Atovaquone + Chemotherapy for Acute Myeloid Leukemia

(ATACC AML Trial)

Recruiting at 3 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Baylor College of Medicine

Must not be taking: Anthracyclines

Disqualifiers: Fanconi anemia, Concurrent malignancy, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

26 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial allows prior use of certain medications like hydroxyurea and ATRA, but they cannot be taken at the same time as the trial treatment. The protocol does not specify about other medications, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination including Atovaquone, Cytarabine, Daunorubicin, Etoposide, and Gemtuzumab Ozogamicin for treating Acute Myeloid Leukemia?

Research shows that a combination of Gemtuzumab Ozogamicin with Daunorubicin and Cytarabine has improved overall survival in patients with newly diagnosed acute myeloid leukemia compared to standard chemotherapy. Additionally, Vyxeos, a formulation of Daunorubicin and Cytarabine, demonstrated a significant survival benefit in high-risk AML patients. ^{1 2 3 4 5}

What safety data exists for Atovaquone + Chemotherapy in treating Acute Myeloid Leukemia?

The combination of gemtuzumab ozogamicin (Mylotarg) with daunorubicin and cytarabine for acute myeloid leukemia has common side effects like bleeding and infection. Vyxeos, a combination of daunorubicin and cytarabine, shows side effects such as rash, fever, and low blood cell counts. Another combination with idarubicin, high-dose cytarabine, and etoposide was well-tolerated, with side effects like nausea and liver function changes. ^{5 6 7 8 9}

What makes the drug Atovaquone combined with chemotherapy unique for treating acute myeloid leukemia?

This treatment is unique because it combines Atovaquone, a drug typically used for pneumonia, with standard chemotherapy to suppress energy production in leukemia cells, potentially enhancing the treatment's effectiveness. Atovaquone's ability to reduce leukemia burden by targeting oxidative phosphorylation (a process cells use to produce energy) is a novel approach in acute myeloid leukemia therapy. ^{9 10 11 12 13}

What is the purpose of this trial?

This study will test daily dosing of atovaquone at established pneumocystis jiroveci pneumonia (PJP) prophylaxis dosing in combination with standard induction chemotherapy for de novo AML. The primary objectives are to determine the frequency of omission of atovaquone doses due to standard induction chemotherapy toxicity, to quantify the steady-state plasma levels of atovaquone, and to determine the time to achievement of steady state atovaquone levels in this population.

Research Team

Alexandra Stevens, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Eligibility Criteria

This trial is for children over 1 month and young adults under 21 with newly diagnosed acute myeloid leukemia (AML) that hasn't been treated before. They must have specific genetic abnormalities or a certain percentage of bone marrow blasts, among other criteria. Those who've had extensive prior anthracycline treatment, are pregnant or breastfeeding, or have certain genetic conditions like Fanconi anemia aren't eligible.

Inclusion Criteria

I have AML with more than 20% bone marrow blasts, as per WHO guidelines.

My leukemia has specific genetic features or less than 20% immature blood cells.

My myelodysplastic syndrome has progressed to acute myeloid leukemia.

Exclusion Criteria

I am currently pregnant.

Lactating females unless they have agreed not to breastfeed their infants

I have AML and have been treated with high doses of anthracyclines.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive induction chemotherapy with cytarabine, daunorubicin, etoposide, and atovaquone

5 weeks

Multiple visits for chemotherapy administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Atovaquone
• Cytarabine
• Daunorubicin
• Etoposide
• Gemtuzumab Ozogamicin

Trial Overview The study tests atovaquone combined with standard chemotherapy drugs (Daunorubicin, Gemtuzumab Ozogamicin, Etoposide, Cytarabine) in treating new cases of AML. It aims to see how often atovaquone doses are missed due to chemo side effects and measure the levels and timing of atovaquone in the blood during treatment.

Participant Groups

Group I: DA 3+10 with GO plus AQ Experimental Treatment 4 Interventions

Induction I DA: daunorubicin, cytarabine 3+10 with GO: gemtuzumab ozogamicin, atovaquone daily

Group II: ADE 10+3+5 plus Atovaquone (AQ) Experimental Treatment 4 Interventions

Induction I ADE: cytarabine, daunorubicin, etoposide 10+3+5, atovaquone daily

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?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

William Marsh Rice University

Collaborator

Trials

50

Recruited

28,400+

Findings from Research

In a study of 237 older patients with acute myeloid leukemia, treatment with gemtuzumab ozogamicin (GO) significantly improved overall survival (OS) compared to best supportive care, with a median OS of 4.9 months for GO versus 3.6 months for BSC.

The treatment was well-tolerated, showing similar rates of serious adverse events between the GO and BSC groups, indicating that GO can be a safe and effective first-line therapy for patients unsuitable for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. Amadori, S., Suciu, S., Selleslag, D., et al.[2022]

In a study of 2,157 adult patients with newly diagnosed acute myeloid leukemia (AML), the overall complete remission (CR) rate was similar (69%) across three different anthracyclines: daunorubicin, idarubicin, and mitoxantrone.

However, patients treated with daunorubicin had significantly shorter disease-free survival (DFS) rates compared to those treated with idarubicin or mitoxantrone, suggesting that using either idarubicin or mitoxantrone may enhance long-term chemotherapy efficacy for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. Mandelli, F., Vignetti, M., Suciu, S., et al.[2022]

The combination treatment of gemtuzumab ozogamicin, intermediate-dose cytarabine, and mitoxantrone (MIDAM) resulted in a 63% overall response rate in 62 patients with refractory or relapsed CD33(+) acute myeloid leukemia, with 50% achieving complete remission.

While the MIDAM regimen showed promising efficacy, it also had safety concerns, including a 16% rate of severe hyperbilirubinemia and four early toxic deaths, highlighting the need for further randomized trials to establish its safety and effectiveness as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. Chevallier, P., Delaunay, J., Turlure, P., et al.[2019]

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]

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]

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]

In a study involving five patients with therapy-related acute myeloid leukemia, a combination of idarubicin, high-dose cytarabine, and etoposide achieved complete remission in all patients after just one course of treatment.

The treatment was well-tolerated, with low levels of toxicity and no deaths during the induction therapy, suggesting it is a promising option for inducing remission in secondary acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. Philpott, N., Mehta, J., Treleaven, J., et al.[2019]

Atovaquone (AQ) combined with standard chemotherapy for pediatric acute myeloid leukemia (AML) was found to be feasible and safe, with 79% of patients achieving effective plasma concentrations by the end of the first induction phase.

Correlative studies indicated that AQ not only induced apoptosis in leukemia cells but also suppressed oxidative phosphorylation, suggesting it has potential anti-leukemic effects, making it a promising adjunct therapy for pediatric AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated. Stevens, AM., Schafer, ES., Li, M., et al.[2023]

Current frontline treatments for acute myeloid leukemia (AML) using ara-C and topoisomerase II agents achieve complete response rates of 70%, but long-term survival remains low at 25%.

Newer agents like nucleoside analogs and hypomethylating agents show promise, with combination therapies yielding higher complete response rates, particularly when used alongside traditional treatments like ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. Kantarjian, HM., Estey, EH., Keating, MA.[2013]

The VALOR study, involving 711 patients, showed that the combination of vosaroxin and cytarabine resulted in better complete remission rates and survival for older patients (≥60 years) with relapsed/refractory acute myeloid leukemia (AML) compared to placebo/cytarabine.

Vosaroxin demonstrated a safety profile similar to existing AML treatments, making it a promising option for older patients who often face poor outcomes due to comorbidities and unfavorable cytogenetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape. Sedov, V., Stuart, RK.[2020]

References

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

Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia. [2019]

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

Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. [2022]

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

Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. [2019]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

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

7. 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]

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

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated. [2023]

11. England pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape. [2020]

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

New agents for treatment of children with acute myelogenous leukemia. [2019]