Clinical Trials /

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

NCT03568994

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Atovaquone (Mepron®) Combined With Conventional Chemotherapy for de Novo Acute Myeloid Leukemia (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)

Clinical Trial IDs

  • ORG STUDY ID: H-42691
  • NCT ID: NCT03568994

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
AtovaquoneMepronADE 10+3+5 plus Atovaquone (AQ)
CytarabineADE 10+3+5 plus Atovaquone (AQ)
DaunorubicinADE 10+3+5 plus Atovaquone (AQ)
EtoposideADE 10+3+5 plus Atovaquone (AQ)
Gemtuzumab OzogamicinDA 3+10 with GO plus AQ

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
ADE 10+3+5 plus Atovaquone (AQ)ExperimentalInduction I ADE: cytarabine, daunorubicin, etoposide 10+3+5, atovaquone daily
  • Atovaquone
  • Cytarabine
  • Daunorubicin
  • Etoposide
DA 3+10 with GO plus AQExperimentalInduction I DA: daunorubicin, cytarabine 3+10 with GO: gemtuzumab ozogamicin, atovaquone daily
  • Atovaquone
  • Cytarabine
  • Daunorubicin
  • Gemtuzumab Ozogamicin

Eligibility Criteria

        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) and serum glutamic oxaloacetic
                  transaminase (SGOT) (AST) ≤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. Pregnancy or Breast-Feeding 5.1 Female patients who are pregnant are ineligible since
             fetal toxicities and teratogenic effects have been noted for several of the study
             drugs.

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

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

          6. Informed Consent: All patients and/or their parents or legally authorized
             representatives must sign a written informed consent. Assent, when appropriate, will
             be obtained according to institutional guidelines.
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Plasma Concentrations
Time Frame:5 weeks
Safety Issue:
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).

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Baylor College of Medicine

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