Chemotherapy for Acute Myeloid Leukemia in Young Patients with Down Syndrome

Recruiting at 202 trial locations

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Disqualifiers: Promyelocytic leukemia, Prior therapy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

280 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies a chemotherapy treatment that adjusts based on how well patients respond initially. It targets younger patients with Down syndrome who have certain types of blood cancer. The treatment aims to effectively kill cancer cells while reducing side effects.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that children who have previously received chemotherapy, radiation therapy, or any anti-leukemic therapy are not eligible, except for cytarabine for treating transient myeloproliferative disorder.

What safety data exists for chemotherapy treatments in young patients with Down syndrome and acute myeloid leukemia?

Children with Down syndrome treated for myeloid leukemia using reduced-dose chemotherapy have shown favorable survival rates while minimizing toxicity. Common side effects of treatments like Vyxeos, which includes daunorubicin and cytarabine, are hypersensitivity, febrile neutropenia (low white blood cell count with fever), and prolonged neutropenia (low white blood cell count) and thrombocytopenia (low platelet count). ^{1 2 3 4 5}

What makes this chemotherapy treatment for acute myeloid leukemia in young patients with Down syndrome unique?

This treatment is unique because it combines multiple drugs, including asparaginase and cytarabine, which have shown increased sensitivity in Down syndrome patients, allowing for potentially better outcomes with reduced toxicity compared to standard treatments. The approach also involves optimizing drug dosing and scheduling to improve survival rates while minimizing side effects. ^{1 2 6 7 8}

What data supports the effectiveness of the drug for treating acute myeloid leukemia in young patients with Down syndrome?

Research shows that children with Down syndrome and myeloid leukemia have better survival rates when treated with less intensive chemotherapy regimens, including drugs like cytarabine and daunorubicin, due to their heightened sensitivity to these drugs. A study reported a 5-year event-free survival rate of 89.9% and overall survival of 93.0% for patients treated with a modified regimen, highlighting the effectiveness of these drugs in this specific group. ^{1 2 8 9 10}

Who Is on the Research Team?

Jason N Berman

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for young patients with Down syndrome who have newly diagnosed acute myeloid leukemia or myelodysplastic syndrome. They must not have received any anti-leukemic therapy except cytarabine for transient myeloproliferative disease, and they should not have promyelocytic leukemia. Patients need to show a certain percentage of blasts in their bone marrow or blood and meet specific diagnostic criteria.

Inclusion Criteria

It has been over 8 weeks since my temporary blood disorder with high blast cells resolved.

I have a new diagnosis of AML with more than 20% bone marrow blasts.

I have Down syndrome confirmed by genetic testing.

Exclusion Criteria

I received my last cytarabine dose for TMD treatment within the last 30 days.

I have been diagnosed with a specific type of leukemia (FAB M3).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction I

Patients receive cytarabine intrathecally and intravenously, daunorubicin hydrochloride, and thioguanine orally. Induction I continues for a minimum of 28 days.

4 weeks

Induction II

Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine. Induction II continues for a minimum of 28 days.

4 weeks

Induction III

Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days.

4 weeks

Intensification I

Patients receive cytarabine and etoposide. Intensification I continues for a minimum of 28 days.

4 weeks

Intensification II

Patients receive cytarabine and etoposide. Intensification II continues for a minimum of 28 days.

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes visits at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, and annually for 10 years.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Asparaginase
• Asparaginase Erwinia chrysanthemi
• Cytarabine
• Daunorubicin Hydrochloride
• Etoposide
• Mitoxantrone Hydrochloride
• Thioguanine

Trial Overview The study tests response-based chemotherapy using drugs like Asparaginase Erwinia chrysanthemi, Cytarabine, Daunorubicin Hydrochloride, among others. It aims to categorize patients by risk based on their initial treatment response and adjust subsequent treatments accordingly to reduce side effects while treating the cancer effectively.

How Is the Trial Designed?

Group I: Arm B (high risk) Experimental Treatment 5 Interventions

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi IM or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

Group II: Arm A (standard risk) Experimental Treatment 5 Interventions

INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. (This arm is closed to accrual and treatment with amendment #4A 01/07/2019)

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Vyxeos, a liposomal formulation combining daunorubicin and cytarabine, significantly improves overall survival in patients aged 60-75 with untreated high-risk acute myeloid leukemia (AML), showing a median survival of 9.56 months compared to 5.95 months with standard chemotherapy.

The study demonstrated that Vyxeos not only enhances survival rates but also increases the likelihood of patients undergoing hematopoietic stem cell transplantation, which is crucial for potentially curing AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. Tzogani, K., Penttilä, K., Lapveteläinen, T., et al.[2022]

CPX-351, a liposomal-encapsulated combination of daunorubicin and cytarabine, has been approved for treating therapy-related acute myeloid leukemia (tAML) and AML with myelodysplasia-related changes (AML-MRCs), showing improved overall survival and remission rates in older patients compared to the traditional '7 + 3' treatment.

In a Phase III trial involving patients aged 60-75, CPX-351 demonstrated higher rates of complete remission and event-free survival, suggesting that its fixed 5:1 drug ratio may enhance efficacy in these challenging subgroups of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. Chen, EC., Fathi, AT., Brunner, AM.[2020]

Vyxeos (CPX-351) received FDA approval for treating adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), based on a study involving 309 patients aged 60-75 that showed improved overall survival (9.6 months vs. 5.9 months with standard treatment).

The safety profile of Vyxeos was comparable to the standard treatment, but it was associated with longer periods of neutropenia and thrombocytopenia, highlighting the need for careful monitoring and a warning against switching between different formulations of daunorubicin and cytarabine during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Krauss, AC., Gao, X., Li, L., et al.[2020]

Gemtuzumab ozogamicin (Mylotarg) has been approved for treating acute myeloid leukemia (AML) in patients aged 15 and older, showing significant improvements in event-free survival and reduced relapse risk based on a meta-analysis of 3,325 patients.

While Mylotarg is effective, it is associated with common side effects such as hemorrhage and infection, particularly when used in combination with other chemotherapy drugs like daunorubicin and cytarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia. Ali, S., Dunmore, HM., Karres, D., et al.[2020]

Glasdegib, an oral Hedgehog pathway inhibitor, has shown promising response rates in treating acute myeloid leukemia (AML) in elderly patients, with moderate toxicity and reduced early mortality compared to standard treatments.

Approved by the FDA and EMA for use with low-dose cytarabine in patients aged 75 and older or those unfit for intensive chemotherapy, glasdegib represents a significant advancement in AML therapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors. Fersing, C., Mathias, F.[2023]

Citations

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

Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. [2022]

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

Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. [2009]

3. England pubmed.ncbi.nlm.nih.gov

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. [2020]

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

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. [2021]

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

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. [2020]

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

Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. [2021]

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

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia. [2020]

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

Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. [2015]

10. Poland pubmed.ncbi.nlm.nih.gov

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors. [2023]