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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03793478
Recruitment Status : Recruiting
First Posted : January 4, 2019
Last Update Posted : May 17, 2023
Sponsor:
Collaborators:
Innovative Therapies For Children with Cancer Consortium
Children's Oncology Group
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Quizartinib Drug: Fludarabine Drug: Cytarabine Drug: Intrathecal (IT) triple chemotherapy prophylaxis Drug: Etoposide Phase 1 Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: A single group will progress through a multiple phase study design as described in the detailed description.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 15, 2018
Estimated Primary Completion Date : May 1, 2027
Estimated Study Completion Date : May 1, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: All Participants
All 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.
 Drug: Quizartinib

Administered orally once daily starting on Day 6 and continuing through Day 28;

Optional low intensity consolidation with chemotherapy:

Administered orally once daily starting on Day 1 and continuing through Day 28

Other Names:
  • Quizartinib dihydrochloride
  • Vanflyta

Drug: Fludarabine
30 mg/m^2/day IV infusion given over 30 minutes on Days 1 through 5 (administered based on body weight)

Drug: Cytarabine

2000 mg/m^2/day IV infusion given over 3 hours on Days 1 through 5 (begin 4 hours after the start of fludarabine) (administered in accordance with standard of care);

Optional high intensity consolidation with chemotherapy and quizartinib:

500 mg/m^2/day as a continuous 96-hour IV infusion on Days 1 through 4;

Optional low intensity consolidation with chemotherapy:

75 mg/m^2/day as once daily subcutaneous or IV on Days 1 through 4 and Days 15 through 18


Drug: Intrathecal (IT) triple chemotherapy prophylaxis
IT cytarabine, methotrexate, and either prednisolone or hydrocortisone; doses are based on the participant's age and standard practice at each site

Drug: Etoposide

Optional high intensity consolidation with chemotherapy and quizartinib:

100 mg/m^2/dose once daily as an IV infusion over 3 hours on Days 1 through 5


Outcome Measures
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Primary Outcome Measures :
  1. Number of dose-limiting toxicities (Phase 1) [ Time Frame: Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days) ]
  2. Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    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

  3. Pharmacokinetic parameter area under the concentration curve for quizartinib and AC886 (Phase 1 and 2) [ Time Frame: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) ]
  4. Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2) [ Time Frame: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) ]
  5. Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2) [ Time Frame: Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) ]

Secondary Outcome Measures :
  1. Complete remission (CR) rate among participants with AML (Phase 1 and 2) [ Time Frame: on Day 56 (± 3 Days) for the last subject, within 4 years ]
    CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles

  2. Complete remission with incomplete recovery (CRi) rate among participants with AML (Phase 1 and 2) [ Time Frame: on Day 56 (± 3 Days) for the last subject, within 4 years ]
    CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles

  3. Duration of CR among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    Duration of CR is defined as the time from the first documented CR until documented relapse

  4. Duration of CRi among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    Duration of CRi is defined as the time from the first documented CRi until documented relapse

  5. Duration of composite complete remission (CRc) among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse

  6. Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) [ Time Frame: on Day 56 (± 3 Days) for the last subject, within 4 years ]
    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

  7. Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) [ Time Frame: on Day 56 (± 3 Days) for the last subject, within 4 years ]
    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

  8. Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) [ Time Frame: on Day 56 (± 3 Days) for the last subject, within 4 years ]
    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

  9. Time to relapse among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse

  10. Rate of relapse among participants with AML after 1, 2 and 3 years (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    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

  11. Cumulative incidence of relapse among participants with AML at the end of study (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    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

  12. Overall survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    Overall survival is defined as the time from the start of re-induction therapy until death from any cause

  13. Event-free survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]

    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

  14. Number of participants proceeding to high-dose conditioning therapy/allogeneic hematopoietic stem cell transplantation (HSCT) (including transplant-related mortality) among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
  15. Rate of CRc (CR or CRi) without minimal residual disease (MRD) using next generation sequencing among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]

    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


  16. Acceptability of including the palatability of quizartinib formulations among participants with AML (Phase 1 and 2) [ Time Frame: within 8 years, 8 months ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Month to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for enrollment into the study:

  • Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease
  • 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 quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later
  • If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
  • Male participants must be surgically sterile or willing to use highly effective birth control during the treatment period, and for 6 months following the last dose of quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later.
  • 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

Exclusion Criteria:

Participants who meet any of the following criteria will be disqualified from entering the study:

  • Has been diagnosed with isolated central nervous system relapse, acute promyelocytic leukemia (APL), juvenile myelomonocytic leukemia, French-American-British classification M3 or WHO classification of APL with translocation, 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03793478


Contacts
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Contact: Daiichi Sankyo Contact for Clinical Information 908-992-6400 CTRinfo@dsi.com

Locations
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Sponsors and Collaborators
Daiichi Sankyo, Inc.
Innovative Therapies For Children with Cancer Consortium
Children's Oncology Group
Investigators
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Study Director: Global Clinical Leader Daiichi Sankyo, Inc.
More Information
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT03793478    
Other Study ID Numbers: AC220-A-U202
2016-002919-18 ( EudraCT Number )
First Posted: January 4, 2019    Key Record Dates
Last Update Posted: May 17, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daiichi Sankyo, Inc.:
Acute myeloid leukemia recurrent
Relapsed or refractory
FMS-like tyrosine kinase 3 positive
 Cancer of the blood
AML
FLT3-ITD mutation
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Etoposide
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
 Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents