Sequential Gilteritinib in Combination with Venetoclax and Azacitidine for Patients with Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutations Ineligible for Intensive Treatment (SEQUENCE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Technische Universitat Dresden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

25 Apr 2025 → ongoing

Decision date (initial)

2024-08-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Astellas Pharma Europe Ltd.

External identifiers

EU CT number

2023-507878-41-00

ClinicalTrials.gov

NCT06696183

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety, Dose response

To explore the best tolerable and efficacious dose of gilteritinib (GILT) when combined with standard treatment with venetoclax (VEN) plus azacitidine (AZA) in AML patients with FLT3 mutations and ineligible for intensive treatment as evaluated at end of study (EOS). The primary endpoint will be the ratio of dose delivered/dose planned as this measure reflects both treatment efficacy and tolerability/safety.

Secondary objectives 5

1. Ratio of dose delivered/dose planned over 2 cycles as evaluated after 75 days
2. Rate of remission; duration of response; relapse-free survival; overall survival; cumulative incidence of relapse
3. Depth of response by assessment of measurable residual disease
4. Tolerability
5. Duration of cytopenias, transfusion dependence

Conditions and MedDRA coding

Acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Signed informed consent
2. Newly diagnosed AML according to WHO 2022 criteria or AML according to ICC 2022 criteria with a minimum bone marrow (BM) blast count of ≥20%, excluding Acute Promyelocytic Leukemia (APL)
3. FLT3 mutation at initial diagnosis (ID): FLT3-internal tandem duplication (ITD) or FLT3-tyrosine kinase domain (TKD) determined by local lab
4. Age ≥18 years
5. Ineligibility for standard induction therapy as defined by: (a) ≥75 years of age OR (b) ≥18 to 74 years of age with at least one of the following comorbidities: • Eastern Cooperative Oncology Group (ECOG) Performance Sta-tus 2 or 3; • Cardiac history of congestive heart failure requiring treatment or Ejection Fraction ≤50% or chronic stable angina; • Diffusing capacity of the lungs for carbon monoxide ≤65% or Forced Expiratory Volume in 1 Second ≤65%; • Creatinine clearance ≥30 mL/min to <45 mL/min; • Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal; • Any other comorbidity that the physician judges to be incompati-ble with intensive chemotherapy must be reviewed and approved by the coordinating investigator before study enrollment
6. Pre-treatment with approved combination of VEN+AZA (one cycle only) and availability of the results of BM assessment of this VEN+AZA precycle
7. Male subjects must agree to refrain from unprotected sex and sperm donation from time point of signing the informed consent until 4 months after the last dose of study drug
8. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 3 days before first dose of study drug

Exclusion criteria 22

1. Relapsed or primary refractory AML
2. Mean of triplicate corrected QT interval by Fredericia (QTcF) >450 ms at screening
3. Long QT Syndrome at screening
4. Uncontrolled hypokalemia and hypomagnesemia (defined as values below lower limit of normal)
5. Treatment with concomitant strong cytochrome P450, family 3, subfamily A (CYP3A) inducers or St. John's wort
6. Treatment with concomitant strong P-glycoprotein (P-gp) inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the subject
7. Hypersensitivity known from medical history to GILT or VEN or AZA or their ingredients or to drugs with a similar chemical structure
8. Live-virus vaccines given within 28 d prior initiation of study treatment
9. Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before planned treatment start within the trial) and the use of any other investigational medicinal product within five times the half-life of the investigational medicinal product or of relevant metabolites prior to screening
10. Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences
11. Pregnant or breastfeeding women
12. Previous treatment for AML (except for hydroxyurea and/or one cycle of approved combination treatment with VEN+AZA according to standard of care (SOC))
13. Women of childbearing potential, except women who meet the following criteria: post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum follicle-stimulating hormone >40 U/mL); postoperative (6 weeks after bilateral ovariectomy with or without hysterectomy); regular and correct use of a contraceptive method with a Pearl Index <1% per year (i.e., combined estrogen and progesterone containing or progesterone-only hormonal contraception associated with inhibition of ovulation, an intrauterine device, or an intrauterine hormone-releasing system) in combination with a barrier method since GILT as well as VEN may reduce the effectiveness of hormonal contraceptives; sexual abstinence; vasectomy of the partner
14. Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance)
15. Previous treatment with GILT
16. Known active involvement of central nervous system with AML
17. Human immunodeficiency virus (HIV) infection and/or positive HIV serology due to potential drug-drug interactions between antiretroviral medications and VEN
18. History of active or chronic infectious hepatitis B or C unless serology demonstrates clearance of infection, i.e., polymerase chain reaction (PCR) undetectable viral load for hepatitis
19. Malabsorption syndrome or other condition that precludes enteral route of administration
20. Inability to swallow oral medication
21. History of other malignancies within 2 years prior to study entry, with the exception of adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected; incidental histologic finding of prostate cancer
22. Persons dependent on the sponsor, investigator or medical staff of the trial team

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Ratio of dose delivered/dose planned over the 12-cycle treatment period as evaluated at 12 months. This endpoint reflects both treatment efficacy (patients live longer event-free), and safety (less dose reductions, less omitted doses)

Secondary endpoints 5

1. Ratio of dose delivered/dose planned over 2 cycles evaluated after 75 days
2. Complete hematologic remission/complete remission with partial hematologic recovery (CR/CRh), DOR, RFS, OS, CIR
3. Depth of response by MRD
4. Tolerability (Adverse events)
5. Duration of cytopenias, transfusion dependence

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Technische Universitat Dresden

Sponsor organisation

Technische Universitat Dresden

Address

Mommsenstrasse 11, Raecknitz/zschertnitz Raecknitz/zschertnitz

City

Dresden

Postcode

01069

Country

Germany

Scientific contact point

Organisation

Technische Universitat Dresden

Contact name

Prof. Christoph Röllig

Public contact point

Organisation

Technische Universitat Dresden

Contact name

Prof. Christoph Röllig

Locations

1 EU/EEA country · 13 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

Documents 9 files

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

Application history

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