Daunorubicin + Cytarabine ± Uproleselan for Acute Myeloid Leukemia

Recruiting at 211 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

670 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial studies how well daunorubicin and cytarabine with or without uproleselan works in treating older adult patients with acute myeloid leukemia receiving intensive induction chemotherapy. Drugs used in chemotherapy, such as daunorubicin 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. Uproleselan may prevent cancer from returning or getting worse. Giving daunorubicin and cytarabine with uproleselan may work better in treating patients with acute myeloid leukemia compared to daunorubicin and cytarabine alone.

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.

What data supports the effectiveness of the drug combination Daunorubicin and Cytarabine for treating Acute Myeloid Leukemia?

Research shows that a combination of high-dose cytarabine and daunorubicin has significant anti-leukemic activity in adults with acute myeloid leukemia, achieving complete remission in 90% of patients in one study. However, relapses were common, and the treatment had substantial toxicity. ^{1 2 3 4 5}

Is the combination of Daunorubicin, Cytarabine, and Uproleselan safe for humans?

The combination of Daunorubicin and Cytarabine has been used in treating acute myeloid leukemia and is generally well-tolerated, but it can cause severe side effects like neutropenia (low white blood cell count), infections, and thrombocytopenia (low platelet count). Serious complications like severe cerebellar toxicity (affecting the brain) have been observed but are often reversible. Uproleselan's safety in combination with these drugs is not specifically detailed in the provided studies. ^{1 2 6 7 8}

What makes the drug combination of Daunorubicin, Cytarabine, and Uproleselan unique for treating acute myeloid leukemia?

This treatment is unique because it combines Daunorubicin and Cytarabine, which are standard drugs for acute myeloid leukemia, with Uproleselan, a novel drug that may enhance the effectiveness of chemotherapy by targeting specific pathways in leukemia cells. This combination aims to improve outcomes by potentially reducing drug resistance and increasing the cancer-killing effects of the chemotherapy. ^{2 6 7 9 10}

Research Team

Geoffrey L Uy

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

References

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

High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. [2021]

2. 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]

3. England 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. [2021]

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

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

5. England pubmed.ncbi.nlm.nih.gov

Post-remission therapy of adult acute myeloid leukaemia: one cycle of high-dose versus standard-dose cytarabine. Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK). [2020]

6. United States 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. [2019]

7. Greece pubmed.ncbi.nlm.nih.gov

Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine. [2015]

8. England pubmed.ncbi.nlm.nih.gov

RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. [2022]

9. England 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. [2021]

10. United States 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. [2021]