A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination with Re-Induction Chemotherapy, and as a Single-Agent Continuation Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) with FLT3-ITD mutations
- Conditions
- cancer of the bone marrowleukemia10024324
- Registration Number
- NL-OMON52604
- Lead Sponsor
- Daiichi Pharmaceutical
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 2
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 to 2 cycles of induction
chemotherapy) at remission induction. Prior HSCT is permitted.
3. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral
blood that is confirmed by central testing. The results of FLT3 ITD testing
must be obtained prior to the first dose of quizartinib (Re-Induction Cycle 1,
Day 6). Subjects may be enrolled and begin treatment with the systemic
protocol therapy pending the result of the FLT3 ITD testing; however, subjects
with a negative central and local FLT3 ITD test who are enrolled and have begun
systemic protocol treatment will be discontinued from the study. Subjects may
also 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 R/R disease);
however, a sample must be sent to the central laboratory for confirmation.
Subjects with a negative central FLT3-ITD test who are enrolled and have begun
treatment based upon results of a FLT3-ITD test conducted at a local laboratory
may continue on the study at the investigator*s discretion after discussion
with the medical monitor.
4. Subjects must be between 1 month and <=21 years of age at the time the ICF 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 clinically significant
toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy
prior to Re-Induction Cycle 1, Day 1:
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 1 day prior to the start of systemic protocol therapy.
Subjects may also receive
low dose cytarabine (100 mg/m2/dose once daily for up to 5 days) for
cytoreduction and completed up to 1 day prior to the start of systemic protocol
therapy.
* Subjects who have received other FLT3 inhibitors (eg,
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. For subjects with a
history of graft versus host disease (GVHD), immunosuppressive therapy must be
stable f
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), French-American-British (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 ms:
* QTc interval corrected with Bazett*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 beats/minute on screeening electrocardiogram (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 prior to the start of systemic protocol therapy..
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoints:<br /><br>Safety:<br /><br>* The safety profile of quizartinib administered in combination with reinduction<br /><br>chemotherapy for up to 2 cycles, with optional consolidation<br /><br>chemotherapy, and as a single-agent maintenance therapy over <=12 cycles.<br /><br>* Phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1.<br /><br>Efficacy (i.e., the primary outcome measure):<br /><br>* CRc rate after completion of up to 2 Re-Induction Cycles.<br /><br>Pharmacokinetic:<br /><br>* Estimates of AUC, apparent clearance (CL/F), and apparent volume of<br /><br>distribution (Vd) for quizartinib and AC886 by the use of<br /><br>PopPK modeling or other applicable methods.</p><br>
- Secondary Outcome Measures
Name Time Method