NCT05146739

Highest Dose of Uproleselan in Combination With Fludarabine and Cytarabine for Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Mixed Phenotype Acute Leukemia Relapsed or Refractory That Expresses E-selectin Ligand on the Cell Membrane

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

• Status: Active Not Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 8 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 17 Years
• Healthy volunteers: Not accepted

Summary

This phase I trial tests the safety, side effects, and determination of the best dose of uproleselan in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia, myelodysplastic syndrome or mixed phenotype acute leukemia that has come back (relapsed) or does not respond to treatment (refractory) and that expresses E-selectin ligand on the cell membrane. Uproleselan binds to E-selectin expressed on endothelial cells of the bone marrow and prevents their interaction with selectin-E ligand-expressing cancer cells. This may prevent leukemia cells from being sequestered in the bone marrow niche and escaping the effect of chemotherapy. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving uproleselan in combination with fludarabine and cytarabine may expose more cancer cells to the effect of chemotherapy.

Detailed description

PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose or recommended Phase 2 dose of uproleselan (GMI-1271) administered in combination with fludarabine and cytarabine to patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or mixed phenotype acute leukemia (MPAL) whose blasts express the E-selectin ligand and that are in second or greater relapse or refractory to relapse therapy. II. To characterize the pharmacokinetics of uproleselan (GMI-1271) in combination with fludarabine and cytarabine in patients with refractory and/or relapsed AML, MDS or MPAL. III. To define and describe the toxicities of uproleselan (GMI-1271) in combination with fludarabine and cytarabine among patients with relapsed and/or refractory AML, MDS or MPAL. SECONDARY OBJECTIVES: I. To describe the expression of E-selectin ligand on the surface of myeloid leukemic blasts at relapse prior to initiation of uproleselan (GMI-1271) in combination with fludarabine and cytarabine and at completion of the cycle. II. To describe the antileukemic activity of uproleselan (GMI-1271) (Children's Oncology Group \[COG\]-complete remission \[CR\]/CR with partial recover of platelet count \[CRp\]/CR with incomplete blood count recovery \[CRi\] and rates of minimal residual disease \[MRD\] negative response after up to two cycles of therapy) in combination with fludarabine and cytarabine within the limits of a Phase 1 study. EXPLORATORY OBJECTIVE: I. To determine the largest relative reduction in myeloid leukemic blast percentage in the bone marrow, calculated from baseline at time of enrollment to up to two cycles of therapy. OUTLINE: This is a dose escalation study of uproleselan. Patients receive uproleselan intravenously (IV) once daily (QD) over 20 minutes on day 1 and IV over 20 minutes twice daily (BID) on days 2-8, fludarabine IV QD over 30 minutes on days 2-6, and high dose cytarabine IV QD over 1-3 hours on days 2-6. Patients also receive cytarabine intrathecal therapy (IT) or intrathecal triple therapy (ITT) on day 0. CNS2 and CNS3 patients receive additional cytarabine IT or ITT once weekly starting on day 7-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with Down syndrome will receive leucovorin orally (PO) or IV BID following each intrathecal administration of methotrexate.

Conditions

• Acute Myeloid Leukemia Post Cytotoxic Therapy
• Myelodysplastic Syndrome Post Cytotoxic Therapy
• Myeloid Leukemia Associated With Down Syndrome
• Recurrent Acute Myeloid Leukemia
• Recurrent Mixed Phenotype Acute Leukemia
• Recurrent Myelodysplastic Syndrome
• Refractory Acute Myeloid Leukemia
• Refractory Mixed Phenotype Acute Leukemia
• Refractory Myelodysplastic Syndrome

Interventions

Type	Name	Description
DRUG	Cytarabine	Given IV and IT
DRUG	Fludarabine	Given IV
DRUG	Leucovorin	Give PO or IV
DRUG	Triple Intrathecal Chemotherapy	Given IT
DRUG	Uproleselan	Given IV

Timeline

• Start date: 2023-10-10
• Primary completion: 2025-03-31
• Completion: 2026-05-09
• First posted: 2021-12-07
• Last updated: 2025-11-12

Locations

19 sites across 1 country: United States

Regulatory

• FDA-regulated drug study