Uproleselan + Chemotherapy for Leukemia

Recruiting at 20 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

8 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Uproleselan + Chemotherapy for Leukemia?

Research shows that combining fludarabine with cytarabine (a chemotherapy drug) can be effective in treating relapsed or refractory acute leukemias, with studies reporting complete remission in a significant number of patients. This suggests that the combination of these drugs, which are part of the Uproleselan + Chemotherapy regimen, may be effective in treating leukemia. ^{1 2 3 4 5}

What safety data exists for Uproleselan + Chemotherapy for Leukemia?

The combination of fludarabine and cytarabine, often used in leukemia treatments, has been shown to have manageable side effects such as anemia, fever, and infections. High-dose cytarabine can cause serious side effects like severe infections and low blood cell counts, but these are generally considered acceptable for the potential benefits in treating relapsed or refractory leukemia. ^{1 3 6 7 8}

What makes the drug Uproleselan + Chemotherapy unique for treating leukemia?

Uproleselan combined with chemotherapy is unique because it includes Uproleselan, which is not commonly used in standard leukemia treatments, potentially offering a novel mechanism of action. This combination may enhance the effectiveness of traditional chemotherapy drugs like Cytarabine and Fludarabine by targeting specific pathways in leukemia cells. ^{1 2 3 9 10}

Research Team

Maria Luisa Sulis, MD

Principal Investigator

Pediatric Early Phase Clinical Trial Network

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 only) receive leucovorin PO or IV BID on days 1, 8, 15, 22, and 29.

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+

Findings from Research

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]

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]

References

1. India pubmed.ncbi.nlm.nih.gov

The Efficacy of Fludarabine, High Dose Cytosine Arabinoside with Granulocyte Colony Stimulating Factor (FLAG) Protocol as Salvage Therapy for Refractory/Relapsed Acute Leukemias in Adult Iraqi Patients. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and pharmacodynamic studies of fludarabine and cytosine arabinoside administered as loading boluses followed by continuous infusions after a phase I/II study in pediatric patients with relapsed leukemias. The Children's Cancer Group. [2016]

3. Germany 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. [2013]

4. England pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. [2021]

6. England 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? [2019]

7. Japan pubmed.ncbi.nlm.nih.gov

Phase I trial of FLAGM with high doses of cytosine arabinoside for relapsed, refractory acute myeloid leukemia: study of the Japan Adult Leukemia Study Group (JALSG). [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

Phase II study of FLAGM (fludarabine + high-dose cytarabine + granulocyte colony-stimulating factor + mitoxantrone) for relapsed or refractory acute myeloid leukemia. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

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

10. United States pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. [2023]