Atovaquone (Mepron®) Combined With Conventional Chemotherapy for de Novo Acute Myeloid Leukemia (AML)

NCT03568994 | Completed Early Phase 1 DMC FDA Drug

• 1 other identifier: H-42691
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Plasma Concentrations

  The investigators will determine plasma levels of atovaquone at the following time points: Day 6, 11, 13, 15, 18, 20, 22, 29 and on the day of the end of induction bone marrow (BM) assessment (generally around Day 36).

  5 weeks

• Dose Omission Frequency

  To quantify the frequency of atovaquone doses omitted due to standard MRC related toxicity. Administration of doses of atovaquone will be monitored while the patient is hospitalized in the electronic medical record and abstracted to case report forms. Families will also be given a diary to complete.

  5 weeks

• Time to Achieve Steady State

  Time to achieving steady state concentrations of atovaquone when given in combination with standard chemotherapy in children with de novo AML will be determined using stepwise tests of linear trend.

  5 weeks

Study Arms (2)

ADE 10+3+5 plus Atovaquone (AQ)

EXPERIMENTAL

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

DA 3+10 with GO plus AQ

EXPERIMENTAL

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

Drug: Atovaquone; Drug: Cytarabine; Drug: Daunorubicin; Drug: Gemtuzumab Ozogamicin

Interventions

Daunorubicin DRUG

As part of routine Induction 1 chemotherapy (ADE 10+3+5)

DA 3+10 with GO plus AQ

Etoposide DRUG

As part of routine Induction 1 chemotherapy (ADE 10+3+5)

Gemtuzumab Ozogamicin DRUG

As part of routine Induction 1 chemotherapy(DA 3+10 + GO)

DA 3+10 with GO plus AQ

Atovaquone DRUG

Patients will receive standard of care MRC based Induction chemotherapy (such as ADE 10+3+5 with daily atovaquone dosing starting on day 6. In order to accommodate potential drug shortages modifications to ADE 10+3+5 that retain the MRC based induction backbone regimen of DA are allowed (see second Arm). These include but are not limited to substitution of etopophos for etoposide, exclusion of etoposide, use of CPX-351 (VYXEOS (daunorubicin and cytarabine) liposome) only, and daunorubicin and cytarabine (DA) + gemtuzumab ozogamicin (GO). Patients will be monitored for adherence to and tolerance of daily dosing of atovaquone. Peripheral blood (PB) and bone marrow plasma samples will be obtained to measure atovaquone concentrations.

Also known as: Mepron

DA 3+10 with GO plus AQ

Cytarabine DRUG

As part of routine Induction 1 chemotherapy (ADE 10+3+5)

DA 3+10 with GO plus AQ

Eligibility Criteria

• Age: 1 Month - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Children ≥1 month and children and young adults \< 21 years of age
• Diagnosis: Patients must be newly diagnosed with acute myelogenous leukemia
• Patients with previously untreated primary AML who meet the customary criteria for AML with ≥ 20% bone marrow blasts as set out in the 2008 World Health Organization (WHO) Myeloid Neoplasm Classification are eligible.
• Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive. In cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/Fluorescent in situ hybridization (FISH) testing is feasible can be substituted for the marrow exam at diagnosis
• Patients with \< 20% bone marrow or peripheral blood blasts are eligible if they have:
• A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities,
• The unequivocal presence of megakaryoblasts, or
• Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis).
• Pre-existing myelodysplastic syndrome:
• Patients with a history of myelodysplastic syndrome that has progressed to AML which meets the criteria above are eligible.
• Therapy-related or secondary AML Patients with AML which is thought to be therapy related but meet the criteria above are eligible.
• Prior Therapy:
• Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and IT cytarabine given at diagnosis is allowed. Hydroxyurea and ATRA cannot be given concurrently with protocol therapy. There is no specific amount of time mandated between the last dose of hydroxyurea or ATRA and the start of protocol therapy.
• With the exception of infants who had previously received low dose cytarabine to control disease, patients who have previously received any other antileukemic therapy (i.e. chemotherapy or radiation therapy) are not eligible for this protocol.
• Organ Function Requirement:

You may not qualify if:

• Excluded Constitutional Conditions
• Patients with a history of any of the following constitutional conditions are not eligible:
• Fanconi anemia
• Shwachman syndrome
• Any other known constitutional bone marrow failure syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21 who are eligible to receive treatment for Down Syndrome (DS) related AML Note: Enrollment and initiation of therapy may occur pending results of clinically indicated studies to exclude these conditions. If a patient is found to have any of these conditions they should be removed from the study once results are received. Patients who are removed due to ineligibility after results are received will be replaced.
• Other Excluded Conditions
• Patients with any of the following oncologic diagnoses are not eligible:
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Biphenotypic or bilineal acute leukemia
• Acute promyelocytic leukemia Note: Enrollment and initiation of therapy may occur pending results of clinically indicated studies to exclude these conditions. If a patient is found to have any of these conditions they should be removed from the study once results are received. Patients who are removed due to ineligibility after results are received will be replaced.
• Prior receipt of anthracyclines Patients with treatment-related AML who have received more than 250mg/m2 of anthracyclines (in daunorubicin equivalents) are not eligible.
• Known Allergy or Intolerance to Atovaquone Patients with a known allergy or intolerance to atovaquone are not eligible.

Sponsors & Collaborators

• William Marsh Rice University: collaborator
• Baylor College of Medicine: lead

Study Sites (2)

Johns Hopkins Medicine

Baltimore, Maryland, 21205, United States

Location

Baylor College of Medicine - Texas Childrens Hospital

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Conneely SE, Stevens AM. Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy. Curr Oncol Rep. 2021 Jan 13;23(2):16. doi: 10.1007/s11912-020-01009-3.

  PMID: 33439382 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Atovaquone; Cytarabine; Daunorubicin; Etoposide; Gemtuzumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Naphthoquinones; Quinones; Organic Chemicals; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Glucosides; Calicheamicins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alexandra Stevens, MD

  Baylor College of Medicine - Texas Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D. Associate Professor

Model Details: Choice of Induction I regimen is at the treating physician's discretion (will be influenced based on drug availability)

Study Record Dates

• First Submitted: May 31, 2018
• First Posted: June 26, 2018
• Study Start: July 10, 2018
• Primary Completion: September 29, 2020
• Study Completion: September 20, 2025
• Last Updated: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)