Daunorubicin + Cytarabine ± Uproleselan for Acute Myeloid Leukemia

Not currently recruiting at 217 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Hypomethylating agents

Disqualifiers: CNS involvement, FLT3 mutation, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining chemotherapy drugs, daunorubicin and cytarabine, with or without an additional drug called uproleselan, in treating acute myeloid leukemia (AML). The researchers aim to determine if adding uproleselan prevents the cancer from returning or worsening. Participants may qualify if they have AML and have not received specific prior treatments for it. The study focuses on the treatment's effectiveness in older adults with this condition. As a Phase 2, Phase 3 trial, it evaluates the treatment's efficacy in a larger group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you should not have had prior chemotherapy for certain conditions like myelodysplastic syndrome or acute myeloid leukemia, except for specific treatments like emergency leukapheresis or hydroxyurea.

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

Research has shown that adding uproleselan to the chemotherapy drugs daunorubicin and cytarabine is generally well-tolerated by patients with acute myeloid leukemia (AML). In a study with 25 patients, this combination did not cause any unexpected side effects. Most side effects resembled those seen with standard chemotherapy treatments.

Daunorubicin and cytarabine, the other drugs in this trial, have long been used to treat AML. They have known side effects, but doctors can manage these effectively. Overall, research suggests that the combination of these drugs, including uproleselan, is manageable for most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore the addition of uproleselan to the standard chemotherapy regimen for Acute Myeloid Leukemia (AML). Uproleselan is unique as it targets E-selectin, a molecule that helps cancer cells stick to bone marrow, potentially making the cancer cells more vulnerable to chemotherapy. While standard treatments for AML, like the combination of daunorubicin and cytarabine, focus on killing cancer cells directly, uproleselan may enhance the effectiveness of these drugs by disrupting the protective environment of the cancer cells. This approach could lead to better patient outcomes by improving the response to treatment and reducing the chances of relapse.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that combining daunorubicin and cytarabine effectively treats acute myeloid leukemia (AML). In this trial, one group of participants will receive this combination, while another group will receive daunorubicin, cytarabine, and uproleselan. Studies suggest that adding uproleselan might offer additional benefits. In some trials, patients who received uproleselan with chemotherapy lived about 13 months on average, compared to 12.3 months with chemotherapy alone. However, the improvement in overall survival with uproleselan was not substantial. Some evidence indicates that uproleselan might be more beneficial for certain AML cases, such as those resistant to initial treatment. While uproleselan shows promise, it is not yet a major breakthrough for all AML patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Geoffrey L Uy

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for older adults with acute myeloid leukemia (AML), excluding those with certain types of AML like acute promyelocytic leukemia. Participants must not have a specific mutation in the FLT3 gene and should show no signs of AML in their central nervous system. They can receive emergency treatments like leukapheresis, hydroxyurea, or a single dose of intrathecal chemotherapy.

Inclusion Criteria

My acute myeloid leukemia has not spread to my brain or spinal cord.

I am 60 years old or older.

Total bilirubin =< 3 x upper limit of normal (ULN)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive induction chemotherapy with daunorubicin and cytarabine, with or without uproleselan, to achieve remission

1-2 weeks

Daily visits for drug administration

Consolidation

Patients receive consolidation therapy with cytarabine, with or without uproleselan, to maintain remission

Up to 3 cycles of 4 weeks each

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 2 months for 1 year, every 3 months in year 2, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Daunorubicin
• Uproleselan

Trial Overview The study compares the effectiveness of two treatment methods for AML: one group receives daunorubicin and cytarabine alone, while another gets these drugs plus uproleselan. The goal is to see if adding uproleselan improves outcomes by preventing cancer from worsening or returning.

How Is the Trial Designed?

Group I: Arm II (uproleselan, daunorubicin, cytarabine) Experimental Treatment 8 Interventions

INDUCTION: Patients receive uproleselan IV QD on day 1 and then every 12 hours on days 2-10. Patients also receive daunorubicin IV on days 2-4 and cytrarabine CIVI over 168 hours on days 2-8 over 168 hours. Patients with residual disease indicated by bone marrow examination receive a second induction including uprleselan IV QD on day 1 and then every 12 hours on days 2-8, daunorubicin IV on days 2-3, and cytarabine CIVI over 120 hours on days 2-6. CONSOLIDATION: Patients who achieve a CR or CRi receive uproleselan IV QD on day 1 and every 12 hours on days 2-8 and cytarabine IV over 3 hours on days 2-6. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Additionally, all patients undergo MUGA or ECHO during baseline, and bone marrow aspirate, bone marrow biopsy, and blood collection throughout the study.

Group II: Arm I (daunorubicin, cytarabine) Active Control 7 Interventions

INDUCTION: Patients receive daunorubicin IV on days 1-3 and cytarabine via CIVI over 168 hours on days 1-7. Patients with residual disease indicated by bone marrow examination receive a second induction including daunorubicin IV on days 1-2 and cytarabine CIVI over 12 hours on days 1-5. CONSOLIDATION: Patients receive cytarabine IV over 3 hours on days 1-5. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Additionally, all patients undergo MUGA or ECHO during baseline, and bone marrow aspirate, bone marrow biopsy, and blood collection throughout the study.

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+

Published Research Related to This Trial

In a phase II trial involving 20 patients with relapsed acute myeloid leukemia (AML), the combination of cladribine, cytarabine, and idarubicin achieved a complete remission rate of 60%, demonstrating its efficacy in this challenging condition.

