Clinical Trials /

International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

NCT02724163

Description:

The main purpose of this study is : 1. To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction 2. To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. 3. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy. 4. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients. 5. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloid Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia
  • Official Title: International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia - Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination With Induction Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: RG_14-088
  • SECONDARY ID: 2014-005066-30
  • NCT ID: NCT02724163

Conditions

  • Acute Myeloid Leukaemia

Interventions

DrugSynonymsArms
Gemtuzumab ozogamicinMylotargGemtuzumab Ozogamicin Dose Finding Study
Liposomal daunorubicinLiposomal daunorubicin
MitoxantroneMitoxantrone
FludarabineFludarabine & cytarabine
CytarabineMitoxantrone
BusulfanMyeloablative conditioning
CyclophosphamideMyeloablative conditioning

Purpose

The main purpose of this study is : 1. To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction 2. To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. 3. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy. 4. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients. 5. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Detailed Description

      MyeChild 01 is an international phase III clinical trial in children with acute myeloid
      leukaemia (AML); a disease with significant mortality. It will compare two induction
      chemotherapy regimens: mitoxantrone and cytarabine (current standard treatment) with
      liposomal daunorubicin and cytarabine. This will test liposomal daunorubicin, which is
      believed to be less cardiotoxic than similar conventional drugs, although this is unproven.
      Patients responding well to induction chemotherapy are eligible for a randomisation of two
      consolidation regimens: high dose cytarabine (current standard treatment) or fludarabine and
      cytarabine (FLA); a regimen commonly used in patients with relapsed disease, testing whether
      FLA is more effective in front line therapy than standard consolidation treatment. Patients
      with cytogenetic features associated with a higher risk of relapse and those responding
      sub-optimally to induction treatment are candidates for haemopoietic stem cell transplant
      (HSCT) and are eligible for a randomisation comparing two HSCT conditioning regimens:
      myeloablative conditioning (MAC) (current UNited Kingdom (UK) standard) or reduced intensity
      conditioning (RIC). HSCT has not consistently shown benefit in high risk patients because the
      mortality associated with the procedure has outweighed the advantage from a reduction in
      relapse risk. This will test whether reducing the intensity of conditioning improves survival
      by reducing transplant related deaths without increasing the relapse rate. The trial
      incorporates a dose finding study for gemtuzumab ozogamicin. The aim is to identify the
      optimum tolerated number of doses of gemtuzumab ozogamicin (up to a total of 3 doses), which
      can be safely combined with either of the induction chemotherapy regimens and then to compare
      this number of doses with one dose of gemtuzumab ozogamicin. The intensity of treatment will
      be directed by cytogenetics/molecular genetics and response assessed by minimal residual
      disease (MRD) levels measured by flow cytometry and molecular methodology.
    

Trial Arms

NameTypeDescriptionInterventions
MitoxantroneActive ComparatorCourse 1 Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2, 3 and 4 (total 4 doses). Cytarabine:100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2 and 3 (total 3 doses). Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
  • Mitoxantrone
  • Cytarabine
Liposomal daunorubicinExperimentalCourse 1 Liposomal daunorubicin: 80 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 Liposomal daunorubicin: 60 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
  • Liposomal daunorubicin
  • Cytarabine
Gemtuzumab Ozogamicin Dose Finding StudyExperimentalCohort 1: 1x3mg/m2 IV infusion over 2hours on day 4. Cohort 2: 2x3mg/m2 IV infusion over 2hours on day 4 and day 7. Cohort 3: 3x3mg/m2 IV infusion over 2hours on days 4, 7 and 10.
  • Gemtuzumab ozogamicin
High dose cytarabineActive ComparatorTwo courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).
  • Cytarabine
Fludarabine & cytarabineExperimentalTwo courses of: Fludarabine: 30 mg/m2 daily by IV infusion over 30 minutes on days 1-5 inclusive (total 5 doses). Cytarabine: 2 g/m2 daily by IV infusion over 4 hours on days 1-5 inclusive (total 5 doses).The cytarabine infusion should be started 4 hours after the start of the fludarabine infusion
  • Fludarabine
  • Cytarabine
Myeloablative conditioningActive ComparatorBusulfan Area Under the Curve (AUC) 70-100mg/L x hr by IV infusion over 3 hours, given 12 hourly on days -10 to -7 (8 doses). Cyclophosphamide 50mg/kg/day by IV infusion over 1 hour, on days -5 to -2 (4 doses).
  • Busulfan
  • Cyclophosphamide
Reduced intensity conditioningExperimentalBusulfan AUC60-65mg/L X hr by IV infusion over 3 hours, given 12 hourly on days -5 to -2 (8 doses). Fludarabine 30mg/m2/day by IV infusion over 30 minutes on days -8 to -3 (6 doses).
  • Fludarabine
  • Busulfan

Eligibility Criteria

        Inclusion Criteria:

        Inclusion criteria for trial entry and R1 randomisation.

