| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or
Refractory Acute Myeloid Leukemia (AML)
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| E.1.1.1 | Medical condition in easily understood language |
| AML is cancer of myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in bone marrow and interfere with production of normal blood cells |
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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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 (Dose Escalation Phase):
To determine the maximum tolerated dose (MTD) and/or optimally safe and biologically active recommended phase 2 dose (RP2D) of gilteritinib given in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) in children, adolescents and young adults with relapsed/refractory (R/R) FMS like tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD)] acute myeloid leukemia (AML).
Phase 2 (Dose Expansion Phase):
To determine complete remission (CR) rates and composite complete remission (CRc) rates after 2 cycles of gilteritinib in sequential combination with FLAG in children, adolescents and young adults in R/R FLT3/ITD AML who are refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles).
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
● To assess the safety, tolerability and toxicities of gilteritinib when given in sequential combination with FLAG in children, adolescents, and young adults with R/R FLT3/ITD AML.
● To evaluate FLT3 inhibition due to gilteritinib treatment
● To characterize gilteritinib pharmacokinetics.
● To perform serial measurements of minimal residual disease (MRD) and examine the relationship with study endpoints.
● To obtain preliminary estimates of 1-year event-free survival (EFS) and overall survival (OS) rate.
● To assess the acceptability and palatability of the formulation. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent and privacy language as required per national regulations (e.g., Health Insurance
Portability and Accountability Act Authorization for US sites) must be obtained from the subject or subject’s parent or legal guardian and if required child assent prior to any study-related procedures.
2. Phase 1: Subject is positive for FLT3 (ITD and/or TKD) mutation in bone marrow or blood as determined by the local institution
Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow
or blood as determined by the local institution.
3. Subject is aged ≥ 6 months and < 21 years of age at the time of signing informed consent and/or assent, as applicable.
* For phase 2: Enrollment of subjects from 6 months to less than 1 year (Group 3) and 1 year to less than 2 years (Group 2) will be dependent on the establishment of RP2D in the respective for age groups during phase 1.
4. Subject has a diagnosis of AML according to The French–American–British (FAB) classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease (except subjects with active central nervous system [CNS] leukemia).
a) In the phase 1 portion of the study, subject must be in first or greater relapse or refractory to induction therapy with no more than 1 attempt at remission induction (up to two induction cycles).
b) For the phase 2 portion of the study, subject must be in first relapse or refractory to induction therapy with no more than 1 attempt at remission induction (up to 2 induction cycles).
5.Subject has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
6. For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD).
7. Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the subject's leukemia in the investigators judgment.
8. Subject must meet the following criteria as indicated on the clinical
laboratory tests.
• Serum AST and ALT ≤ 3.0 x upper limit normal (ULN) for age
• Total serum bilirubin ≤ 1.5 x ULN for age
• Estimated glomerular filtration rate of > 60 mL/min/1.73 m2.
9. A female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 Contraception Requirements]
OR
b) WOCBP who agrees to follow the contraceptive guidance as defined in throughout the treatment period and for at least 180 days after the final study drug administration.
10. Female subject must agree not to breastfeed starting at Screening, and throughout the study period and for 60 days after the final study drug administration.
11. Female subject must not donate ova starting at Screening and throughout the study, and for 180 days after the final study drug administration.
12.A male subject with female partner(s) of childbearing potential must agree to use contraception as detailed in [Appendix 12.3 Contraception Requirements] during the treatment period and for at least 180 days after the final study drug administration.
13. A male subject must not donate sperm during the treatment period and for at least 120 days after the final study drug administration.
14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 180 days after the final study drug administration.
15. Subject and subject's parent(s) or legal guardian agrees not to participate in another interventional study while on treatment.
16. Live Vaccines: At least 6 weeks must have elapsed since the administration of the last dose of a live vaccine and prior to initiation of study treatment (cycle 1 day -1).
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| E.4 | Principal exclusion criteria |
1. Subject has active CNS leukemia.
2. This criterion has been removed.
3. Subject has uncontrolled or significant cardiovascular disease, including:
-Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or TdPtorsades de pointes); any history of arrhythmia will be discussed with the sponsor’s medical monitor prior to subject’s entry into the study
- Prolonged QTcF interval on pre-entry ECG (≥ 450 ms)
- Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
- Heart rate < 50 beats/minute on pre-entry ECG
- Uncontrolled hypertension
- Complete left bundle branch block
4. Subject 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 subject needs to be off pressors and have negative blood cultures for 48 hours.
5. Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
6. Subject has active clinically significant GVHD or is on treatment with immunosuppressive drugs for treatment of active GVHD, with the exception of subjects being weaned from systemic corticosteroids where the subjects is receiving ≤ 0.5 mg/kg of prednisone (or equivalent) daily dose for prior GVHD. Subjects has received calcineurin inhibitors within 4 weeks prior to screening unless used as GVHD prophylaxis.
7. Subject has active malignant tumors other than AML.
8. Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results.
9. Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels during the screening period is allowed.
10. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).
11. Subject is known to have human immunodeficiency virus infection.
12. Subject has active hepatitis B or C, or other active hepatic disorder.
● Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
● Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA undetectable.
● Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable.
13. This criterion has been removed.
14. Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib.
15. Subject has known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, G-CSF or any components of the formulations used.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Determination of MTD and/or RP2D
Phase 2:
o CRc rates (overall best response) after 2 cycles of therapy.
o CR rates after 2 cycles of therapy CR rate will be further described by the duration of CR ( only for USA)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
DLT observation period will be 28 days from the start of cycle 1 day 1; for the first cycle only.
Phase 2:
CRc and CR rates after 2 cycles of therapy.
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| E.5.2 | Secondary end point(s) |
-Inhibition of phosphorylated FLT3 (pFLT3) measured by PIA assay
-Gilteritinib plasma concentration
-Pharmacokinetic parameters (e.g., oral clearance [CL/F], apparent volume of distribution [Vd/F], maximum concentration [Cmax], time of maximum concentration [tmax], area under the concentration-time curve [AUC]) of gilteritinib
-Safety, tolerability and toxicity assessments of gilteritinib when given in combination with and FLAG
-EFS rate
-OS rate
-MRD assessment
-Acceptability and palatability assessment of the liquid formulation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 2 cycles of therapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Acceptability and palatability assessment of the liquid formulation |
|
| 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) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| sequential combination with FLAG |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Canada |
| Japan |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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