Current Research Studies

PEPN2113, A Phase 1 and Pharmacokinetic Study of Uproleselan (GMI-1271, NSC #801708) in Combination with Fludarabine and Cytarabine for Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Mixed Phenotype Acute Leukemia That Expresses E-selectin Ligand on the Cell Membrane and is in Second or Greater Relapse or that is Refractory to Relapse Therapy


What is the goal of the study?

The survival of children with relapsed acute myeloid leukemia (AML) has not improved over the past decades and remains dismal. Novel therapeutic strategies with tolerable side effects are needed. While most novel therapeutic approaches have attempted to target leukemic cell-intrinsic genomic defects, it is becoming evident that extrinsic factors such as the bone marrow microenvironment also plays a significant role. E-selectin is an adhesion molecule implicated in cancer progression, development of metastases and adhesion mediated chemotherapy resistance. Preclinical in vivo studies have shown that the bone marrow microvasculature of mice with AML have 5-10 fold higher expression of E-selectin compared to healthy mice and that AML blasts cells, which almost universally express the E-selectin ligand, are able to bind E-selectin more efficiently than normal hematopoietic cells. Uproleselan (GMI-1271) is a selective E-selectin competitive inhibitor which antagonizes the binding of the ligand to E-selectin. In vivo studies have shown that treatment with GMI-1271 in combination with cytarabine and/or daunorubicin reverses chemotherapy resistance and allows longer disease-free survival in an MLL-AF9 AML mouse model compared to mice treated with chemotherapy only or vehicle. The mechanism underlying the increased sensitivity to chemotherapy when GMI-1271 is used, is unclear but it appears to be related to the release of AML blasts and leukemia-initiating cells from the bone marrow niche to the peripheral blood. GMI-1271 has been studied in combination with mitoxantrone and cytarabine in adult patients with relapsed and refractory AML and in combination with daunorubicin and cytarabine in adult patients with newly diagnosed AML. GMI-1271 was well tolerated with no dose limiting toxicities reported at any of the tested dose levels and a maximum tolerated dose was not identified. Rates of responses compared favorably with historical controls and appeared to be related to the functional binding of E-selectin ligand expressed on the AML blasts to E-selectin expressed on the endothelial cells of the bone marrow. Importantly, and as also reported in the preclinical studies, the incidence of mucositis and related infectious events was significantly lower than in historical controls. A randomized phase 3 trial of GMI-1271 with chemotherapy in adult patients with relapsed and newly diagnosed and relapsed AML is ongoing. This is a Phase 1 and pharmacokinetic study of GMI-1271 in combination with fludarabine and cytarabine for children with relapsed and refractory AML, MDS (myelodysplastic syndrome) and MPAL (mixed phenotype acute leukemia) whose blasts express the E-selectin ligand. Patients are allowed to receive up to two cycles of therapy. Once the MTD and /or RP2D is determined, an expansion cohort will further assess the safety and preliminary activity of this combination.

Who can participate in the study?

Please contact the study team listed below to learn more.

Study Team: