QUIZARTINIB DIHYDROCHLORIDE for Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease\n- 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.\n- 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\n- Female subjects must not donate or retrieve for their own use ova from the time of Screening and throughout the treatment period, and for at least 7 months following the last dose\n- Male subjects must not freeze or donate sperm starting at Screening and throughout the treatment period, and at least 4 months following the last dose.\n- 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\n- Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol\n- Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed\n- Has protocol-defined adequate performance status score\n- Has fully recovered from the acute clinically significant toxicity effects of previous anti-cancer therapy prior to Re-Induction Cycle 1, Day 1, defined as toxicities (other than alopecia) not yet resolved by the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) to Grade ≤ 1 or baseline.\n- Has protocol-defined adequate renal, hepatic and cardiac functions\n- 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\n- If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed"}

Exclusion criteria

• {"criterion_text":"- 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\n- Is otherwise considered inappropriate for the study by the Investigator\n- Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol\n- 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\n- Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)\n- Has known history of human immunodeficiency virus (HIV)\n- Has history of hypersensitivity to any of the study medications or their excipients\n- Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol\n- 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\n- Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)"}

Primary endpoints

• {"endpoint_text":"- Efficacy (ie, the primary outcome measure): CRc rate after completion of up to 2 Re-Induction Cycles.(based on investigator’s assessment).","definition_or_measurement_approach":"CRc rate after completion of up to 2 Re-Induction Cycles (based on investigator’s assessment)."}
• {"endpoint_text":"- Safety: The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation chemotherapy, and as a single-agent continuation therapy over ≤12 cycles. And phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1","definition_or_measurement_approach":"Safety profile assessment of quizartinib in combination with re-induction chemotherapy up to 2 cycles and as single-agent continuation up to ≤12 cycles; Phase 1 only: number of dose-limiting toxicities (DLTs) in dose cohorts in Re-Induction Cycle 1."}
• {"endpoint_text":"- Estimates of AUC, apparent clearance (CL/F), and apparent volume of distribution (Vz/F) for quizartinib and AC886 by the use of PopPK modeling or other applicable methods","definition_or_measurement_approach":"Pharmacokinetic parameter estimation (AUC, CL/F, Vz/F) for quizartinib and AC886 using population PK (PopPK) modelling or other applicable methods."}

Secondary endpoints

• {"endpoint_text":"- Efficacy (ie, the secondary outcome measures): CR rate, which is defined as the percent of subjects achieving a CR after completion of up to 2 Re-Induction cycles","definition_or_measurement_approach":"CR rate defined as percent of subjects achieving CR after completion of up to 2 Re-Induction cycles."}
• {"endpoint_text":"- CRi rate, which is defined as the percent of subjects achieving CRi after completion of up to 2 Re-Induction Cycles.","definition_or_measurement_approach":"CRi rate defined as percent of subjects achieving CRi after completion of up to 2 Re-Induction cycles."}
• {"endpoint_text":"- Duration of CR defined as the time from the first documented CR until documented relapse","definition_or_measurement_approach":"Time from first documented CR until documented relapse."}
• {"endpoint_text":"- Duration of CRi, defined as the time from the first documented CRi until documented relapse","definition_or_measurement_approach":"Time from first documented CRi until documented relapse."}
• {"endpoint_text":"- Duration of CRc, defined as the time from the first documented CR or CRi until documented relapse","definition_or_measurement_approach":"Time from first documented CR or CRi until documented relapse."}
• {"endpoint_text":"- CR rate after completion of Re-Induction Cycle 1 which is defined as the percent of subjects achieving CR after completion of Re-Induction Cycle 1","definition_or_measurement_approach":"Percent of subjects achieving CR after completion of Re-Induction Cycle 1."}
• {"endpoint_text":"- CRi rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving a CRi after completion of Re-Induction Cycle 1","definition_or_measurement_approach":"Percent of subjects achieving CRi after completion of Re-Induction Cycle 1."}
• {"endpoint_text":"- CRc rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving CR+ CRi after completion of Re- Induction Cycle 1","definition_or_measurement_approach":"Percent of subjects achieving CR or CRi after completion of Re-Induction Cycle 1."}
• {"endpoint_text":"- Time to relapse, defined as the time from the first documented response (CR, CRi) until documented relapse","definition_or_measurement_approach":"Time from first documented response (CR or CRi) until documented relapse."}
• {"endpoint_text":"- Rate of relapse after 1, 2 and 3 years","definition_or_measurement_approach":"Proportion of subjects experiencing relapse at 1, 2 and 3 years."}
• {"endpoint_text":"- Cumulative incidence of relapse at the end of the study, defined as the percentage of subjects who achieved CRc at the end of Re-Induction and relapse at these defined time points","definition_or_measurement_approach":"Percentage of subjects who achieved CRc at end of Re-Induction and subsequently relapsed by defined time points (cumulative incidence at end of study)."}
• {"endpoint_text":"- OS, defined as the time from the start of Re-Induction therapy until death from any cause","definition_or_measurement_approach":"Overall survival measured as time from start of Re-Induction therapy until death from any cause."}
• {"endpoint_text":"- EFS defined as the time from the start of Re-Induction therapy until the earliest date of the following: - Refractory disease (or treatmetn failure) at the end of Re-Induction. - Relapse after CR or CRi. - Death from any cause at any time during the study.","definition_or_measurement_approach":"Event-free survival measured from start of Re-Induction until first occurrence of refractory disease at end of Re-Induction, relapse after CR/CRi, or death from any cause."}
• {"endpoint_text":"- Pharmacodynamic: Inhibition of FLT3-ITD autophosphorylation activity in an ex-vivo PIA during Re-Induction, Continuation, and at the time of relapse","definition_or_measurement_approach":"Ex-vivo plasma inhibitory activity (PIA) assay measuring inhibition of FLT3-ITD autophosphorylation during Re-Induction, Continuation and at relapse."}
• {"endpoint_text":"- FLT3-ITD to FLT3-WT allelic ratio at Screening, during Re- Induction, and at the time of relapse","definition_or_measurement_approach":"Measurement of FLT3-ITD/FLT3-WT allelic ratio at Screening, during Re-Induction and at relapse."}
• {"endpoint_text":"- Mutations present in blasts (eg, in the kinase and juxtamembrane domains of FLT3 and other mutations known to be associated with AML) at Screening and at the time of refractory disease or relapse","definition_or_measurement_approach":"Genetic sequencing of blasts to identify somatic mutations (including FLT3 domains) at Screening and at refractory disease/relapse."}
• {"endpoint_text":"- Biomarker: Rate of CRc (CR, CRi) without MRD using next generation sequencing","definition_or_measurement_approach":"Rate of CRc without minimal residual disease (MRD) assessed by next-generation sequencing."}
• {"endpoint_text":"- Others: Acceptability including palatability of quizartinib formulations","definition_or_measurement_approach":"Assessments of acceptability and palatability of quizartinib formulations (subject questionnaires / hedonic scale as per protocol)."}

Italy

Earliest CTIS Part Ii Submission Date

09-04-2024

Latest Decision Or Authorization Date

14-01-2025

Processing Time Days

280

Number Of Sites

3

Number Of Participants

4

Sweden

Earliest CTIS Part Ii Submission Date

05-04-2024

Latest Decision Or Authorization Date

09-12-2024

Processing Time Days

248

Number Of Sites

1

Number Of Participants

2

Belgium

Earliest CTIS Part Ii Submission Date

23-04-2024

Latest Decision Or Authorization Date

19-12-2024

Processing Time Days

240

Number Of Sites

1

Number Of Participants

1

Denmark

Earliest CTIS Part Ii Submission Date

04-04-2024

Latest Decision Or Authorization Date

09-01-2025

Processing Time Days

280

Number Of Sites

1

Number Of Participants

2

France

Earliest CTIS Part Ii Submission Date

23-04-2024

Latest Decision Or Authorization Date

09-12-2024

Processing Time Days

230

Number Of Sites

3

Number Of Participants

4

Netherlands

Earliest CTIS Part Ii Submission Date

04-04-2024

Latest Decision Or Authorization Date

06-12-2024

Processing Time Days

246

Number Of Sites

1

Number Of Participants

2

Spain

Earliest CTIS Part Ii Submission Date

05-04-2024

Latest Decision Or Authorization Date

09-04-2025

Processing Time Days

369

Number Of Sites

2

Number Of Participants

3

Primary sponsor

Full Name

Daiichi Sankyo Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Almac

Responsibilities

sponsorDuties codes: 3

Name

Eresearchtechnology Inc.

Responsibilities

ECG analysis

Name

Fortrea Inc.

Responsibilities

multiple operational roles (sponsorDuties codes: 1,10,12,2,5,6,8)

Name

Inotiv Inc.

Responsibilities

PK samples analysis

Name

Labcorp Central Laboratory Services SARL

Responsibilities

central laboratory services (sponsorDuties codes: 4)

Name

Invivoscribe Inc.

Responsibilities

FLT3 result confirmation and MRD testing; laboratory role

Third parties

• {"country":"United States","full_name":"Almac","duties_or_roles":"sponsorDuties codes: 3","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"ECG analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Inotiv Inc.","duties_or_roles":"PK samples analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)","duties_or_roles":"paediatric networks","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Invivoscribe Inc.","duties_or_roles":"FLT3 Result confirmation and Minimal Residual Disease (MRD) testing; sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"The Children's Oncology Group Foundation Inc.","duties_or_roles":"paediatric networks","organisation_type":"Patient organisation/association"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"sponsorDuties codes: 1,10,12,2,5,6,8","organisation_type":"Pharmaceutical company"}