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 Continuation 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
  • NCT ID: NCT03793478

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
QuizartinibQuizartinib dihydrochloride, VanflytaAll Participants
Intrathecal (IT) triple chemotherapy prophylaxisAll Participants
FludarabineAll Participants
CytarabineAll Participants
EtoposideAll 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 participants 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. 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 and will be
      convened at the end of Phase 1.

      A. Dose Escalation/De-escalation Phase:

      Number of participants is determined by age group. Participants will be enrolled by
      dose-level 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 orally once daily.

      B. Dose-Expansion Phase:

      Participants will receive the RP2D of quizartinib for their respective age group.

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

      Re-Induction Therapy

        -  Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles

        -  In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as
           a single agent

      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 may 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. The options for
      consolidation therapy are as follows:

        -  High intensity chemotherapy with quizartinib, or

        -  Low intensity chemotherapy alone, or

        -  Low intensity therapy with quizartinib as a single agent

      Continuation Therapy:

      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 continuation therapy at the same dose received during re-induction in the dose
      expansion phase.

      Long-term Follow-up:

      The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation
      Therapy 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 a year thereafter until the last participant enrolled has been followed for three
           years from the date of enrollment
    

Trial Arms

NameTypeDescriptionInterventions
All ParticipantsExperimentalAll participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
  • Quizartinib
  • Intrathecal (IT) triple chemotherapy prophylaxis
  • Fludarabine
  • Cytarabine
  • Etoposide

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 to 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 clinically significant 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 continuation therapy 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 prior to the start of systematic protocol
             therapy.

          -  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 among participants with acute myeloid leukemia (AML)
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:Complete remission (CR) rate among participants with acute myeloid leukemia (AML)
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:Complete remission with incomplete recovery (CRi) rate among participants with acute myeloid leukemia (AML)
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 complete remission (CR) among participants with acute myeloid leukemia (AML)
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 complete remission with incomplete recovery (CRi) among participants with acute myeloid leukemia (AML)
Time Frame:within 8 years, 8 months
Safety Issue:
Description:Duration of CRi is defined as the time from the first documented CRi until documented relapse
Measure:Duration of composite complete remission (CRc) among participants with acute myeloid leukemia (AML)
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:Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML)
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:Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML)
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:Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML)
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 among participants with acute myeloid leukemia (AML)
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 among participants with acute myeloid leukemia (AML) 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 among participants with acute myeloid leukemia (AML) 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 among participants with acute myeloid leukemia (AML)
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 among participants with acute myeloid leukemia (AML)
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) (including transplant-related mortality) among participants with acute myeloid leukemia (AML)
Time Frame:within 8 years, 8 months
Safety Issue:
Description:
Measure:Rate of composite complete remission (CRc; complete remission [CR] or complete remission with incomplete recovery [CRi]) without minimal residual disease (MRD) using next generation sequencing among participants with acute myeloid leukemia (AML)
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:Acceptability of including the palatability of quizartinib formulations among participants with acute myeloid leukemia (AML): 5-point hedonic scale
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

Last Updated

June 8, 2020