Clinical Trials /

Safety and Effectiveness of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood

NCT03793478

Description:

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research. Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission, or is not responding to treatment.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Effectiveness of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood
  • Official Title: A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination With Re-Induction Chemotherapy, and as a Single-Agent Maintenance Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) With FLT3-ITD Mutations

Clinical Trial IDs

  • ORG STUDY ID: AC220-A-U202
  • SECONDARY ID: 2016-002919-18
  • SECONDARY ID: P/102/2018
  • SECONDARY ID: EU/3/09/622
  • NCT ID: NCT03793478

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
QuizartinibQuizartinib dihydrochlorideAll Participants
Intrathecal (IT) triple chemotherapy prophylaxisStandard practiceAll Participants
Fludarabinepart of FLAAll Participants
Cytarabinepart of FLAAll Participants
EtoposideChemotherapyAll Participants
DaunorubicinLiposomal daunorubicin (preferred), Conventional daunorubicin (if liposomal not available), Daunoxome (DNX)All Participants

Purpose

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research. Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission, or is not responding to treatment.

Detailed Description

      The medical condition being investigated is relapsed or refractory AML in patients aged ≥1
      month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal
      tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive
      chemotherapy.

      The trial will be conducted in multiple phases, using an adaptive trial design. An
      independent data monitoring committee (DMC) will protect the rights, safety, and well-being
      of participants by monitoring the progress and results. The DMC will comprise qualified
      physicians and scientists who are not Investigators in the study and not otherwise directly
      associated with the Sponsor.

      A. Dose Escalation/De-escalation Phase:

      Cohorts of up to 9 participants per dose-level will be enrolled to determine the recommended
      Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure
      to adult patients treated at the target adult dose of 60 mg once daily.

      B. Dose-Expansion Phase:

      Participants will receive the RP2D of quizartinib for their respective age group,
      administered in combination with re-induction chemotherapy

      During both dose escalation and dose expansion phases, participants will receive:

        -  Intrathecal (IT) triple chemotherapy prophylaxis (given three times)

        -  In re-induction Cycle 1, fludarabine/cytarabine (FLA) plus daunorubicin (liposomal
           daunorubicin preferred), followed by quizartinib

        -  In re-induction Cycle 2, FLA followed by quizartinib as a single agent

      C. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:

      After re-induction therapy, participants will be evaluated for eligibility to undergo
      allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants might receive a
      single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without
      quizartinib) if an allogeneic HSCT is not available immediately, as follows:

        -  High intensity chemotherapy with quizartinib, or

        -  Low intensity chemotherapy alone, or

        -  Low intensity therapy with quizartinib as a single agent

      D. Maintenance:

      Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a
      partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of
      quizartinib maintenance therapy at the same dose received during re-induction in the dose
      expansion phase.

      E. Long-term Follow-up:

      The long-term follow-up phase begins upon completion of the 12 cycles of quizartinib
      Maintenance or permanent discontinuation of quizartinib at any time. After completion of the
      30-day safety follow-up visit, subsequent visits will occur at the following frequencies to
      assess survival and anti-leukemic treatments:

        -  every 3 months for the first 2 years, and then

        -  once yearly thereafter until the last participant enrolled has been followed for three
           years from the date of enrollment
    

Trial Arms

NameTypeDescriptionInterventions
All ParticipantsExperimentalIn an adaptive trial design, participants will receive intrathecal (IT) triple chemotherapy prophylaxis, fludarabine with cytarabine (FLA), daunorubicin, and quizartinib. Some participants might also receive etoposide as part of optional high intensity consolidation with chemotherapy and quizartinib.
  • Quizartinib
  • Intrathecal (IT) triple chemotherapy prophylaxis
  • Fludarabine
  • Cytarabine
  • Etoposide
  • Daunorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Has diagnosis of AML according to the World Health Organization (WHO) 2008
             classification with >5% blasts in bone marrow, with or without extramedullary disease

          -  Is in first relapse or refractory to first-line high-dose chemotherapy with no more
             than 1 attempt (1−2 cycles of induction chemotherapy) at remission induction - prior
             HSCT is permitted

          -  Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as
             defined in the protocol

          -  Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is
             signed

          -  Has protocol-defined adequate performance status score

          -  Has fully recovered from the acute toxicity effects of all prior chemotherapy,
             immunotherapy, or radiotherapy, per protocol guidelines

          -  Has protocol-defined adequate renal, hepatic and cardiac functions

          -  If of reproductive potential, is permanently sterile or agrees to use highly effective
             birth control upon enrollment, during the period of therapy, and for 6 months
             following the last dose of study drug or cytarabine, whichever is later