The treatment was associated with significant toxicity, primarily infections, but when combined with allogeneic stem cell transplantation, it led to a 5-year survival rate of 55% among those who underwent the transplant, indicating potential for long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of Cladribine, high-dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review. Mayer, K., Hahn-Ast, C., Schwab, K., et al.[2021]

In a study of 24 patients with acute myeloid leukemia (AML) treated with a combination of idarubicin, cytarabine, and cladribine (ICC), 79.2% achieved complete remission (CR), indicating a high efficacy of this treatment regimen.

The study also reported a 33-month overall survival rate of 56% and a disease-free survival rate of 36%, suggesting that ICC can be an effective induction therapy, especially in high-risk AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine. Wiedower, E., Jamy, O., Martin, MG.[2015]

In a study of 70 adult patients with acute myelogenous leukemia (AML), high-dose cytarabine followed by daunorubicin achieved a complete remission (CR) rate of 90%, indicating strong efficacy for this treatment regimen.

While the treatment showed significant antileukemic activity, it also resulted in notable toxicity, including severe cerebellar toxicity in some patients, highlighting the need for careful management and further research to optimize its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Phillips, GL., Reece, DE., Shepherd, JD., et al.[2021]

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]

The study found significant variations in how acute myeloid leukemia (AML) patients respond to the chemotherapy drug cytarabine (Ara-C), with some patients being sensitive and others resistant based on their gene expression profiles.

Higher expression levels of certain genes like deoxycytidine kinase (DCK) and ribonucleotide reductase M1 (RRM1) were associated with better treatment outcomes, while a newly proposed Ara-C resistance index (RI) could help predict drug response and potential treatment toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. Abraham, A., Varatharajan, S., Karathedath, S., et al.[2022]

Intensive research is being conducted to understand and overcome resistance to chemotherapy in acute myeloid leukemia (AML), particularly focusing on the drugs daunorubicin and cytarabine, which are currently the most effective treatments.

Current studies are exploring ways to enhance the effectiveness of cytarabine by improving its delivery to leukemic cells and increasing the number of cells in the S-phase of the cell cycle, which may lead to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular and pharmacologic aspects of drug resistance in acute myeloid leukemia. Ross, DD.[2019]

In a study of adult patients with acute myeloid leukemia (AML) receiving the '7 + 3' induction therapy, 59% achieved remission, but many required multiple induction courses, leading to prolonged myelosuppression and increased infection rates.

High-dose cytarabine (HDARA-C) consolidation significantly improved disease-free survival for patients who achieved remission, while the myelosuppression and infection risks were comparable to those seen with single induction courses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia in Manitoba. The consequences of standard "7 + 3" remission-induction therapy followed by high dose cytarabine postremission consolidation for myelosuppression, infectious morbidity, and outcome. Bow, EJ., Kilpatrick, MG., Scott, BA., et al.[2019]

In a phase 3 trial involving 309 patients aged 60-75 with high-risk acute myeloid leukaemia, CPX-351 demonstrated a median overall survival of 9.33 months compared to 5.95 months for standard chemotherapy (7+3), indicating a significant improvement in survival rates.

After 5 years, the overall survival rate was 18% for the CPX-351 group versus 8% for the 7+3 group, suggesting that CPX-351 may lead to long-term remission and better outcomes for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet, JE., Uy, GL., Newell, LF., et al.[2021]

CPX-351, a liposomal formulation of cytarabine and daunorubicin, showed high efficacy in treating childhood acute lymphoblastic leukemia (ALL) xenograft models, achieving complete responses in four B-lineage models and a partial response in one T-lineage model.

The drug was administered at a dose that resulted in plasma drug exposures similar to those seen in patients with acute myeloid leukemia (AML), indicating its potential effectiveness and safety for use in pediatric leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of CPX-351, (cytarabine:daunorubicin) liposome injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical Testing Program. Carol, H., Fan, MM., Harasym, TO., et al.[2021]

Citations

1. 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03701308

NCT03701308 | Daunorubicin and Cytarabine With or ... Giving daunorubicin and cytarabine with uproleselan may work better in treating patients with acute myeloid leukemia compared to daunorubicin and cytarabine ...

3. onclive.com onclive.com/view/uproleselan-plus-chemotherapy-fails-to-improve-efs-in-older-patients-with-aml

Uproleselan Plus Chemotherapy Fails to Improve EFS in ... Topline results indicated that the median OS was 13 months with the combination vs 12.3 months with chemotherapy alone. In terms of safety, ...

4. 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.

5. allianceforclinicaltrialsinoncology.org allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=/Public/News-A041701-Jul2019

Alliance A041701 The researchers will test whether the addition of uproleselan may work better in treating patients with AML compared to daunorubicin and cytarabine alone. Note: ...

6. targetedonc.com targetedonc.com/view/uproleselan-misses-primary-os-end-point-in-aml-but-may-benefit-subgroups

Uproleselan Misses Primary OS End Point in AML, But May ... A phase 3 trial of uproleselan in relapsed/refractory acute myeloid leukemia failed to meet the primary overall survival end point but ...

7. clinicaltrials.uihealthcare.org clinicaltrials.uihealthcare.org/studies/alliance-a041701-randomized-phase-iiiii-study-conventional-chemotherapy-uproleselan-gmi

ALLIANCE A041701: A Randomized Phase II/III Study of ... PRIMARY OBJECTIVES: I. Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus daunorubicin and cytarabine in subjects ...