A Study of Gilteritinib (ASP2215) Combined With Chemotherapy in Children Adolescents and Young Adults With FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

  • STATUS
    Recruiting
  • End date
    Nov 30, 2028
  • participants needed
    97
  • sponsor
    Astellas Pharma Global Development, Inc.
Updated on 19 August 2021
remission
fludarabine
tyrosine
hydroxyurea
cytarabine
filgrastim
granulocyte colony stimulating factor
serum bilirubin level
refractory acute myeloid leukemia (aml)
blast cells
colony stimulating factor
hematopoietic growth factors

Summary

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).

Details
Condition Acute myeloid leukemia, Acute Myelogenous Leukemia (AML), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), acute myelogenous leukemia, anll, acute myeloblastic leukemia, Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD)
Treatment cytarabine, Fludarabine, Gilteritinib, granulocyte colony-stimulating factor (G-CSF)
Clinical Study IdentifierNCT04240002
SponsorAstellas Pharma Global Development, Inc.
Last Modified on19 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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 [CNS] leukemia)
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
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 screening
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)
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 disease (GVHD)
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 tests
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 administration
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, day -1)
Subject and subject's parent(s) or legal guardian agrees not to participate in another interventional study while on treatment
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

Exclusion Criteria

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
Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib
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 is undetectable
Subject has a known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte colony-stimulating factor (G-CSF) or any components of the formulation used
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