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

Primary Purpose

Acute Myeloid Leukemia

Status
Active
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Atovaquone
Cytarabine
Daunorubicin
Etoposide
Gemtuzumab Ozogamicin
Sponsored by
Baylor College of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

1 Month - 20 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age: Children ≥1 month and children and young adults < 21 years of age
  2. Diagnosis: Patients must be newly diagnosed with acute myelogenous leukemia

    2.1 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

    2.2 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).
  3. Pre-existing myelodysplastic syndrome:

    Patients with a history of myelodysplastic syndrome that has progressed to AML which meets the criteria above are eligible.

  4. Therapy-related or secondary AML Patients with AML which is thought to be therapy related but meet the criteria above are eligible.
  5. 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.

  6. Organ Function Requirement:

    Adequate Liver Function Defined as:

    • Direct Bilirubin ≤2x upper limit of normal (ULN) for age and institution (unless related to leukemic involvement), and
    • serum glutamate-pyruvate transaminase (SGPT) (ALT) ≤2.5x ULN for age and institution (unless it is related to leukemic involvement)
  7. Ability to receive enteral medication:

Eligible patients should have no contraindication to enteral administration of medication (e.g. oral, Nasogastric (NG), G-tube, etc) as determined by the evaluating physician.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Prior receipt of anthracyclines Patients with treatment-related AML who have received more than 250mg/m2 of anthracyclines (in daunorubicin equivalents) are not eligible.
  4. Known Allergy or Intolerance to Atovaquone Patients with a known allergy or intolerance to atovaquone are not eligible.
  5. Enrollment on another ongoing treatment study Patients who are enrolled on a treatment study are not eligible
  6. Pregnancy or Breast-Feeding 6.1 Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs.

6.2 Lactating females are not eligible unless they have agreed not to breastfeed their infants.

6.3 Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.

Sites / Locations

  • Johns Hopkins Medicine
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

ADE 10+3+5 plus Atovaquone (AQ)

DA 3+10 with GO plus AQ

Arm Description

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

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

Outcomes

Primary Outcome Measures

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).
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.
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.

Secondary Outcome Measures

Full Information

First Posted
May 31, 2018
Last Updated
October 7, 2022
Sponsor
Baylor College of Medicine
Collaborators
William Marsh Rice University
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1. Study Identification

Unique Protocol Identification Number
NCT03568994
Brief Title
Atovaquone (Mepron®) Combined With Conventional Chemotherapy for de Novo Acute Myeloid Leukemia (AML)
Acronym
ATACC AML
Official Title
A Trial of Atovaquone (Mepron®) Combined With Conventional Chemotherapy for de Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults (ATACC AML)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 10, 2018 (Actual)
Primary Completion Date
September 29, 2020 (Actual)
Study Completion Date
October 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Baylor College of Medicine
Collaborators
William Marsh Rice University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
Standard cytotoxic chemotherapy is based on the Medical Research Council (MRC) backbone of cytarabine, and daunorubicin. This combination of chemotherapy is highly myelosuppressive and can lead to oral aversions, dietary intolerance, and gastrointestinal infections necessitating holding of oral drugs. Because of the toxicity of the best currently available therapy, new drugs that are considered for incorporation into existing treatment regimens will ideally have a tolerable side effect profile. This study will evaluate the tolerability of incorporating the orally bioavailable drug atovaquone in combination with standard cytotoxic induction chemotherapy for newly diagnosed pediatric AML patients. Therefore, quantifying the frequency with which atovaquone is held due to a side effect of therapy is crucial information to gather in this population.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Choice of Induction I regimen is at the treating physician's discretion (will be influenced based on drug availability)
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ADE 10+3+5 plus Atovaquone (AQ)
Arm Type
Experimental
Arm Description
Induction I ADE: cytarabine, daunorubicin, etoposide 10+3+5, atovaquone daily
Arm Title
DA 3+10 with GO plus AQ
Arm Type
Experimental
Arm Description
Induction I DA: daunorubicin, cytarabine 3+10 with GO: gemtuzumab ozogamicin, atovaquone daily
Intervention Type
Drug
Intervention Name(s)
Atovaquone
Other Intervention Name(s)
Mepron
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
As part of routine Induction 1 chemotherapy (ADE 10+3+5)
Intervention Type
Drug
Intervention Name(s)
Daunorubicin
Intervention Description
As part of routine Induction 1 chemotherapy (ADE 10+3+5)
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
As part of routine Induction 1 chemotherapy (ADE 10+3+5)
Intervention Type
Drug
Intervention Name(s)
Gemtuzumab Ozogamicin
Intervention Description
As part of routine Induction 1 chemotherapy(DA 3+10 + GO)
Primary Outcome Measure Information:
Title
Plasma Concentrations
Description
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).
Time Frame
5 weeks
Title
Dose Omission Frequency
Description
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.
Time Frame
5 weeks
Title
Time to Achieve Steady State
Description
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.
Time Frame
5 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: Children ≥1 month and children and young adults < 21 years of age Diagnosis: Patients must be newly diagnosed with acute myelogenous leukemia 2.1 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 2.2 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: Adequate Liver Function Defined as: Direct Bilirubin ≤2x upper limit of normal (ULN) for age and institution (unless related to leukemic involvement), and serum glutamate-pyruvate transaminase (SGPT) (ALT) ≤2.5x ULN for age and institution (unless it is related to leukemic involvement) Ability to receive enteral medication: Eligible patients should have no contraindication to enteral administration of medication (e.g. oral, Nasogastric (NG), G-tube, etc) as determined by the evaluating physician. Exclusion Criteria: 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. Enrollment on another ongoing treatment study Patients who are enrolled on a treatment study are not eligible Pregnancy or Breast-Feeding 6.1 Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. 6.2 Lactating females are not eligible unless they have agreed not to breastfeed their infants. 6.3 Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandra Stevens, MD
Organizational Affiliation
Baylor College of Medicine - Texas Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33439382
Citation
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.
Results Reference
derived

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

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