Clinical Trials /

Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia

NCT02680951

Description:

This study will examine the appropriate dose and side effects of dasatinib, when it is given with the standard of care chemotherapy for children and adolescents with Acute Myeloid Leukemia (AML).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia
  • Official Title: Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia: A Phase I Study (AflacLL1401)

Clinical Trial IDs

  • ORG STUDY ID: IRB00078620
  • NCT ID: NCT02680951

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
DasatinibSprycel, BMS-354825Dose Level 1
FludarabineFludaraDose Level 1
CytarabineDepocyt, Cytosar-UDose Level 1
IdarubicinIdamycinDose Level 1
Intrathecal (IT) cytarabineDepocyt, Cytosar-UDose Level 1

Purpose

This study will examine the appropriate dose and side effects of dasatinib, when it is given with the standard of care chemotherapy for children and adolescents with Acute Myeloid Leukemia (AML).

Detailed Description

      This Phase I study is for children and adolescents who have acute myelogenous leukemia (AML)
      that has come back (relapsed) or has become resistant (refractory) to standard therapies.
      Researchers want to know if a drug called dasatinib is safe when used together with standard
      chemotherapy in treating patients who have relapsed or have resistant AML. Their leukemia has
      a particular genetic mutation, called core-binding factor.

      This type of leukemia has an increase of a cancer promoting protein called c-KIT. Dasatinib
      can target this protein in laboratory experiments. Laboratory and other studies suggest that
      dasatinib may prevent acute myeloid leukemia cells from growing and may lead to the
      destruction of leukemia cells.

      The main goal of this study is to find a safe dose of dasatinib and to find out the side
      effects of dasatinib when it is given in combination with standard chemotherapy to children
      and adolescents. Similar studies are currently being done in adult patients. Dasatinib has
      been proven safe and effective in the treatment of other types of leukemia, both by itself
      and in combination with standard chemotherapy. It is not, however, FDA-approved for use in
      children.

      Three to six participants will receive the starting dose of the drug. If the side effects are
      not too severe, the next group of participants will take the study drug at a higher dose
      level. Up to two dose levels of the study drug will be tested. Dasatinib is given by mouth
      once daily on days 6 to 29 of each 42-day cycle. Participants may receive two cycles in this
      study.

      In addition to dasatinib, participants receive chemotherapy intravenously (IV) with
      fludarabine, cytarabine, idarubicin, as well as in the spinal fluid (intrathecal or IT
      chemotherapy). Intrathecal chemotherapy includes cytarabine at the start of each cycle. These
      drugs are part of standard AML treatment. If at the time of study entry a subject has
      leukemia cells in their spinal fluid (CNS leukemia), they may receive additional intrathecal
      chemotherapy with cytarabine, methotrexate, and hydrocortisone (IT triples) during each
      cycle.

      Required research tests include pharmacokinetic (PK) and pharmacodynamics (PD) blood draws
      (about 1 teaspoon each time) during cycle 1. Optional research tests include extra marrow
      (about 1 teaspoon each time) for genetic testing and banking of marrow (1 teaspoon) for
      future studies about cancer.

      Primary Objectives of this study are:

        -  To evaluate the safety of combining dasatinib with reinduction chemotherapy comprised of
           idarubicin, fludarabine and cytarabine (Ida - FLU/Ara) in children with relapsed or
           refractory core binding factor acute myeloid leukemia (CBF AML)

        -  To characterize the toxicity profile of this combination in pediatric patients with
           relapsed or refractory CBF AML

      Secondary Objectives of this study are:

        -  To estimate the response rates to the combination chemotherapy in the context of a Phase
           I study, in children with AML in first or greater relapse or refractory to induction
           chemotherapy

        -  To determine the genotype of c-KIT exons 8 and 17 and correlate with response rate

        -  To characterize c-KIT expression of bone marrow blasts at study entry and at the end of
           course 1 of therapy and describe any correlation with response to therapy

      Exploratory Objectives are:

        -  To investigate descriptively the pharmacodynamic modulation of c-KIT target, Stat3, in a
           cell line by patient-derived plasma

        -  To perform RNA sequencing on bone marrow samples at study entry in order to describe the
           prevalence of mutations in AML associated genes, including c-KIT, and correlate
           descriptively with progression free survival