          -  If female of child-bearing potential, tests negative for pregnancy and agrees not to
             breast feed

          -  Participant/legal representative is capable of understanding the investigational
             nature of the study, potential risks, and benefits, and the patient (and/or legal
             representative) signs a written assent/informed consent

          -  Meets protocol-specified guidelines before inclusion in the maintenance phase

        Exclusion Criteria:

          -  Has been diagnosed with isolated central nervous system relapse, certain kinds of
             leukemia, or with myeloid proliferations related to Down syndrome

          -  Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the
             protocol

          -  Has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing
             signs/symptoms related to the infection without improvement despite appropriate
             antibiotics or other treatment. The patient must be off vasopressors and have negative
             blood cultures for at least 48 hours.

          -  Has known active clinically relevant liver disease (e.g., active hepatitis B or active
             hepatitis C)

          -  Has known history of human immunodeficiency virus (HIV)

          -  Has history of hypersensitivity to any of the study medications or their excipients

          -  Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or
             immunotherapy other than as specified in the protocol

          -  Has any significant concurrent disease, illness, psychiatric disorder or social issue
             that would compromise subject safety or compliance, interfere with consent/assent,
             study participation, follow up, or interpretation of study results

          -  Is currently participating in another investigative interventional procedure
             (observational or long-term interventional follow-up is allowed)

          -  Is otherwise considered inappropriate for the study by the Investigator
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Composite complete remission (CRc) rate
Time Frame:within 8 years, 8 months
Safety Issue:
Description:CRc rate is defined as percentage of participants with best response of complete remission (CR) or CR with incomplete hematological recovery (CRi) after completion of up to 2 re-induction cycles

Secondary Outcome Measures

Measure:CR rate
Time Frame:on Day 56 (± 3 Days) for the last subject, within 4 years
Safety Issue:
Description:CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles
Measure:CRi rate
Time Frame:on Day 56 (± 3 Days) for the last subject, within 4 years
Safety Issue:
Description:CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles
Measure:Duration of CR
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Duration of CR is defined as the time from the first documented CR until documented relapse
Measure:Duration of CRc
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse
Measure:CR rate after completion of re-induction Cycle 1
Time Frame:on Day 56 (± 3 Days) for the last subject, within 4 years
Safety Issue:
Description:CR rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CR after completion of re-induction Cycle 1
Measure:CRi rate after completion of re-induction Cycle 1
Time Frame:on Day 56 (± 3 Days) for the last subject, within 4 years
Safety Issue:
Description:CRi rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CRi after completion of re-induction Cycle 1
Measure:CRc rate after completion of re-induction Cycle 1
Time Frame:on Day 56 (± 3 Days) for the last subject, within 4 years
Safety Issue:
Description:CRc rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving CRc after completion of re-induction Cycle 1
Measure:Time to Relapse
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse
Measure:Rate of Relapse after 1, 2 and 3 years
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Rate of relapse is defined as the percentage of participants who achieved CRc at the end of re-induction and had relapsed at 3 categorical time points Categories: 1 year, 2 years, 3 years
Measure:Cumulative incidence of relapse at the end of study
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Cumulative incidence of relapse at the end of the study is defined as the percentage of participants who achieved CRc at the end of re-induction and relapsed by the end of the study
Measure:Overall survival
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Overall survival is defined as the time from the start of re-induction therapy until death from any cause
Measure:Event-free survival
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Event-free survival is defined as the time from the start of re-induction therapy until the earliest date of the following: Refractory disease at the end of re-induction Relapse after CR or CRi Death from any cause at any time during the study
Measure:Number of participants proceeding to high-dose conditioning therapy/allogeneic hematopoietic stem cell transplantation (HSCT)
Time Frame:within 8 years, 8 months
Safety Issue:
Description:
Measure:Number of participants who achieved CR or CRi with minimal residual disease (MRD)
Time Frame:within 8 years, 8 months
Safety Issue:
Description:MRD is defined as the presence of leukemic cells in the bone marrow detected above a predefined cut-off level by a validated assay in participants who achieved a CR or CRi Categories: at screening, at re-induction cycle 1, at re-induction cycle 2, at time of relapse
Measure:Number of participants who found the quizartinib formulation acceptable
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Acceptability is assessed by palatability using a 5-point hedonic scale (from "Super bad" to "Super good") for participants who are developmentally able to answer. If unable, the caregiver provides information in a free text field stating whether the participant spit it out, may not have liked the flavor, etc.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Acute myeloid leukemia recurrent
  • Relapsed or refractory
  • FMS-like tyrosine kinase 3 positive
  • Cancer of the blood
  • AML
  • FLT3-ITD mutation

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