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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03793478
Other study ID # AC220-A-U202
Secondary ID 2016-002919-18
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date August 15, 2018
Est. completion date May 1, 2027

Study information

Verified date December 2023
Source Daiichi Sankyo, Inc.
Contact Daiichi Sankyo Contact for Clinical Information
Phone 908-992-6400
Email CTRinfo@dsi.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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


Recruitment information / eligibility

Status Recruiting
Enrollment 65
Est. completion date May 1, 2027
Est. primary completion date May 1, 2027
Accepts healthy volunteers No
Gender All
Age group 1 Month to 21 Years
Eligibility 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

Study Design


Intervention

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

Locations

Country Name City State
Belgium Universitair Ziekenhuis Gent Gent
Canada Montreal Children's Hospital Montréal Quebec
Canada The Hospital for Sick Children Toronto Ontario
Canada British Columbia Children's Hospital Vancouver
Denmark Rigshospitalet Copenhagen
France Centre Léon Bérard Lyon
France Hôpital Armand-Trousseau Paris
France Hôpital des Enfants Toulouse
Israel Rambam Medical Center Haifa
Israel Schneider Children's Medical Center of Israel Petah Tikva
Israel Tel Aviv Sourasky Medical Center Tel Aviv-Yafo
Italy Fondazione IRCCS San Gerardo dei Tintori Monza
Italy IRCCS Ospedale Pediatrico Bambino Gesù Rome
Italy Ospedale Infantile Regina Margherita Torino
Netherlands Prinses Maxima Centrum voor Kinderoncologie Utrecht
Spain Hospital Infantil Universitario Nino Jesus Madrid
Spain Hospital Universitario La Paz Madrid
Sweden Sahlgrenska Universitetssjukhuset - Drottning Silvias Barn- och Ungdomssjukhus Göteborg
United Kingdom NHS Greater Glasgow and Clyde - The Queen Elizabeth University Hospital Glasgow
United States Children's Healthcare of Atlanta Atlanta Georgia
United States Children's Hospital Colorado Aurora Colorado
United States Johns Hopkins Baltimore Maryland
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States The University of Texas Southwestern Medical Center Children's Health Dallas Texas
United States Riley Hospital for Children - Indiana University Indianapolis Indiana
United States University of Mississippi Medical Center Jackson Mississippi
United States Loma Linda University Cancer Center Loma Linda California
United States University of Minnesota/Masonic Cancer Center Minneapolis Minnesota
United States Columbia University/Herbert Irving Cancer Center New York New York
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania
United States Washington University School of Medicine Saint Louis Missouri
United States University of California, San Francisco San Francisco California
United States Seattle Children's Hospital Seattle Washington
United States New York Medical College Valhalla New York
United States Children's National Medical Center Washington District of Columbia
United States A.I. duPont Hospital for Children Wilmington Delaware

Sponsors (3)

Lead Sponsor Collaborator
Daiichi Sankyo, Inc. Children's Oncology Group, Innovative Therapies For Children with Cancer Consortium

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Israel,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of dose-limiting toxicities (Phase 1) Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days)
Primary 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 within 8 years, 8 months
Primary Pharmacokinetic parameter area under the concentration curve for quizartinib and AC886 (Phase 1 and 2) 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)
Primary Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2) 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)
Primary Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2) 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 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 on Day 56 (± 3 Days) for the last subject, within 4 years
Secondary Complete remission with incomplete recovery (CRi) rate among participants with AML (Phase 1 and 2) CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles on Day 56 (± 3 Days) for the last subject, within 4 years
Secondary Duration of CR among participants with AML (Phase 1 and 2) Duration of CR is defined as the time from the first documented CR until documented relapse within 8 years, 8 months
Secondary Duration of CRi among participants with AML (Phase 1 and 2) Duration of CRi is defined as the time from the first documented CRi until documented relapse within 8 years, 8 months
Secondary Duration of composite complete remission (CRc) among participants with AML (Phase 1 and 2) Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse within 8 years, 8 months
Secondary Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) 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 on Day 56 (± 3 Days) for the last subject, within 4 years
Secondary Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) 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 on Day 56 (± 3 Days) for the last subject, within 4 years
Secondary Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) 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 on Day 56 (± 3 Days) for the last subject, within 4 years
Secondary Time to relapse among participants with AML (Phase 1 and 2) Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse within 8 years, 8 months
Secondary Rate of relapse among participants with AML after 1, 2 and 3 years (Phase 1 and 2) 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 within 8 years, 8 months
Secondary Cumulative incidence of relapse among participants with AML at the end of study (Phase 1 and 2) 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 within 8 years, 8 months
Secondary Overall survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) Overall survival is defined as the time from the start of re-induction therapy until death from any cause within 8 years, 8 months
Secondary Event-free survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) 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
within 8 years, 8 months
Secondary 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) within 8 years, 8 months
Secondary Rate of CRc (CR or CRi) without minimal residual disease (MRD) using next generation sequencing among participants with AML (Phase 1 and 2) 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
within 8 years, 8 months
Secondary Acceptability of including the palatability of quizartinib formulations among participants with AML (Phase 1 and 2) 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. within 8 years, 8 months
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