          -  Diagnosis of acute myeloid leukaemia (AML) /high risk Myelodysplastic syndrome (MDS)
             (>10% blasts in the bone marrow)/isolated myeloid sarcoma (MS) (either de novo or
             secondary).

          -  Age <18 years.

          -  No prior chemotherapy or biological therapy for AML other than that permitted in the
             protocol.

          -  Normal cardiac function defined as fractional shortening ≥28% or ejection fraction
             ≥55%.

          -  Fit for protocol chemotherapy.

          -  Documented negative pregnancy test for female patients of childbearing potential.

          -  Patient agrees to use effective contraception (patients of child bearing potential).

          -  Written informed consent from the patient and/or parent/legal guardian.

        Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study:

        Centres must be formally activated in order to be take part in the embedded dose escalation
        study. Please contact the trial office for further information.

          -  Patient meets the inclusion criteria for trial entry.

          -  Age:

               -  ≥12 months for the major dose finding study

               -  ≥ 12 weeks and <12 months for the minor dose finding study

          -  Karnofsky or Lansky performance score of ≥50.

          -  Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.

          -  Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN)
             for age unless it is caused by leukaemic involvement or Gilbert's syndrome or similar
             disorder.

          -  Alanine transaminase (ALT) or aspartate transaminase (AST) ≤10 x ULN for age.

          -  Written informed consent from the patient and/or parent/legal guardian.

        Inclusion criteria for participation in R2 (randomisation not yet open).

          -  Patient meets the inclusion criteria for trial entry

          -  Age ≥12 weeks.

          -  Karnofsky or Lansky performance score of ≥50.

          -  Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.

          -  Normal hepatic function defined as total bilirubin ≤2.5 ULN for age and not due to
             leukaemic involvement or Gilbert's syndrome or similar disorder.

          -  ALT or AST ≤10 x ULN for age.

          -  Written informed consent from the patient and/or parent/legal guardian.

        Inclusion criteria for participation in R3.

          -  Patient meets the inclusion criteria for trial entry

          -  Induction treatment as per MyeChild 01 protocol or treated with 2 courses of
             mitoxantrone & cytarabine off trial.

          -  Minimal residual disease (MRD) response (performed in MyeChild 01 centralised
             laboratories, see national MyeChild 01 Laboratory Manual):

               -  Patients with good risk cytogenetics/molecular genetics and a MRD level <0.1% by
                  flow after course 2, or a decrease in transcript levels of >3 logs after course 2
                  for those with an informative molecular marker, but without an informative marker
                  of sufficient sensitivity for flow MRD monitoring or

               -  Patients with intermediate risk cytogenetics/molecular genetics with a MRD level
                  <0.1% by flow after course 1 and course 2, or a decrease in transcript levels of
                  >3 logs after course 1 and course 2 for those with an informative molecular
                  marker, but without an informative marker of sufficient sensitivity for flow MRD
                  monitoring.

          -  Written informed consent from the patient and/or parent/legal guardian.

        Inclusion criteria for participation in R4.

          -  Patient meets the inclusion criteria for trial entry

          -  Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of
             mitoxantrone & cytarabine ± treatment intensification with fludarabine, cytarabine &
             idarubicin (FLA-Ida) off trial.

          -  Patient is in complete remission (CR) or CR with incomplete blood count recovery (CRi)
             defined as <5% blasts confirmed by flow cytometry/ molecular/FISH in a bone marrow
             aspirate taken within 6 weeks prior to randomisation to R4.

          -  Patient meets one of the following criteria and is a candidate for HSCT as per the
             protocol:

               -  High risk after course 1 (all patients with poor risk cytogenetics and patients
                  with intermediate risk cytogenetics who fail to achieve CR/CRi).

               -  Intermediate risk cytogenetics with MRD >0.1% after course 1 and 2 measured by
                  flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular
                  MRD marker with a sensitivity of >0.1% may be used.

               -  Good risk cytogenetics with flow MRD >0.1% confirmed by a decrease in molecular
                  MRD of <3 logs or rising transcript levels after course 3 despite treatment
                  intensification (FLA-Ida) and after discussion with the Clinical Co-ordinators.

          -  Availability of a 9-10/10 human leukocyte antigen (HLA) matched family or unrelated
             donor or 5-8/8 matched cord blood unit with an adequate cell dose as defined by the
             protocol section 17.1.

          -  Written informed consent from the patient and/or parent/legal guardian.

        Exclusion Criteria:

        Exclusion criteria for all randomisations

          -  Acute Promyelocytic Leukaemia.

          -  Myeloid Leukaemia of Down Syndrome.

          -  Blast crisis of chronic myeloid leukaemia.

          -  Relapsed or refractory AML.

          -  Bone marrow failure syndromes.

          -  Prior anthracycline exposure which would inhibit the delivery of study anthracyclines.

          -  Concurrent treatment or administration of any other experimental drug or with any
             other biological therapy for AML.

          -  Pregnant or lactating females.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities (DLTs).
Time Frame:Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.

