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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)

NCT04240002

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation and Expansion 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)

Clinical Trial IDs

  • ORG STUDY ID: 2215-CL-0603
  • SECONDARY ID: 2018-002301-61
  • NCT ID: NCT04240002

Conditions

  • Acute Myeloid Leukemia (AML)
  • Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD)

Interventions

DrugSynonymsArms
gilteritinibASP2215Dose Escalation - 1 year to less than 2 years of age
fludarabineDose Escalation - 1 year to less than 2 years of age
cytarabineDose Escalation - 1 year to less than 2 years of age
granulocyte colony-stimulating factor (G-CSF)Dose Escalation - 1 year to less than 2 years of age

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation - 2 years to less than 21 years of ageExperimentalParticipants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • gilteritinib
  • fludarabine
  • cytarabine
  • granulocyte colony-stimulating factor (G-CSF)
Dose Escalation - 1 year to less than 2 years of ageExperimentalParticipants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • gilteritinib
  • fludarabine
  • cytarabine
  • granulocyte colony-stimulating factor (G-CSF)
Dose Escalation - 6 months to less than 1 year of ageExperimentalParticipants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • gilteritinib
  • fludarabine
  • cytarabine
  • granulocyte colony-stimulating factor (G-CSF)
Dose ExpansionExperimentalParticipants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the dose determined in dose escalation portion. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
  • gilteritinib
  • fludarabine
  • cytarabine
  • granulocyte colony-stimulating factor (G-CSF)

Eligibility Criteria

        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 for 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):

                    -  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
             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 120 days after the final
             study drug administration. (all countries except United Kingdom, Germany and Canada)

          -  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. (in United Kingdom, Germany and Canada)

          -  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 120 days after the final study drug
             administration. (all countries except United Kingdom, Germany and Canada)

          -  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. (United Kingdom, Germany and Canada)

          -  Subject and subject's parent(s) or legal guardian agrees not to participate in another
             interventional study while on treatment.

          -  In United Kingdom, Germany and Canada: 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)

        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.

          -  In United Kingdom, Germany and Canada: Subject has a known or suspected
             hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte
             colony-stimulating factor (G-CSF) or any components of the formulation used.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with dose limiting toxicity (DLT) (phase 1/dose escalation)
Time Frame:Up to 28 days
Safety Issue:
Description:A DLT is defined as any of the events meeting the DLT criteria that occur during the observation period and that is considered to be possibly or probably related to gilteritinib. Nonhematologic Dose-limiting Toxicity will be defined as grade 3 or 4 nonhematologic toxicity attributable to gilteritinib that persists for > 48 hours without resolution to grade ≤ 2, will have gilteritinib dosing interrupted. Exceptions include the toxicities commonly seen with intensive AML reinduction regimens. Hematologic Dose-limiting Toxicity will be defined as failure to recover a peripheral absolute neutrophil count (ANC) > 500/μL and non-transfusion dependent platelet count > 20000/μL due to documented bone marrow aplasia/hypoplasia for greater than or equal to 50 days from the start of cycle 1 day 1. Failure to recover peripheral counts due to disease involvement of the bone marrow will not be considered dose-limiting toxicity.

Secondary Outcome Measures

Measure:Number of participants with Adverse Events (AEs)
Time Frame:Up to 2 years plus 28 day follow up
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.
Measure:Number of participants with vital sign abnormalities and /or adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:Number of participants with potentially clinically significant vital sign values.
Measure:Number of participants with laboratory value abnormalities and/or adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:Number of participants with potentially clinically significant laboratory values.
Measure:Number of participants with electrocardiogram (ECG) abnormalities and/or adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:Number of participants with potentially clinically significant ECG values.
Measure:Percentage of inhibition of phosphorylated FLT3 in participants.
Time Frame:Up to 49 days
Safety Issue:
Description:Inhibition of FLT3 phosphorylation after drug treatment will be determined relative to pre-treatment phosphorylated FLT3 levels in participants to assess the relationship with gilteritinib dose. Phosphorylated FLT3 will be measured by plasma inhibitory activity (PIA) assay.
Measure:Pharmacokinetics (PK) of gilteritinib: oral clearance (CL/F)
Time Frame:Up to 45 days
Safety Issue:
Description:CL/F will be reported from the PK plasma samples collected.
Measure:PK of gilteritinib: apparent volume of distribution (Vd/F)
Time Frame:Up to 45 days
Safety Issue:
Description:Vd/F will be reported from the PK plasma samples collected.
Measure:PK of gilteritinib: Maximum Concentration (Cmax)
Time Frame:Up to 45 days
Safety Issue:
Description:Cmax will be reported from the PK plasma samples collected.
Measure:PK of gilteritinib: Time of Maximum Concentration (tmax)
Time Frame:Up to 45 days
Safety Issue:
Description:tmax will be reported from the PK plasma samples collected.
Measure:PK of gilteritinib: Area Under the Concentration (AUC)
Time Frame:Up to 45 days
Safety Issue:
Description:AUC will be reported from the PK plasma samples collected.
Measure:Duration of Event Free Survival (EFS)
Time Frame:Up to 2 years
Safety Issue:
Description:EFS is defined as the time from the date of enrollment until the date of documented relapse (excluding relapse after PR), treatment failure or death, whichever occurs first. If a participant experiences relapse or death, the participant is defined as having EFS event related to either "relapse" or "death", and the event date is the date of relapse or death. If a participant fails to achieve any of the response of CR, CRp, CRi or PR during the treatment period, the participant is defined as having EFS event related to treatment failure, and the event date is the enrollment date. For a participant who is not known to have had a relapse or treatment failure or death event, EFS is censored at the date of last relapse-free disease assessment. Participant is not censored at hematopoietic stem cell transplant (HSCT).
Measure:Duration of Overall survival (OS)
Time Frame:Up to 4 years and 2 months
Safety Issue:
Description:OS is defined as the time from the date of enrollment until the date of death from any cause. For a participant who is not known to have died by the end-of-study follow-up, OS is censored at the date of last contact.
Measure:The number of participants with negative minimal residual disease (MRD) status
Time Frame:Up to 2 years
Safety Issue:
Description:MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
Measure:Number of participants with MRD negative status in relation to CR rate
Time Frame:Up to 2 years
Safety Issue:
Description:MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
Measure:Number of participants with MRD negative status in relation to CRc rate
Time Frame:Up to 2 years
Safety Issue:
Description:MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
Measure:Number of participants with MRD negative status in relation to Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
Measure:Clinical Outcome Assessment of Taste
Time Frame:Up to 57 days
Safety Issue:
Description:The acceptability and palatability of gilteritinib oral formulation as assessed by the participant using a single scale. The 5 point facial hedonic scale has high to low as: Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • ASP2215
  • Acute Myeloid Leukemia
  • FLT3
  • AML
  • gilteritinib

Last Updated

September 24, 2020