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:

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 I/II study of UPRO combining with IC in AML pts established a recommended Phase II 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 I 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 four (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 one 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 one death from sepsis in the first 60 days. All pts had at least one 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 one ≥grade 3 TEAE, with anemia (n=6), thrombocytopenia (n=6), neutropenia (n=4), and febrile neutropenia (n=2) most common. Four pts (50%) experienced nine total serious AEs (SAEs), including thrombocytopenia (n=2). There were two grade 5 events, sepsis and AML disease progression, both unrelated to UPRO. Two pts remain on study treatment, and six 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 one CRi, for a total CR/CRi rate of 75%, and two 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 I study reveals 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.