Secondary Outcome Measures

Measure:The nature, incidence and severity of adverse events (AEs) (gemtuzumab ozogamicin dose finding study).
Time Frame:Evaluated by day 45 post course 1 and course 2.
Safety Issue:
Description:
Measure:Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).
Time Frame:Evaluated by day 45 post course 1 and course 2.
Safety Issue:
Description:Response is assessed by morphology confirmed by MRD levels measured by flow cytometry, molecular methods or fluorescence in situ hybridisation (FISH) as defined in the protocol, in combination with platelet and neutrophil counts. These results of these assessments will be combined to determine the patient's disease response using the response criteria defined in the protocol.
Measure:Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)
Time Frame:Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
Safety Issue:
Description:Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
Measure:Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)
Time Frame:Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
Safety Issue:
Description:Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
Measure:Complete remission (CR) (R1 & R2).
Time Frame:Evaluated and presented at the completion of course 1 and 2 of treatment up to a maximum of 45 days post each course of treatment
Safety Issue:
Description:Evaluated using remission status at completion of course 1 and course 2.
Measure:Reasons for failure to achieve CR (R1 & R2).
Time Frame:Evaluated and presented at the completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.
Safety Issue:
Description:Evaluated as resistant disease, induction death or not evaluable.This will be evaluated at completion of course 1 and 2 of treatment, once patient's blood counts have recovered or reason for non-recovery has been determined.
Measure:Cumulative Incidence of Relapse (CIR) (all randomisations).
Time Frame:Evaluated as time from randomisation to the relevant question to relapse, up to 16 years.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. CIR estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
Measure:Death in CR (DCR) (R1, R2 & R3).
Time Frame:Evaluated as time from randomisation to relevant question to date of death from any cause in patients who have achieved CR, up to 16 years.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. DCR estimates will be presented at 24 months along with 95% confidence intervals.
Measure:Event Free Survival (EFS) (R1, R2 & R3).
Time Frame:Evaluated as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause, up to 16 years.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
Measure:Overall Survival (OS) (all randomisations).
Time Frame:Evaluated as time from randomisation to the relevant question to death from any cause or date last seen for patients who are alive at the end of the trial, up to 16 years.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. OS estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
Measure:Incidence of toxicities (all randomisations).
Time Frame:Evaluated 30 days after end of trial treatment.
Safety Issue:
Description:
Measure:Incidence of cardiotoxicity (R1, R2 & R4 only).
Time Frame:Evaluated 30 days after end of trial treatment.
Safety Issue:
Description:
Measure:Incidence of bilirubin of grade 3 of higher (R2 & R4 only).
Time Frame:Evaluated 30 days after end of trial treatment.
Safety Issue:
Description:
Measure:Incidence of Veno-Occlusive Disease (R2 & R4 only).
Time Frame:Evaluated 30 days after end of trial treatment.
Safety Issue:
Description:
Measure:Minimal Residual Disease (MRD) clearance after course 1 & 2 (R1 & R2 only).
Time Frame:Evaluated and presented at completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.
Safety Issue:
Description:Evaluated using MRD result at completion of course 1 and 2 once patient's blood counts have recovered or reason for non-recovery has been determined.
Measure:Time to haematological recovery (all randomisations).
Time Frame:Evaluated by day 45 post course 1 and course 2.
Safety Issue:
Description:Evaluated using the date of haematological recovery (platelets to >=80 x 10^9/L, and neutrophils to >=1.0 x 10^9/L). The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. Time to haematological recovery estimates will be presented at 45 days post course 1 and course 2 of treatment along with 95% confidence intervals.
Measure:Days in hospital after each course of treatment (all randomisations).
Time Frame:Evaluated once all patients have completed trial treatment.
Safety Issue:
Description:Total number of days spent in hospital for each course of treatment, collected from date of randomisation until count recovery after final course of treatment, up to a maximum of 45 days post the final course of treatment. This will be summarised per course of treatment.
Measure:Incidence of mixed chimerism at day 100 post-transplant (R4 only).
Time Frame:Evaluated at day 100 post-transplant.
Safety Issue:
Description:
Measure:Treatment Related Mortality (TRM) (R4 only).
Time Frame:Evaluated as time in days between randomisation to R4 and death which is unrelated to the underlying disease and considered related to the transplant procedure.
Safety Issue:
Description:The primary analysis will be carried out once the last patient has a minimum of 1 year follow up which is estimated to be 7 years after the start of recruitment. TRM estimates will be presented at 12 months along with 95% confidence intervals.
Measure:Gonadal function (R4 only).
Time Frame:Evaluated at 1 year post-transplant and at the end of follow-up, which is estimated to be through to study completion, an average timeframe of 10 years.
Safety Issue:
Description:The method of assessment will be by scale (Tanner scale) and physiological parameters. This will be evaluated at 1 year post-transplant and at the end of study follow-up.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Birmingham

Trial Keywords

  • Acute Myeloid Leukaemia
  • Children
  • Gemtuzumab ozogamicin
  • Liposomal daunorubicin
  • Mitoxantrone
  • Randomised controlled trial
  • Risk stratification
  • Minimal residual disease
  • Stem cell transplant

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