Uproleselan + Chemotherapy for Leukemia

Not currently recruiting at 22 trial locations

Overseen By Maria L Sulis, MD

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Cyclosporine, Tacrolimus, others

Disqualifiers: CNS disease, APL, JMML, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 2 cycles

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment that combines uproleselan with the chemotherapy drugs fludarabine and cytarabine for certain types of leukemia, such as acute myeloid leukemia, that have returned or are not responding to treatment. Uproleselan enhances chemotherapy's effectiveness by preventing cancer cells from hiding in the bone marrow. The study aims to determine the safest dose and identify any side effects. It suits children and teens with specific types of relapsed or treatment-resistant leukemia that express a certain marker (E-selectin ligand) on their cells. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. For example, you must stop taking hydroxyurea at least 24 hours before the trial begins, and you cannot be on cyclosporine, tacrolimus, or other medications to prevent graft-versus-host disease. If you are on corticosteroids, you need to be on a stable or decreasing dose for at least 7 days before enrolling.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that uproleselan looks promising when used with chemotherapy. Studies have found that patients with acute myeloid leukemia (AML) generally tolerate it well when combined with other treatments. One study specifically confirmed that uproleselan is safe at a certain dose when used with other cancer drugs over a week.

Fludarabine, another drug in this trial, is effective but can cause serious side effects at high doses. Some leukemia patients have experienced severe effects on the nervous system.

Cytarabine, also part of this treatment, is known to be safe even at high doses for treating AML. It has been used in various settings, including outpatient care, without major risks.

Overall, while researchers continue to study uproleselan, both fludarabine and cytarabine have proven safety records in similar treatments. Participants should be aware of potential side effects, especially with fludarabine. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about uproleselan in combination with chemotherapy for leukemia because it offers a novel approach that targets a protein called E-selectin. Unlike standard chemotherapy drugs, which can sometimes struggle to effectively reach and kill all leukemia cells, uproleselan helps block these cells from sticking to the protective bone marrow environment where they can hide and resist treatment. This innovative mechanism has the potential to make chemotherapy more effective by preventing leukemia cells from escaping its effects. Additionally, with its intravenous delivery, uproleselan can be directly administered alongside traditional chemotherapy agents like cytarabine and fludarabine, which could enhance overall treatment outcomes.

What evidence suggests that this treatment might be an effective treatment for leukemia?

Research has shown that uproleselan, one of the treatments in this trial, can disrupt the processes that help acute myeloid leukemia (AML) cells survive when combined with chemotherapy. This may enhance the effectiveness of chemotherapy. In one study, 46.4% of participants with relapsed or hard-to-treat AML who received uproleselan experienced overall remission, with significant symptom improvement. Additionally, 67.1% of these patients had no minimal residual disease, indicating no tiny amounts of cancer remained after treatment. This suggests that uproleselan may help chemotherapy more effectively target and destroy leukemia cells. ^{6 7 8 9 10}

Who Is on the Research Team?

Maria Luisa Sulis, MD

Principal Investigator

Pediatric Early Phase Clinical Trial Network

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Your heart is pumping normally, with strong enough contractions, based on specific heart tests.

My platelet count is at least 25,000/uL.

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

Exclusion Criteria

Patients who have received a prior solid organ transplantation are not eligible

I have been diagnosed with acute promyelocytic leukemia.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive uproleselan in combination with fludarabine and cytarabine. Uproleselan is administered IV once daily on day 1 and twice daily on days 2-8. Fludarabine is administered IV once daily on days 2-6, and high dose cytarabine is administered IV once daily on days 2-6. Treatment repeats every 28 days for up to 2 cycles.

28 days per cycle, up to 2 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Fludarabine
• Uproleselan

Trial Overview 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.

How Is the Trial Designed?

Group I: Treatment (uproleselan, fludarabine, cytarabine) Experimental Treatment 5 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 will receive leucovorin PO or IV BID following each intrathecal administration of methotrexate.

Cytarabine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Children's Oncology Group

Collaborator

Trials

467

Recruited

241,000+

LLS PedAL LLC

Collaborator

Trials

1

Recruited

20+

Childrens Oncology Group (COG)

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

Combining low-dose fludarabine with arabinosylcytosine (ara-C) enhances the effectiveness of treatment for adult acute myelogenous leukemia, as fludarabine helps increase the accumulation of ara-C's active form.

