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 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: 2215-CL-06032018-002301-612024-512469-15
• Study Type: interventional
• Target: 9
• Locations: 5 countries
• Sites: 7

Brief Summary

The purpose of the phase 1 portion (dose escalation) of the study was 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) was to determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy. The study also assessed safety, tolerability and toxicities of gilteritinib in combination with FLAG, evaluated FLT3 inhibition, assessed pharmacokinetics (PK), performed serial measurements of minimal residual disease, obtained preliminary estimates of 1-year event free survival (EFS) and overall survival (OS) rate and assessed the acceptability as well as palatability of the formulation. One cycle was defined as 28 days of treatment. A participant completing 1 or 2 treatment cycles in phase 1 or 2 had the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Conditions

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

Keywords

ASP2215; Acute Myeloid Leukemia; FLT3; AML; gilteritinib

Outcome Measures

Primary Outcomes (6)

• Phase 1: Maximum Tolerated Dose (MTD) of Gilteritinib

  MTD reflects the highest dose that did not cause a Dose Limiting Toxicity (DLT).DLT:any Grade ≥3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observations like alopecia, anorexia, or fatigue, grade 3 vomiting or diarrhea that resolved(with or without supportive care) to ≤ grade 2 within 48 hours, grade 3 nausea that resolved(with or without supportive care) to ≤ grade 2 within 7 days, grade 3 elevation in total bilirubin (TBL) that is asymptomatic and that returned to ≤ grade 2 elevation within 7 days, grade 3 elevation in hepatic transaminases\[alanine aminotransferase (ALT/SGPT) aspartate aminotransferase (AST/SGOT) and gammaglutamyl transferase (GGT)\] or Alkaline Phosphatase (ALP) level that returns to ≤ grade 2 elevation within 14 days, grade 3 fever with neutropenia, with/without infection, grade 3 infection/grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia, grade 3 mucositis.

  C1D1 up to day 28

• Phase 1: Recommended Phase 2 Dose (RP2D) of Gilteritinib

  The RP2D was a safe dose of gilteritinib that demonstrated sufficient activity.

  C1D1 up to day 28

• Phase 2: Complete Remission (CR) Rate

  CR rate was defined as the number of participants with best response of CR divided by the number of participants in the analysis population. CR was defined as a morphologically leukemia-free state post-baseline and had absolute neutrophil count (ANC) \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were 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 and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Derived and investigator-assessed responses are reported.

  From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)

• Phase 2: Composite CR (CRc) Rate

  CRc was defined as participants who achieved either CR, complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) at the visit. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were 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 and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. CRp was defined as met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi was defined as met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Derived and investigator-assessed responses are reported.

  From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)

• Duration of CR

  Duration of CR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and were 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 and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Relapse was defined as a reappearance of leukemic blasts in the peripheral blood or \>= 5% blasts in the bone marrow aspirate (BMA) not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Duration of CR was estimated using the Kaplan-Meier method.

  From the date of first CR until the date of documented relapse for participants who achieved CR (Maximum duration: 28 months)

• Phase 1: Number of Participants With Dose Limiting Toxicity (DLT) of Gilteritinib

  DLT: any Grade \>=3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observation: Alopecia, anorexia, or fatigue. Grade 3 vomiting or diarrhea that resolved(with or without supportive care) to \<= grade 2 within 48 hours. Grade 3 nausea that resolved(with or without supportive care) to \<= grade 2 within 7 days. Grade 3 elevation in TBL that was asymptomatic and that returned to \<= grade 2 elevation within 7 days. Grade 3 elevation in hepatic transaminases (ALT/SGPT, AST/SGOT) and GGT) or ALP level that returns to \<= grade 2 elevation within 14 days. Grade 3 fever with neutropenia, with or without infection. Grade 3 infection or grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia. Grade 3 mucositis.

