Phase 2 Study of Quizartinib in Participants With Acute Myeloid Leukemia (AML) FLT3 Internal Tandem Duplication (FLT3/ITD) Mutation

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, multi-center, open-label study to evaluate the efficacy, safety and pharmacokinetics of quizartinib monotherapy in Japanese subjects with FLT3-ITD positive refractory or relapsed acute myeloid leukemia.

Official Title
-----------------
Phase 2 Open-label, Single-arm Study of Quizartinib (AC220) Monotherapy in Japanese Patients With FLT3-ITD Positive Refractory or Relapsed Acute Myeloid Leukemia

Conditions
-----------------
Leukemia, Myeloid, Acute

Intervention / Treatment
-----------------
* Drug: Quizartinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: AML patients in first relapse or refractory after all prior therapy Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 Exclusion Criteria: Diagnosis of acute promyelocytic leukemia AML secondary to prior chemotherapy for other neoplasms. Persistent, clinically significant > Grade 1 non-hematologic toxicity from prior AML therapy Prior treatment with a FLT3 targeted therapy Active infection not well controlled by antibacterial, antifungal and/or antiviral therapy

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Initial dose 30 mg/day quizartinib<br>Participants who received an initial dose of 30 mg/day of quizartinib and, if no QT prolongation, the dose escalated to 60 mg/day at Day 15. | Drug: Quizartinib<br>* Quizartinib was orally administered once daily every morning. Treatment with quizartinib was administered in 28-day cycles and continued until the discontinuation criteria for treatment were met.<br>|
| Experimental: Initial dose 20 mg/day quizartinib<br>Participants who received a CYP3A4 strong inhibitor received an initial dose of 20 mg/day of quizartinib and, if no QT prolongation, the dose escalated to 30 mg/day at Day 15. | Drug: Quizartinib<br>* Quizartinib was orally administered once daily every morning. Treatment with quizartinib was administered in 28-day cycles and continued until the discontinuation criteria for treatment were met.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Complete Remission (CRc) Rate After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | The composite complete remission (CRc) rate is defined as the proportion of participants whose best response is complete remission [CR], CR with incomplete platelet recovery [CRp], or CR with incomplete hematological recovery [CRi]) after treatment with quizartinib. | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 up until the end of treatment, except for responses from any subsequent AML therapy including transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | Best response is defined as the best measured response over all response assessments (complete response [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematological recovery [CRi], partial remission [PR], no response [NR], or Unknown) at all time points after the first dose of the study drug to the end of treatment (does not include response from any subsequent AML therapy including transplantation). | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 until the end of treatment, except for responses from any subsequent AML | 
| Response Rate After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML |  | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 until the end of treatment, except for responses from any subsequent AML | 
| Duration of Composite Complete Remission (CRc) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | Duration from the date of first composite complete remission (CRc) (complete remission [CR], CR with incomplete platelet recovery [CRp], or CR with incomplete hematological recovery [CRi]) observed to the date of documented relapse was assessed. | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 up until the end of treatment, except for responses from any subsequent AML therapy including transplantation | 
| Overall Survival (OS) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | OS is defined as the time from registration (enrollment) until death from any cause. | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 until the end of treatment, except for responses from any subsequent AML therapy including transplantation up to 1 year | 
| Event-free Survival (EFS) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | Event-free survival is defined as the time from date of registration until documented refractory disease, relapse after response of composite complete remission (CRc = complete remission [CR], CR with incomplete platelet recovery [CRp], or CR with incomplete hematological recovery [CRi]), or death from any cause, whichever occurs first. | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 until the end of treatment, except for responses from any subsequent AML therapy including transplantation up to 32 weeks | 
| Leukemia-free Survival (LFS) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | Leukemia-free survival (LFS) is the time from the first documented response of CRc until documented relapse or death from any cause. The analysis for LFS will be conditional on the participant having a documented best response of CRc. | Baseline, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 until the end of treatment, except for responses from any subsequent AML therapy including transplantation up to 28 weeks | 
| Hematopoietic Stem Cell Transplantation Rate After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML | Proportion of participants who start hematopoietic stem cell transplantation (HSCT) immediately after the end of treatment with the study drug without receiving other treatment for AML, except for conditioning regiment for HSCT, was assessed. | Up to new AML treatment or 1 year post treatment | 
| Change in the Area Under the Plasma Concentration Time Curve (AUC) of Quizartinib and Its Active Metabolite After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML |  | Cycle 1, Days 1 and 15; Cycle 2, Day 1 | 
| Change in the Maximum Plasma Concentration (Cmax) of Quizartinib and Its Metabolite (AC886) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML |  | Cycle 1, Days 1 and 15; Cycle 2, Day 1 | 
| Change in the Trough Plasma Concentration (Ctrough) of Quizartinib and Its Metabolite (AC886) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML |  | Cycle 1, Day 15 | 
| Change in the Time to Reach Maximum Plasma Concentration (Tmax) of Quizartinib and Its Metabolite (AC886) After Treatment With Quizartinib in Japanese Participants With FLT3-ITD Positive Relapsed or Refractory AML |  | Cycle 1, Days 1 and 15; Cycle 2, Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FLT3-ITD, Positive refractory or relapsed acute myeloid leukemia, Hematology malignancy, Developmental Phase II