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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04240002
Recruitment Status : Active, not recruiting
First Posted : January 27, 2020
Last Update Posted : June 16, 2020
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:

Screening and enrollment are temporarily on hold due to COVID-19.

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).


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD) Drug: gilteritinib Drug: fludarabine Drug: cytarabine Drug: granulocyte colony-stimulating factor (G-CSF) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 27, 2020
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : March 2028


Arm Intervention/treatment
Experimental: Dose Escalation - 2 years to less than 21 years of age
Participants 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).
Drug: gilteritinib
Administered orally.
Other Name: ASP2215

Drug: fludarabine
Administered by intravenous (IV) infusion

Drug: cytarabine
Administered by intravenous (IV) infusion

Drug: granulocyte colony-stimulating factor (G-CSF)
Administered by subcutaneous injection

Experimental: Dose Escalation - 1 year to less than 2 years of age
Participants 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).
Drug: gilteritinib
Administered orally.
Other Name: ASP2215

Drug: fludarabine
Administered by intravenous (IV) infusion

Drug: cytarabine
Administered by intravenous (IV) infusion

Drug: granulocyte colony-stimulating factor (G-CSF)
Administered by subcutaneous injection

Experimental: Dose Escalation - 6 months to less than 1 year of age
Participants 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).
Drug: gilteritinib
Administered orally.
Other Name: ASP2215

Drug: fludarabine
Administered by intravenous (IV) infusion

Drug: cytarabine
Administered by intravenous (IV) infusion

Drug: granulocyte colony-stimulating factor (G-CSF)
Administered by subcutaneous injection

Experimental: Dose Expansion
Participants 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).
Drug: gilteritinib
Administered orally.
Other Name: ASP2215

Drug: fludarabine
Administered by intravenous (IV) infusion

Drug: cytarabine
Administered by intravenous (IV) infusion

Drug: granulocyte colony-stimulating factor (G-CSF)
Administered by subcutaneous injection




Primary Outcome Measures :
  1. Number of participants with dose limiting toxicity (DLT) (phase 1/dose escalation) [ Time Frame: Up to 28 days ]

    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.


  2. Complete Remission (CR) rate after 2 cycles of therapy (phase 2) [ Time Frame: Up to 56 days ]
    CR rate is defined as the number of participants who achieve the best response of CR divided by the number of participants in the analysis population. Complete remission is defined as having bone marrow regenerating normal hematopoietic cells and achieving a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they will be red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia.

  3. Composite complete remission (CRc) rate after 2 cycles of therapy (phase 2) [ Time Frame: Up to 56 days ]
    CRc rate is defined as the number of participants who achieve the best response of CRc (CR, CRp,or CRi) divided by the number of participants in the analysis population. Complete remission with incomplete platelet recovery (CRp) is defined as achieving CR except for incomplete platelet recovery (< 100 x 10^9/L) at a post baseline visit. Complete remission with incomplete hematologic recovery (CRi) is defined as achieving CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery at a post baseline visit. Red blood cell (RBC) and platelet transfusion independence is not required.


Secondary Outcome Measures :
  1. Number of participants with Adverse Events (AEs) [ Time Frame: Up to 2 years plus 28 day follow up ]
    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.

  2. Number of participants with vital sign abnormalities and /or adverse events (AEs) [ Time Frame: Up to 2 years ]
    Number of participants with potentially clinically significant vital sign values.

  3. Number of participants with laboratory value abnormalities and/or adverse events (AEs) [ Time Frame: Up to 2 years ]
    Number of participants with potentially clinically significant laboratory values.

  4. Number of participants with electrocardiogram (ECG) abnormalities and/or adverse events (AEs) [ Time Frame: Up to 2 years ]
    Number of participants with potentially clinically significant ECG values.

  5. Percentage of inhibition of phosphorylated FLT3 in participants. [ Time Frame: Up to 49 days ]
    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.

  6. Pharmacokinetics (PK) of gilteritinib: oral clearance (CL/F) [ Time Frame: Up to 45 days ]
    CL/F will be reported from the PK plasma samples collected.

  7. PK of gilteritinib: apparent volume of distribution (Vd/F) [ Time Frame: Up to 45 days ]
    Vd/F will be reported from the PK plasma samples collected.

  8. PK of gilteritinib: Maximum Concentration (Cmax) [ Time Frame: Up to 45 days ]
    Cmax will be reported from the PK plasma samples collected.

  9. PK of gilteritinib: Time of Maximum Concentration (tmax) [ Time Frame: Up to 45 days ]
    tmax will be reported from the PK plasma samples collected.

  10. PK of gilteritinib: Area Under the Concentration (AUC) [ Time Frame: Up to 45 days ]
    AUC will be reported from the PK plasma samples collected.

  11. Duration of Event Free Survival (EFS) [ Time Frame: Up to 2 years ]
    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).

  12. Duration of Overall survival (OS) [ Time Frame: Up to 4 years and 2 months ]
    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.

  13. The number of participants with negative minimal residual disease (MRD) status [ Time Frame: Up to 2 years ]
    MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

  14. Number of participants with MRD negative status in relation to CR rate [ Time Frame: Up to 2 years ]
    MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

  15. Number of participants with MRD negative status in relation to CRc rate [ Time Frame: Up to 2 years ]
    MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

  16. Number of participants with MRD negative status in relation to Overall survival (OS) [ Time Frame: Up to 2 years ]
    MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.

  17. Clinical Outcome Assessment of Taste [ Time Frame: Up to 57 days ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04240002


Locations
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Canada, Quebec
Site CA15001
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
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Study Director: Medical Director Astellas Pharma Global Development
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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT04240002    
Other Study ID Numbers: 2215-CL-0603
2018-002301-61 ( EudraCT Number )
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: June 16, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
URL: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
ASP2215
Acute Myeloid Leukemia
FLT3
AML
gilteritinib
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Sargramostim
Lenograstim
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic