A study of Gilteritinib combined with chemotherapy to treat Children, Adolescents and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a FLT3 gene mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astellas Pharma Global Development Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Dec 2020 → 18 Mar 2025

Decision date (initial)

2024-05-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Astellas Pharma Global Development Inc.

External identifiers

EU CT number

2024-512469-15-00

EudraCT number

2018-002301-61

ClinicalTrials.gov

NCT04240002

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis, Pharmacogenomic, Therapy, Pharmacokinetic, Pharmacodynamic, Efficacy, Dose response, Others, Safety

● Phase 1 (Dose Escalation Phase):
To determine the maximum tolerated dose (MTD) and/or optimally safe and biologically active recommended phase 2 dose (RP2D) of gilteritinib given in sequential combination with FLAG in children, adolescents and young adults with relapsed/refractory (R/R) FMS-like tyrosine
kinase 3 (FLT3) (internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD) acute myeloid leukemia (AML).
● Phase 2 (Dose Expansion Phase):
To determine complete remission (CR) rates and composite complete remission (CRc) rates after 2 cycles of gilteritinib in sequential combination with FLAG in children, adolescents and young adults with FLT3 (ITD) AML who are refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles).

Secondary objectives 6

1. To assess the safety, tolerability and toxicities of gilteritinib when given in sequential combination with FLAG in children, adolescents, and young adults with R/R FLT3/ITD AML
2. To evaluate FLT3 inhibition due to gilteritinib treatment
3. To characterize gilteritinib pharmacokinetics
4. To perform serial measurements of minimal residual disease (MRD) and examine the relationship with study endpoints
5. To obtain preliminary estimates of 1-year event-free survival (EFS) and overall survival (OS) rate
6. To assess the acceptability and palatability of the formulation.

Conditions and MedDRA coding

FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002064-PIP01-16

Plan to share IPD

Yes

IPD 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 2. Phase 1: Subject is positive for FLT3 (ITD and/or TKD) mutation in bone marrow or blood as determined by the local institution. Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as determined by the local institution.
2. 3. 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 (Group 3) and 1 year to less than 2 years (Group 2) will be dependent on the establishment of RP2D in the respective for age groups during phase 1.
3. 4. Subject has a diagnosis of 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). a) 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). b) For the phase 2 portion of the study, subject must be refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles)

Exclusion criteria 6

1. 1. Subject has active central nervous system (CNS) leukemia.
2. 3. 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); any history of arrhythmia will be discussed with the sponsor’s medical monitor prior to subject’s entry into the study • Prolonged Fridericia-corrected QT interval (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
3. 6. Subject has active clinically significant graft-versus-host disease (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
4. 7. Subject has active malignant tumors other than AML.
5. 9. 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.
6. 10. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Phase 1: Determination of MTD and/or RP2D • Phase 2: o CRc rates (overall best response) after 2 cycles of therapy. o CR rates after 2 cycles of therapy; CR rate will be further described by the duration of CR (only for USA).

Secondary endpoints 8

1. Inhibition of phosphorylated FLT3 (pFLT3) measured by PIA assay
2. Gilteritinib plasma concentration
3. Pharmacokinetic parameters (e.g., oral clearance [CL/F], apparent volume of distribution [Vd/F], maximum concentration [Cmax], time of maximum concentration [tmax], area under the concentration-time curve [AUC]) of gilteritinib
4. Safety, tolerability and toxicity assessments of gilteritinib when given in combination with FLAG
5. EFS rate
6. OS rate
7. MRD assessment
8. Acceptability and palatability assessment of the formulation

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astellas Pharma Global Development Inc.

Sponsor organisation

Astellas Pharma Global Development Inc.

Address

2375 Waterview Drive

City

Northbrook

Postcode

60062-6111

Country

United States

Scientific contact point

Organisation

Astellas Pharma Global Development Inc.

Contact name

Clinical Trial Unit Head

Public contact point

Organisation

Astellas Pharma Global Development Inc.

Contact name

Clinical Trial Unit Head

Third parties 13

Locations

4 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications