Relapsed or Refractory acute myeloid leukemia (AML) in subjects aged =1 month to =21 years with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations following failure of front-line intensive chemotherapy MedDRA version: 20.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT
Conditions
Interventions
Product Name: Quizartinib
Product Code: AC220
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: Quizartinib dihydrochloride
Sponsors
Daiichi Sankyo, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must satisfy all of the following inclusion criteria prior to enrollment: 1. Diagnosis of AML according to the World Health Organization (WHO) 2008 classification with >5% blasts in bone marrow, with or without extramedullary disease. 2. Subjects must be in first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1-2 cycles of induction chemotherapy) at remission induction. 3. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as confirmed by the central laboratory =3% FLT3-ITD/total FLT3). Subjects may be enrolled and begin treatment based upon the results of a local FLT3-ITD laboratory test (performed on or after the date of diagnosis of relapse/refractory disease), however, a sample must be sent to the central laboratory for confirmation. 4. Subjects must be between 1 month and =21 years of age at the time the Informed Consent/Assent form is signed. 5. Karnofsky performance status score of >50% for subjects >16 years of age, and a Lansky performance status score of >50% for subjects =16 years of age. 6. Subjects must have fully recovered from the acute toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study: a. Myelosuppressive chemotherapy: - For subjects who relapse while they are receiving cytotoxic therapy, at least 21 days must have elapsed since the completion of cytotoxic therapy. - Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy. Subjects may also receive low dose cytarabine (100 mg/m2/dose once daily for 5 days) for cytoreduction. - Subjects who have received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib), with the exception of quizartinib, are eligible for this study. b. Hematopoietic growth factors: At least 3 days since the completion of therapy with a growth factor. c. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. However, for agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the medical monitor. d. =14 days for local external radiation therapy (XRT) for CNS chloromas. e. =90 days must have elapsed if prior total body radiation (TBI) or craniospinal XRT occurred. f. At least 90 days must have elapsed since HSCT; and subjects must not have active graft-versus-host disease (GVHD). Immunosuppressive therapy must be stable for =2 weeks in subjects with a history of = Grade 2 GVHD and for =4 weeks in subjects with a history of Grade 3/4 GVHD. g. Investigational Drug/Device: at least 30 days or 5 half-lives since the completion of therapy, whichever is longer. 7. Adequate renal and hepatic functions as indicated by the following laboratory values: a. Serum creatinine concentration = institutional upper limit of nor al (ULN) based on the age and gender. b. Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin (unless related to le
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following criteria will be disqualified from entering the study: 1. Diagnosis of isolated CNS relapse (CNS2/3 disease is allowed if treated with additional IT chemotherapy). 2. Diagnosis of acute promyelocytic leukemia (APL), Juvenile myelomonocytic leukemia (JMML), FAB classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or myeloid proliferations related to Down syndrome. 3. Uncontrolled or significant cardiovascular disease, including: a. Diagnosed or suspected congenital long QT syndrome. b. History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Medical Monitor prior to subject’s entry into the study. c. QT interval corrected >450 msec: • QTc interval corrected with Bazzet’s formula (QTcB) for subjects < 6 years of age at the time of enrollment. • QTc interval corrected with Fridericia’s formula (QTcF) for subjects = 6 years of age at the time of enrollment. d. History of uncontrolled angina pectoris or myocardial infarction within 6 months. e. History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker). f. Heart rate <50/minute on pre-entry ECG. g. Uncontrolled hypertension (i.e., systolic blood pressure and /or diastolic blood pressure that is, on repeated measurement, at or above the 95th percentile for sex, age, and height). h. History of complete left bundle branch block. i. History of New York Heart Association Class 3 or 4 heart failure. 4. Subjects will be excluded if they have a 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 subject needs to be off vasopressors and have negative blood cultures for at least 48 hours. 5. Known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C). 6. Known history of human immunodeficiency virus (HIV). 7. History of hypersensitivity to any of the study medications or their excipients. 8. Subject is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol. 9. 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. 10. Currently participating in other investigational interventional procedures (does not include observational procedures or long-term follow-up for previous interventional studies). 11. Otherwise considered inappropriate for the study by the Investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1 only: - To determine the recommended Phase 2 dose (RP2D) of quizartinib, in combination with chemotherapy, for subjects in the older (=1 year old to =21 years old) and younger (=1 month old to <12 months old) age groups. - To determine the composite complete remission (CRc) rate (i.e., complete remission [CR] + CR with incomplete recovery [CRi]) after completion of up to 2 Re-Induction Cycles. - To determine the safety and cumulative toxicity of quizartinib administered in combination with re-induction therapy for up to 2 cycles, with optional consolidation therapy, and as a single-agent maintenance therapy over =12 cycles. - To determine estimates of individual PK parameters of quizartinib and AC886 (metabolite of quizartinib). ; Secondary Objective: •To determine: o CR rate after completion of up to 2 Re-Induction Cycles o Durations of CRc and CR • To assess: o Time to relapse, rate of relapse after 1, 2 and 3 years, and cumulative incidence of relapse at the EoT o To determine the rates of CR and CRc after completion of Re- Induction Cycle 1 o OS and EFS at 1, 2, and 3 years o Number of subjects proceeding to high-dose conditioning therapy/ HSCT o Activity of quizartinib on FLT3-ITD and FLT3-wild- type autophosphorylation activity by an ex-vivo PIA during Re-Induction, Maintenance, and at time of relapse o FLT-ITD/FLT3-wild-type allelic ratio at Screening, during Re-Induction, and at time of relapse o To evaluate mutations in blasts at Screening and at time of refractory disease or relapse o MRD for subjects in CR or CRi at Screening, end of Re-Induction Cycle 1, end of Re- Induction Cycle 2 and at time of relapse by next generation sequencing o Acceptabil | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy (i.e., the secondary outcome measures): - Duration of CR. - Duration of CRc (i.e., from first documented CRc until documented relapse). - CR rate after completion of Re-Induction Cycle 1. - CR rate after completion of up to 2 Re-Induction Cycles. - CRc rate after completion of Re-Induction Cycle 1. - Time to relapse, the rate of relapse after 1, 2 and 3 years, and the cumulative incidence of relapse at the end of the study. - Overall survival, defined as the time from the start of Re-Induction therapy until death from any cause. - Number of subjects proceeding to high-dose conditioning therapy/HSCT (including transplant-related mortality). - Event-free survival 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. Pharmacodynamic: - Inhibition of FLT3-ITD and FLT3-wild-type autophosphorylation activity in an ex-vivo PIA during Re-Induction, Maintenance, and at the time of relapse. - FLT-ITD to FLT3-wild-type allelic ratio at Screening, during Re- Induction, and at the time of relapse. - Mutations present in blasts (e.g., in the kinase and juxtamembrane domains of FLT3-ITD and other mutations known to be associated with AML) at Screening and at the time of refractory disease or relapse. Biomarker: - MRD for subjects who are in CR or CRi at Screening, end of Re-Induction Cycle 1, end of Re-Induction Cycle 2, and at the time of | — |
Countries
Belgium, Denmark, France, Germany, Ireland, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Contact
Daiichi Sankyo, Inc.
Outcome results
None listed