| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory acute myeloid leukemia (AML) in subjects aged ≥1 month to ≤21 years with feline McDonough sarcoma-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations following failure of front-line intensive chemotherapy
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| E.1.1.1 | Medical condition in easily understood language |
Relapsed/Refractory acute myeloid leukemia (subjects aged ≥1month- ≤21years) with FMS-like tyrosine kinase 3 internal tandem duplication mutations after failure of front-line intensive chemotherapy
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060558 |
| E.1.2 | Term | Acute myeloid leukemia recurrent |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076230 |
| E.1.2 | Term | Fms-like tyrosine kinase 3 positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 (ie, 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 continuation therapy over ≤12 cycles.
- To determine estimates of individual PK parameters of quizartinib and AC886 (metabolite of quizartinib).
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| E.2.2 | Secondary objectives of the trial |
•To determine:
o CR and CRi rate after completion of up to 2 Re-Induction Cycles
o Durations of CRi, 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, CRi 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 autophosphorylation activity by an ex-vivo PIA during Re-Induction, Continuation, 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 rate of CRc (CR, CRi) without MRD using next generation sequencing
o Acceptability including palatability of quizartinib formulations. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of AML according to the (WHO) 2008 classification with >5% blasts in bone marrow, with/without extramedullary disease.
2. Subjects must be in 1st relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt at remission induction. Prior HSCT is permitted
3. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood. The results of FLT3-ITD testing must be obtained prior to the first dose of quizartinib. Subjects may be enrolled and begin treatment with the systemic protocol therapy pending the result of the 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, however, a sample must be sent to the central lab for confirmation.
Subjects with a negative central FLT3-ITD test who are enrolled and have begun treatment based upon results of a local FLT3-ITD lab test 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 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 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 for cytoreduction and completed up to 1 day prior to the start of systemic protocol therapy.
- Subjects who have received other FLT3 inhibitors, except 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: At least 7 days since the completion of therapy with a biologic agent. However, for agents that have known (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 ≥90 days must have elapsed if prior (TBI) or craniospinal XRT occurred.
e. At least 90 days must have elapsed since HSCT. For subjects with a history of (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 30D 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 ≤1.5 institutional (ULN) based on the age and sex, or (CrCl) >0.84 mL/s. (as measured preferably by a nuclear glomerular filtration rate scan, timed urine collection for CrCl, or calculated by the Schwartz formula [for subjects <18 years old] or Cockcroft-Gault [for subjects ≥18 years old] and normalized to a body surface area of 1.73m2).
b. Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin
c. (ALT) <5 × ULN
8. LV fractional shortening of ≥29% by echocardiogram, OR a left ventricular ejection fraction of ≥50% by echocardiogram or radionuclide angiogram.
9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2W prior to enrollment. Female subjects of childbearing potential must be willing to use highly effective birth control upon enrollment, during the treatment period, and for 6 months following the last dose of quizartinib or cytarabine, whichever is later. Female subjects are considered of childbearing potential following menarche, unless permanently sterile.
10. Female subjects with infants must agree not to breastfeed their infants while on this study.
11. Male subjects must be surgically sterile or willing to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of quizartinib or cytarabine, whichever is later.
12. Subjects and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks, and benefits of the study. All subjects and/or their parents or legal guardians must sign a written informed consent.
Please refer to the protocol for a complete description of inclusion criteria for the maintenance phase. |
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| E.4 | Principal 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); 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 screening ECG.
g. Uncontrolled hypertension (ie, 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 (eg, 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
- The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation therapy, and as a single-agent continuation therapy over ≤12 cycles.
- Phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1.
Efficacy (ie, the primary outcome measure):
- CRc rate after completion of up to 2 Re-Induction Cycles.
Pharmacokinetic:
- Estimates of AUC, CL, and apparent volume of distribution (Vz/F)for quizartinib and AC886 by the use of PopPK modeling or other applicable methods. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Safety: From the time the Informed Consent/Assent Form signature and up to the 30-Day Safety Follow-up Visit
• Efficacy: after completion of up to 2 Re-Induction Cycles.
• PK: Re-Induction Cycles 1 and 2; Maintenance Cycle 1
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| E.5.2 | Secondary end point(s) |
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.
- CRi rate, which is defined as the percent of subjects achieving CRi after completion of up to 2 Re-Induction Cycles.
- Duration of CR defined as the time from the first documented CR until documented relapse.
- Duration of CRi, defined as the time from the first documented CRi until documented relapse.
- Duration of CRc, defined as the time from the first documented CR or CRi until documented relapse.
- 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.
- 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.
- 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.
- Time to relapse, defined as the time from the first documented response (CR, CRi) until documented relapse.
- Rate of relapse after 1, 2 and 3 years.
- Cumulative incidence of relapse at the end of study and is defined as the percentage of subjects who achieved CRc at the end of Re-Induction and relapse at these defined time points.
- 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 autophosphorylation activity in an ex-vivo PIA during Re-Induction, Continuation, 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 (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.
Biomarker:
- Rate of CRc (CR, CRi) without MRD using next generation sequencing.
Others:
- Acceptability including palatability of quizartinib formulations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Efficacy
o CR, CRi rate after completion of up to 2 re-induction cycles, and completion of C1 and 2
o Time to relapse, the rate of relapse after 1, 2 and 3 years, and cumulative incidence of relapse at the EoT
o OS, defined as the time from the start of Re-Induction therapy until death from any cause
o Event-free survival from the start of Re-Induction therapy until the earliest date of: Refractory disease at the end of Re-Induction, Relapse after CR or Cri or death
• PD: during Re-Induction, Maintenance, and at time of relapse
• Biomarker: MRD measured after Re-Induction. Bone marrow aspirate samples collected at Screening, end of Re-Induction C1 and C2, and at the time of relapse will be analyzed for MRD
• Other: Palatability during Re-Induction C1 and Maintenance C1 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Denmark |
| France |
| Ireland |
| Israel |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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