The rationale for this combination therapy is that both drugs work together to inhibit DNA replication and repair, potentially leading to improved response rates in patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine for treatment of adult acute myelogenous leukemia. Gandhi, V.[2019]

In a case study of a patient with relapsed/refractory B-cell acute lymphoblastic leukemia, lymphodepletion using clofarabine and cyclophosphamide before CAR-T-cell therapy led to successful remission, demonstrating clofarabine's potential as an alternative to fludarabine.

Clofarabine did not impair the effectiveness of the CAR-T cells, as evidenced by the patient's cytokine release syndrome and the absence of minimal residual disease, indicating a successful treatment outcome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. Foti, A., Stein, D., Seidel, D., et al.[2023]

The DAF regimen, which includes daunorubicin, fludarabine, and cytarabine, showed a 56% overall response rate in 34 patients with relapsed or refractory acute myeloid leukemia (AML), with 15 out of 16 patients achieving complete remission after the first course.

The treatment was well tolerated, with severe neutropenia and serious infections occurring in a significant number of patients, but no severe long-term complications like liver or kidney failure were observed, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. Hołowiecki, J., Grosicki, S., Kyrcz-Krzemien, S., et al.[2013]

In a pilot study involving 17 patients with acute myeloid leukemia (AML), the combination of fludarabine, topotecan, and cytarabine (FTA) resulted in a 35% complete remission rate, indicating its potential efficacy in treating this condition.

However, the treatment was associated with significant side effects, as 41% of patients experienced severe diarrhea, highlighting the need for careful monitoring and further investigation of FTA's safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. Giles, FJ., Cortes, JE., Kantarjian, HM., et al.[2013]

In a study of 15 patients with refractory or relapsed acute myeloid leukemia (AML), high-dose cytarabine (ARA-36) achieved a complete remission rate of 60%, demonstrating significant efficacy as a salvage therapy.

Despite the promising remission rates, the one-year overall survival was only 54%, indicating that while ARA-36 is effective, the prognosis for these high-risk patients remains poor, with manageable but notable toxicities observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia--is more better or more of the same? Wolach, O., Itchaki, G., Bar-Natan, M., et al.[2019]

Citations

1. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper209097.html

733 Efficacy and Safety of Uproleselan Combined with ... Introduction: Uproleselan (GMI-1271) is an E-selectin antagonist that disrupts AML cell survival pathways, overcomes chemotherapy resistance, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11017789/

Phase 1/2 study of uproleselan added to chemotherapy in ... Among the 25 newly diagnosed patients who received uproleselan at 10 mg/kg in combination with 7 + 3, the median OS rate was 12.6 months (95% CI, 9.9 to not ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03616470

Study to Determine the Efficacy of Uproleselan (GMI-1271) ... This study will evaluate the efficacy of uproleselan (GMI-1271), a specific E-selectin antagonist, in combination with chemotherapy to treat ...

4. healthtree.org healthtree.org/aml/community/articles/ash-24-uproleselan-for-relapsed-refractory-aml

Uproleselan for Relapsed/Refractory AML 46.4% of people who received uproleselan had an overall remission · Minimal residual disease (MRD) was negative in 67.1% of those treated with ...

5. cancernetwork.com cancernetwork.com/view/uproleselan-does-not-reach-os-end-point-shows-select-efficacy-in-aml

Uproleselan Does Not Reach OS End Point, Shows Select ... Phase 3 data show meaningful benefits with uproleselan in patients with primary refractory AML and post-transplant survival.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40348597/

The Clinical Safety and Efficacy of Cytarabine ... Results: CPX-351 exhibited an adverse event profile that was comparable to that of conventional chemotherapy. It resulted in complete remission rates of 18%-41% ...

7. ashpublications.org ashpublications.org/ashclinicalnews/news/8741/Intermediate-Dose-of-Cytarabine-as-Effective-as

Intermediate Dose of Cytarabine as Effective as Higher Dose ... Cytarabine-based induction therapy of AML results in remission rates of 60% to 80%; however, the remissions are short-lived. Intensification ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.77.6112

CPX-351 (cytarabine and daunorubicin) Liposome for ... CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML.

9. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.70024

Outpatient cytarabine consolidation in acute myeloid leukemia ... Outpatient cytarabine consolidation for select patients is safe and cost-effective without an increased risk of major treatment ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S253113792300161X

Toxicity and outcome of adults with acute myeloid leukemia ... In conclusion, our data suggest that high-dose of cytarabine (18 g/m2) is a safe option after induction of AML. Conflicts of interest. None. Recommended ...