        -  To collect biology specimens at study entry and completion of therapy for future biology
           studies
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1ExperimentalStudy participants #1 - #6 receive dose level 1 of dasatinib (60/mg/m2/day) in addition to the standard treatment, for up to 2 courses. Each treatment course is 29 days. Treatment course 1 consists of: Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5 Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5 Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5 Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines Dasatinib orally, once daily on days 6-29 Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.
  • Dasatinib
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Intrathecal (IT) cytarabine
Dose Level 2ExperimentalStudy participants # 7 - # 12 receive dose level 2 of dasatinib (80/mg/m2/day) in addition to the standard treatment (up to 2 courses), if the participants receiving Dose Level 1 did not experience intolerable side effects. Each treatment course is 29 days. Treatment course 1 consists of: Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5 Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5 Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5 Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines Dasatinib orally, once daily on days 6-29 Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.
  • Dasatinib
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Intrathecal (IT) cytarabine
Dose Level 3ExperimentalStudy participants # 13 - # 18 receive dose level 3 of dasatinib (100/mg/m2/day) in addition to the standard treatment (up to 2 courses), if the participants receiving Dose Level 2 did not experience intolerable side effects. Each treatment course is 29 days. Treatment course 1 consists of: Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5 Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5 Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5 Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines Dasatinib orally, once daily on days 6-29 Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.
  • Dasatinib
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Intrathecal (IT) cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed relapsed or refractory Acute Myeloid Leukemia (AML) and meet
             the following criteria: Relapsed disease is defined as AML in 1st or greater marrow
             relapse; Refractory disease is defined as AML which failed to go into remission after
             1st or greater relapse, OR AML which failed to go into remission after two or more
             induction attempts from original diagnosis

          -  ≥ 5% blasts by morphology in the bone marrow or molecular evidence of at least 0.1%
             leukemic blasts in the bone marrow

          -  Definitive evidence of t(8;21) or inv(16) by a CLIA approved cytogenetics laboratory
             from initial diagnosis

          -  CNS or other sites of extramedullary disease. No cranial irradiation is allowed during
             the protocol therapy

          -  Lansky ≥ 50 for patients ≤ 16 years old; Karnofsky ≥ 50 for patients > 16 years old

          -  Have fully recovered from the acute toxic effects of all prior chemotherapy,
             immunotherapy, or radiation therapy prior to entering this study

          -  Have adequate renal and hepatic functions

          -  A shortening fraction greater than or equal to 27% by echocardiogram, OR ejection
             fraction greater than or equal to 50% by radionuclide angiogram (MUGA)

          -  Must not have any evidence of dyspnea at rest, exercise intolerance, and must have a
             pulse oximetry > 94% at sea level

          -  Patients with a seizure disorder may be enrolled if well controlled on anticonvulsants
             at a dose that has been stable for at least 14 days

          -  Female participants of childbearing potential must have a negative urine or serum
             pregnancy test confirmed within 24 hours prior to enrollment

          -  Female participants with infants must agree not to breastfeed their infants while on
             this study

          -  Male and female participants of child-bearing potential must agree to use an effective
             method of contraception approved by the investigator during the study and for a
             minimum of 6 months after study treatment

        Exclusion Criteria:

          -  Known allergy to any of the drugs used in the study

          -  Systemic fungal, bacterial, viral or other infection of which they exhibit ongoing
             signs/symptoms related to the infection without improvement despite appropriate
             antibiotics or other treatment

          -  Any clinically significant cardiovascular disease including: myocardial infarction or
             ventricular tachyarrhythmia within 6 months, prolonged QTc > 480 msec by the
             Fridericia correction, major conduction abnormality, such as 2nd or 3rd degree heart
             block or symptomatic bundle branch block, unless a cardiac pacemaker is present

          -  Plans to administer non-protocol chemotherapy, radiation therapy, or immunotherapy
             during the study period

          -  Refractory to red blood cell or platelet transfusions

          -  Receiving anti-coagulation therapy

          -  A need to administer drugs that inhibit platelet function, such as aspirin or
             clopidogrel

          -  Receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin,
             clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St.
             John's Wort

          -  Significant concurrent disease, illness, psychiatric disorder or social issue that
             would compromise patient safety or compliance with the protocol treatment or
             procedures, interfere with consent, study participation, follow up, or interpretation
             of study results

          -  Individuals with Down syndrome and DNA fragility syndromes (such as Fanconi anemia,
             Bloom syndrome)
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of Dasatinib assessed by the Number of Adverse Events
Time Frame:Duration of Study (Up to 161 Days)
Safety Issue:
Description:The number of adverse events throughout the duration of the study will be collected to assess the safety of dasatinib.

Secondary Outcome Measures

Measure:Remission Status assessed by Bone Marrow Aspiration/Biopsy
Time Frame:Between Day 29 and Day 43
Safety Issue:
Description:A single bone marrow aspiration/biopsy will be performed to assess remission status between day 29 and 43. The exact time point of the bone marrow aspiration/biopsy is dependent on blood count recovery (absolute neutrophil count of greater than 500). Day 43 is the last day remission status must be assessed.
Measure:Effect of Dasatinib on c-KIT Expression assessed by Phosphorylation of Stat3
Time Frame:Baseline, End of course 1 (Up to 49 days)
Safety Issue:
Description:The effect of dasatinib on c-KIT expression will be measured by phosphorylation of Stat3 in a core binding factor acute myeloid leukemia (CBF AML) cell line treated with patient plasma.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Emory University

Trial Keywords

  • Pediatric
  • Adolescent

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