What side effects are associated with this type of intervention?

Common treatments for Acute Leukemia, such as fludarabine and cytarabine, often cause side effects including myelosuppression (neutropenia, anemia, thrombocytopenia), gastrointestinal symptoms (nausea, vomiting, diarrhea), and increased risk of infections due to immunosuppression. Uproleselan, which is being studied to enhance chemotherapy efficacy by preventing leukemia cells from interacting with the bone marrow niche, may also have side effects, potentially related to vascular or endothelial cell-related issues.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of acute leukemia that enhance chemotherapy efficacy or target specific mechanisms in cancer cells. Notably, gemtuzumab ozogamicin (GO) is an antibody-drug conjugate that targets CD33 on leukemia cells, enhancing the efficacy of chemotherapy. Venetoclax, a BCL-2 inhibitor, and glasdegib, a hedgehog pathway inhibitor, have also been approved for newly diagnosed acute myeloid leukemia (AML), particularly in older patients or those unfit for intensive chemotherapy. These drugs, like Uproleselan, aim to improve treatment outcomes by targeting specific pathways or interactions in leukemia cells.

What other types of research exist?

Promising novel alternatives to Uproleselan for Acute Leukemia patients include: 1) Venetoclax, an orally available BCL2 inhibitor, which has shown efficacy in combination with low-dose cytarabine (LoDAC) for initial treatment of AML. 2) Vorinostat, a histone deacetylase inhibitor, which has been studied in combination with idarubicin and cytarabine for newly diagnosed AML. Both alternatives have demonstrated potential in clinical trials and could be considered for treatment in 2024.

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Anti-metabolites

Uproleselan + Chemotherapy for Leukemia

Q: What is the mechanism of action of this treatment?

Common treatments for Acute Leukemia include chemotherapy, hypomethylating agents, and targeted therapies like Uproleselan. Chemotherapy drugs, such as fludarabine and cytarabine, work by killing cancer cells or stopping them from dividing. Hypomethylating agents alter the DNA methylation of leukemia cells, targeting leukemia stem cells and altering their metabolic environment. Uproleselan, a targeted therapy, binds to E-selectin on endothelial cells, preventing leukemia cells from interacting with the bone marrow niche, thereby enhancing the efficacy of chemotherapy. These treatments are crucial as they address different aspects of leukemia cell survival and proliferation, improving patient outcomes by reducing resistance and relapse rates.

Phase 1

Waitlist Available

Led By Maria Luisa Sulis

Research Sponsored by Children's Oncology Group

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life

Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

Must not have

Patients with acute promyelocytic leukemia (APL)

Patients who have an uncontrolled infection are not eligible

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to cycle 1 (28 days)

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a new drug called uproleselan combined with two chemotherapy drugs in patients whose leukemia has come back or doesn't respond to treatment. Uproleselan helps make the cancer cells more vulnerable to chemotherapy by preventing them from hiding in the bone marrow.

Who is the study for?

This trial is for patients under 18 with acute myeloid leukemia, myelodysplastic syndrome, or mixed phenotype acute leukemia that's relapsed or refractory and expresses E-selectin ligand. They must have recovered from previous cancer treatments, meet specific blood count criteria, and not been exposed to uproleselan before. Pregnant individuals or those unable to follow the study plan are excluded.

What is being tested?

The trial tests the highest safe dose of uproleselan combined with fludarabine and cytarabine in young patients whose leukemia cells express a certain protein. The goal is to see if this combination can better target cancer cells in the bone marrow compared to standard chemotherapy alone.

What are the potential side effects?

Potential side effects may include reactions at the infusion site, changes in blood counts leading to increased infection risk, liver issues indicated by altered blood tests, heart function changes detectable by echocardiogram or radionuclide study, fatigue, nausea, and potential risks during pregnancy.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My condition has no cure or treatments that would extend life with good quality.

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My bilirubin levels are within the normal range for my age.

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My cancer returned outside the bone marrow after a complete remission.

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I have had a stem cell transplant, with or without full-body radiation.

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My leukemia has not responded to treatment after a second relapse.

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I can perform most of my daily activities without assistance.

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I am under 18 years old.

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My kidney function is normal or near normal.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been diagnosed with acute promyelocytic leukemia.

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I do not have any infections that are not under control.

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I have been diagnosed with juvenile myelomonocytic leukemia.

Select...

I am not taking medication to prevent graft-versus-host disease after a bone marrow transplant.

Select...

My cancer has only returned in my brain or testicles and is not responding to treatment.

Select...

I have a genetic condition that affects my bone marrow.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to cycle 1 (28 days)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to cycle 1 (28 days)

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to cycle 1 (28 days) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Area under the plasma concentration versus time curve of uproleselan

Dose limiting toxicity of uproleselan

Elimination half-life of uproleselan

+2 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (uproleselan, fludarabine, cytarabine)Experimental Treatment5 Interventions

Patients receive uproleselan IV QD over 20 minutes on day 1 and IV over 20 minutes 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 IT on day 0 then weekly starting on day 7-28 or ITT on day 0 then 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 only) receive leucovorin PO or IV BID on days 1, 8, 15, 22, and 29.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Fludarabine

2012

Completed Phase 4

~1860

Cytarabine

2016

Completed Phase 3

~3330

Leucovorin

2005

Completed Phase 4

~6010

Uproleselan

2021

Completed Phase 2

~100

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Acute Leukemia include chemotherapy, hypomethylating agents, and targeted therapies like Uproleselan. Chemotherapy drugs, such as fludarabine and cytarabine, work by killing cancer cells or stopping them from dividing. Hypomethylating agents alter the DNA methylation of leukemia cells, targeting leukemia stem cells and altering their metabolic environment. Uproleselan, a targeted therapy, binds to E-selectin on endothelial cells, preventing leukemia cells from interacting with the bone marrow niche, thereby enhancing the efficacy of chemotherapy. These treatments are crucial as they address different aspects of leukemia cell survival and proliferation, improving patient outcomes by reducing resistance and relapse rates.

Acute Myeloid Leukemia Chemo-Resistance Is Mediated by E-selectin Receptor CD162 in Bone Marrow Niches.Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance.Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective?