The purpose of the phase 1 portion (dose escalation) of the study will be to establish an
optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine
maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine,
cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2
portion (dose expansion) is to determine complete remission (CR) rates and composite complete
remission (CRc) rates after two cycles of therapy. The study will also assess safety,
tolerability and toxicities of gilteritinib in combination with FLAG, evaluate FLT3
inhibition, assess pharmacokinetics (PK), perform serial measurements of minimal residual
disease, obtain preliminary estimates of 1-year event free survival (EFS) and overall
survival (OS) rate and assess the acceptability as well as palatability of the formulation.
One cycle is defined as 28 days of treatment. A participant completing 2 cycles in phase 1 or
2 will have the option to participate in long term treatment (LTT) with gilteritinib (for up
to 2 years).
- 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 and 1 year
to less than 2 years will be dependent on the establishment of recommended phase
2 dose (RP2D) in the respective age groups during phase 1.
- Subject has a diagnosis of acute myeloid leukemia (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
- 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
- For the phase 2 portion of the study, subject must be in first relapse.
- Subject has fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.
- Myelosuppressive chemotherapy:
- For subject who relapses while receiving cytotoxic therapy, at least 21 days
must have elapsed since the completion of cytotoxic therapy and prior to
- Cytoreduction with hydroxyurea can be initiated and continued for up to 24
hours prior to the start of systemic protocol therapy (cycle 1 day -1).
Subject may also receive low dose cytarabine (100 mg/m^2 per dose once daily
for 5 days) for cytoreduction until 24 hours prior to cycle 1 day -1.
- Subject who has received other FLT3 inhibitors (e.g., lestaurtinib,
sorafenib, etc) is eligible for this study.
- Hematopoietic growth factors: at least 7 days must have elapsed since the
completion of therapy with a growth factor and prior to screening.
- Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the
completion of therapy with a biologic agent and prior to screening. 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.
- X-ray treatment (XRT):
- 14 days must have elapsed for local palliative XRT for CNS chloromas and
prior to screening; no washout period is necessary for other chloromas;
- Prior to screening, 90 days must have elapsed if the subject had a prior
traumatic brain injury or has received craniospinal XRT.
- 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
- 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.
- Subject must meet the following criteria as indicated on the clinical laboratory
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x
upper limit normal (ULN) for age
- Total serum bilirubin ≤ 1.5 x ULN for age
- Serum creatinine ≤ 1.5 x ULN for age or an estimated glomerular filtration rate
of > 60 mL/min/1.73 m^2.
- A female subject is eligible to participate if she is not pregnant and at least 1 of
the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- WOCBP who agrees to follow the contraceptive guidance throughout the treatment
period and for at least 180 days after the final study drug administration.
- 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.
- Female subject must not donate ova starting at Screening and throughout the study, and
for 180 days after the final study drug administration.
- A male subject with female partner(s) of childbearing potential must agree to use
contraception during the treatment period and for at least 180 days after the final
study drug administration.
- A male subject must not donate sperm during the treatment period and for at least 120
days after the final study drug administration.
- 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
- Subject and subject's parent(s) or legal guardian agrees not to participate in another
interventional study while on treatment.
- Live Vaccines - At least 6 weeks must have elapsed since the administration of the
last dose of a live vaccine and prior to the initiation of study treatment (cycle 1,
- Phase 1: Subject is positive for FLT3 (ITD and/or tyrosine kinase domain [TKD])
mutation in bone marrow or blood as determined by the local institution except for
sites in the USA. USA sites - subject is positive for the FLT3 (ITD) mutation.
- Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as
determined by the local institution.
- Subject has active CNS leukemia.
- 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 Torsades de Pointes (TdP)); any history of arrhythmia will be
discussed with the sponsor prior to subject's entry into the study
- Prolonged Fridericia's Correction Formula (QTcF) interval on pre-entry
electrocardiogram (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
- 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.
- Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy,
or immunotherapy other than as specified in the protocol.
- Subject has active clinically significant graft-versus-host disease (GVHD) or is on
treatment with systemic corticosteroids and is receiving > 0.5 mg/kg of prednisone (or
equivalent) daily dose for GVHD.
- Subject has active malignant tumors other than AML.
- 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.
- 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.
- Subject requires treatment with concomitant drugs that are strong inducers of
cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).
- Subject is known to have human immunodeficiency virus infection.
- 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 is undetectable.
- Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA
- Subject must wait for at least 5 half-lives after stopping therapy with any
investigational agent and before starting gilteritinib.
- Subject has a known or suspected hypersensitivity to gilteritinib, cytarabine,
fludarabine, granulocyte colony-stimulating factor (G-CSF) or any components of the