A Double-Blind, Placebo-Controlled, Phase 3 Registration Trial to Evaluate the Efficacy of Uproleselan (GMI-1271) with Standard Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia
Authors: DeAngelo Daniel J. , Erba Harry P. , Jonas Brian A , O'Dwyer Michael E , Marlton Paula , Huls Gerwin , Liesveld Jane L. , Cooper Brenda , Bhatnagar Bhavana , Uy Geoffrey L. , Cull Gavin , Armstrong Michael B. , Fogler William E. , Chen Mary M , Magnani John L. , Thackray Helen M , Feldman Eric J. , Advani Anjali S. , Becker Pamela S. 
Published: November 2019

Background
Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand, on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Higher expression of E-sel ligand is associated with relapse and poor survival. Uproleselan (GMI-1271), a novel E-selectin antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination of uproleselan with chemotherapy improves response without additional toxicity. A phase 1/2 study (NCT02306291) of uproleselan added to chemotherapy (mitoxantrone, etoposide, cytarabine, MEC) in R/R AML showed promising outcomes at the recommended phase 2 dose (RP2D), including a CR/CRi rate of 41% and median OS of 8.8 m (95% CI 5.7-11.4). 11/16 (69%) evaluable patients were MRD negative (DeAngelo et al ASH 2018). Patients with sufficient expression of the appropriate E-selectin ligand (the target of the E-selectin inhibitor) exhibited higher CR/CRi rate and longer survival. Median OS for Leukemic blasts/E-sel ligand ≥10% vs leukemic blasts/E-sel ligand <10% was 12.7m and 5.2 m, respectively (report in progress). Collectively, these data indicate that high E-sel ligand expression may contribute to clinical chemotherapy resistance, particularly increasing the risk of relapse, which can be reversed with E-sel inhibition. In addition, chemotherapy is well known to cause severe mucositis, with resultant infections, prolongation of hospital stay, morbidity and mortality, and a dramatic reduction in the expected incidence and severity of mucositis was seen with uproleselan in combination with MEC. At the RP2D, Grade 3/4 mucositis was 2%. Breakthrough Therapy Designation was granted by FDA for treatment of patients with R/R AML. A pivotal phase 3 study (NCT03616470) is underway. The aims of this phase 3, double-blind, placebo controlled study are to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML, evaluate the incidence of MRD, and assess for correlation of E-sel ligand expression on blasts with outcomes in R/R AML.
Study Design and Methods
This study is a global, randomized, double-blind, placebo-controlled phase 3 registration trial.
Major Eligibility Criteria ≥18 to ≤75 years old Primary refractory AML, first or second relapse of AML Prior transplant (HSCT) is allowed Must be medically eligible for chemotherapy ECOG performance status ≤2
Study treatment and endpoints
Treatment is MEC or FAI (fludarabine, cytarabine, idarubicin) induction with blinded study drug (uproleselan/placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HiDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, event free survival, safety, and pharmacokinetics will also be evaluated. In addition, the relationship between E-sel ligand expression on leukemic cells in the bone marrow and clinical outcomes in AML will be determined.
Statistical methods
The phase III primary endpoint will compare overall survival between the treatment arms using a stratified log-rank test. Stratification factors will be age group, disease status, backbone chemotherapy and prior transplant status. Median time to event values will be estimated using the Kaplan-Meier method. The study is powered to detect an improvement in median OS using a log-rank test (HR= 0.68, one-sided 0.025 type I error rate). A hierarchical testing procedure will be used to assess the statistical significance of the key secondary analyses, incidence of severe oral mucositis and remission rate (CR/CRh, CR).
Study status
This trial is expected to enroll 380 patients across approximately 9 countries in North America, Europe, and Australia. The first patient was enrolled in November 2018.

Disclosures
DeAngelo: Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Abbvie: Research Funding; GlycoMimetics: Research Funding; Celgene: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Shire: Consultancy. Erba:Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. O'Dwyer:AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Bhatnagar:Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Cull:Amgen: Other: Travel, accommodation ; AbbVie: Other: Travel, accommodation; Glycomimetics: Other: Travel, accommodation. Armstrong:GlycoMimetics: Consultancy. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Thackray:GlycoMimetics Inc: Employment. Feldman:GlycoMimetics Inc: Employment. Advani:Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.