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2764 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

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Brian A. Jonas, MD, PhD1, Jeanna L Welborn, MD2, Naseem S Esteghamat, MD3, Rasmus T Hoeg, MD3*, Aaron S Rosenberg, MD3, Laura Molnar, CCRP4*, Ashley Linh Dang-Chu, CCRP4*, Susan L Stewart, PhD5* and Joseph M Tuscano, MD3

1Department of Internal Medicine, Division of Malignant Hematology, Transplantation and Cellular Therapy, University of California Davis School of Medicine, Sacramento, CA
2Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento, CA
3Department of Internal Medicine, Division of Cellular Therapy, Bone Marrow Transplantation and Malignant Hematology, University of California Davis School of Medicine, Sacramento, CA
4UC Davis Comprehensive Cancer Center, Sacramento, CA
5Division of Biostatistics, University of California Davis, Sacramento, CA


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.


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.


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.


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.

Disclosures: Jonas: Pfizer: Consultancy, Research Funding; Servier: Consultancy; Jazz: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; 47: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Accelerated Medical Diagnostics: Research Funding; Amgen: Research Funding; AROG: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Roche: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; LP Therapeutics: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; AbbVie: Consultancy, Other: Travel Reimbursement, Research Funding; Rigel: Consultancy, Other: Travel Reimbursement. Esteghamat: Seagen: Speakers Bureau. Hoeg: Orca Bio: Research Funding. Rosenberg: Janssen, Takeda: Speakers Bureau; Bristol Myers Squib: Research Funding; Kangpu: Other: Institutional Research; Takeda: Other: Institutional Research; Adaptive: Consultancy. Tuscano: BMS: Research Funding; ADC therapeutics: Research Funding; Achrotech: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene: Research Funding.

*signifies non-member of ASH