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

Phase 2Active Not RecruitingNCT03793478

Daiichi Sankyo65 enrolled

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myeloid Leukemia

Interventions

QuizartinibDRUG

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

FludarabineDRUG

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

CytarabineDRUG

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

Eligibility

Sex: ALLMin age: 1 MonthMax age: 21 Years

Medical Language ↔ Plain English

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

Locations (27)

Outcomes

Primary Outcomes

Number of dose-limiting toxicities (Phase 1)

Time frame: Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days)

Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) (Phase 1 and 2)

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

Time frame: within 8 years, 8 months

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)

Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2)

Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2)

Secondary Outcomes

Complete remission (CR) rate among participants with AML (Phase 1 and 2)

CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles

Data from ClinicalTrials.gov

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