Atovaquone + Chemotherapy for Acute Myeloid Leukemia

(ATACC AML Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for patients with newly diagnosed acute myeloid leukemia (AML). It combines atovaquone, a medicine typically used to prevent a specific type of pneumonia, with standard chemotherapy drugs such as cytarabine, daunorubicin, etoposide, and gemtuzumab ozogamicin. The trial aims to assess patient tolerance to this combination and monitor atovaquone levels in the body during treatment. This trial suits children and young adults under 21 who have been newly diagnosed with AML and meet certain health criteria. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research shows that atovaquone is generally well-tolerated when combined with standard chemotherapy treatments for acute myeloid leukemia (AML). In past studies, atovaquone was safely used at doses typically given to prevent pneumocystis jiroveci pneumonia (PJP).

One study found that most patients reached effective blood levels of atovaquone, indicating good absorption by the body. This absorption is crucial for the treatment's effectiveness.

The chemotherapy drugs used, such as daunorubicin, cytarabine, and gemtuzumab ozogamicin, can cause side effects like bleeding and infections. These side effects are common with chemotherapy, but healthcare providers usually manage them during treatment.

Overall, past research has shown that combining atovaquone with these chemotherapy drugs is feasible and well-tolerated. This suggests the treatment could be safe for participants, although individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia because they incorporate atovaquone, a drug typically used to treat infections but now being explored for its potential to enhance cancer treatment. Unlike standard options like cytarabine and daunorubicin alone, these treatments combine atovaquone with chemotherapy agents, potentially offering a new mechanism of action by disrupting cancer cell metabolism. Additionally, the inclusion of gemtuzumab ozogamicin in one arm targets leukemia cells more precisely, aiming to improve treatment outcomes. This innovative approach could make these treatments more effective and offer hope for better patient responses.

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

Research has shown that atovaquone can help treat acute myeloid leukemia (AML) by killing cancer cells and slowing the disease. In this trial, participants will receive atovaquone alongside chemotherapy drugs. One treatment arm combines atovaquone with cytarabine, daunorubicin, and etoposide, while another combines atovaquone with cytarabine, daunorubicin, and gemtuzumab ozogamicin. Atovaquone may enhance the effectiveness of these chemotherapy drugs by targeting the unusual energy use of AML cells, potentially improving treatment results. Although early findings are promising, further research is needed to fully understand its potential in fighting AML. ^{1 3 6 7 8}

Who Is on the Research Team?

Alexandra Stevens, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Are You a Good Fit for This Trial?

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

Lactating females unless they have agreed not to breastfeed their infants

I am currently pregnant.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03568994

Study Details | NCT03568994 | Atovaquone (Mepron®) ... The primary objectives are to determine the frequency of omission of atovaquone doses due to standard induction chemotherapy toxicity, to quantify the steady- ...

2. ashpublications.org ashpublications.org/blood/article/130/Supplement%201/3899/71842/Atovaquone-Demonstrates-Single-Agent-Activity-and

Atovaquone Demonstrates Single Agent Activity and an ... Our drug combination assays found an antagonistic effect in combination with etoposide, and an additive effect with cytarabine and daunorubicin.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6929386/

Atovaquone is active against AML by upregulating the ... Atovaquone induces AML blast apoptosis and prolongs survival in AML xenografts. Atovaquone induces proapoptotic signaling and inhibits the ...

4. ctv.veeva.com ctv.veeva.com/study/atovaquone-mepron-r-combined-with-conventional-chemotherapy-for-de-novo-acute-myeloid-leukemia-aml

Atovaquone (Mepron®) Combined with Conventional ... This study will test daily dosing of atovaquone at established pneumocystis jiroveci pneumonia (PJP) prophylaxis dosing in combination with ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119844154

Atovaquone Demonstrates Single Agent Activity and an ... Our drug combination assays found an antagonistic effect in combination with etoposide, and an additive effect with cytarabine and daunorubicin.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9954468/

Repurposing Atovaquone as a Therapeutic against Acute ... Atovaquone is an anti-infective agent which can be used to prevent and treat a type of pneumonia that all children with acute myeloid leukemia ...

7. clinicaltrial.be clinicaltrial.be/en/details/7116?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Atovaquone (Mepron®) Combined with Conventional ... This study will evaluate the tolerability of incorporating the orally bioavailable drug atovaquone in combination with standard cytotoxic ...

8. researchgate.net researchgate.net/publication/368707841_Repurposing_Atovaquone_as_a_Therapeutic_against_Acute_Myeloid_Leukemia_AML_Combination_with_Conventional_Chemotherapy_Is_Feasible_and_Well_Tolerated

Repurposing Atovaquone as a Therapeutic against Acute ... A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day ...