  C1D1 up to day 28

Secondary Outcomes (15)

• Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3)

  Baseline, predose on C1D15, C1D21, C2D8, C2D15, C2D21 and 4 to 6 hours post-dose on C1D21

• Gilteritinib Plasma Concentration

  Predose on C1D8, C1D15, C1D21, C2D15, and 4 to 6 hours post-dose on C1D21

• Pharmacokinetics (PK) of Gilteritinib: Oral Clearance (CL/F)

  Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21

• PK of Gilteritinib: Apparent Volume of Distribution (Vd/F)

  Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21

• PK of Gilteritinib: Maximum Plasma Concentration (Cmax)

  Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21

Study Arms (1)

Gilteritinib 2 mg/kg/day (Escalation Phase)

EXPERIMENTAL

Participants aged 2 years to less than 21 years with relapsed/refractory (R/R) FLT3 ITD and/or TKD Acute Myeloid Leukemia (AML) received 2 cycles (Cycle \[C\] 1 and C2) induction therapy with gilteritinib in combination with FLAG \[fludarabine, cytarabine and granulocyte colony-stimulating factor (G-CSF)\] chemotherapy. Gilteritinib tablet was administered at a starting dose of 2 milligrams/kilogram/day (mg/kg/day) (maximum 120 mg/day) orally once daily (QD) from days 8 to 21. FLAG regimen consisted of fludarabine: 30 milligrams per square meter (mg/m\^2) per day intravenously (IV) from day 1 to day 5; cytarabine: 2000 mg/m\^2 per day IV from day 1 to day 5; G-CSF (filgrastim): 5 micrograms per kilogram (μg/kg) per day subcutaneously (SC) or IV from day -1 to day 5. Each cycle = 28 days.

Drug: gilteritinib; Drug: fludarabine; Drug: cytarabine; Drug: granulocyte colony-stimulating factor (G-CSF)

Interventions

gilteritinib DRUG

Administered orally.

Also known as: ASP2215

Gilteritinib 2 mg/kg/day (Escalation Phase)

fludarabine DRUG

Administered by intravenous (IV) infusion

Gilteritinib 2 mg/kg/day (Escalation Phase)

cytarabine DRUG

Administered by intravenous (IV) infusion

Gilteritinib 2 mg/kg/day (Escalation Phase)

granulocyte colony-stimulating factor (G-CSF) DRUG

Administered by subcutaneous injection

Gilteritinib 2 mg/kg/day (Escalation Phase)

Eligibility Criteria

• Age: 6 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 (up to 2 induction cycles).
• For the phase 2 portion of the study, subject must be in refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles).
• 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, unless the subject has recovered earlier than 21 days.
• Cytoreduction with the following can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy (cycle 1 day -1).
• hydroxyurea,
• low dose cytarabine (100 mg/m\^2 per dose once daily for 5 days) or
• other low dose/maintenance therapies as per local site practice.
• 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.

You may not qualify if:

• 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 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 subject is receiving ≤ 0.5 mg/kg of prednisone (or equivalent) daily dose for prior GVHD. Subject has received calcineurin inhibitors within 4 weeks prior to screening, unless used as GVHD prophylaxis.
• 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).

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (7)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Site DE49004

Essen, North Rhine-Westphalia, 45147, Germany

Location

SIte IT39001

Roma, 165, Italy

Location

Site ES34001

Barcelona, 08950, Spain

Location

Site GB44001

Birmingham, B4 6NH, United Kingdom

Location

Site GB44005

Cardiff, CF14 4XW, United Kingdom

Location

Site UK44007

Sutton, United Kingdom

Location

Related Publications (1)

• Abematsu T, Nishikawa T, Shiba N, Iijima-Yamashita Y, Inaba Y, Takahashi Y, Nakagawa S, Kodama Y, Okamoto Y, Kawano Y. Pediatric acute myeloid leukemia co-expressing FLT3/ITD and NUP98/NSD1 treated with gilteritinib plus allogenic peripheral blood stem cell transplantation: A case report. Pediatr Blood Cancer. 2021 Nov;68(11):e29216. doi: 10.1002/pbc.29216. Epub 2021 Jul 10. No abstract available.

  PMID: 34245496 DERIVED

Related Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

gilteritinib; fludarabine; Cytarabine; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Limitations and Caveats

The study was terminated because of enrollment challenges due to the rarity of R/R AML in children and not related to any safety or efficacy issues.

Results Point of Contact

• Title: Clinical Transparency
• Organization: Astellas Pharma Global Development, Inc. (APGD)

astellas.resultsdisclosure@astellas.com

800-888-7704

Study Officials

• Medical Director

  Astellas Pharma Global Development

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2020
• First Posted: January 27, 2020
• Study Start: September 4, 2020
• Primary Completion: March 11, 2025
• Study Completion: March 17, 2025
• Last Updated: January 5, 2026
• Results First Posted: January 5, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); GB (3); IT (1); ES (1); DE (1)