRi.

Reference
Jonas BA, Welborn JL, Esteghamat NS, et al. 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. Abstract presented at: 64th Annual ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.