FILOAML-RR-01-OGILAR: Open-label, phase 2 study investigating the efficacy and safety of the addition of oral-azacitidine to salvage treatment by gilteritinib in subjects ≥18 years of age with relapsed/refractory FLT3-mutated acute myeloid leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

French Innovative Leukemia Organization

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

10 Jan 2024 → ongoing

Decision date (initial)

2023-05-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety, Therapy

Characterize the clinical activity of oral-azacitidine associated with gilteritinib by the rate of composite complete remission (CRc) [defined by addition of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and complete remission with incomplete platelet recovery (CRp)] as the best response to treatment during the first 3-months treatment.

Secondary objectives 4

1. characterize the safety and tolerability of the combination of oral-azacitidine and gilteritinib
2. rate of complete remission (CR), rate of complete remission with incomplete hematologic recovery (CRi), rate of complete remission with incomplete platelet recovery (CRp), rate of complete remission with partial hematologic recovery (CRh), rate of partial remission (PR), rate of morphological leukemia free state (MLFS), rate of stable disease (SD), rate of MRD-negative CR/CRi/CRp/CRh/MLFS (CR/CRi/CRp/CRh/MLFSMRD-) during the first 6-months treatment
3. rate of per protocol allogeneic SCT (HSCT), rate of HSCT in CRc, rate of complete donor chimerism (>95%) at day +100 post HSCT, rate of patients receiving gilteritinib at day +100 post HSCT
4. overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) after HSCT at 3, 6 and 12 months

Conditions and MedDRA coding

Patients aged 18 years and older with relapsed or refractory FLT3 mutated acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Confirmed diagnosis of acute myeloid leukemia (AML) according to world health organization (WHO) 2016 classification
2. 2. Presence of FLT3-mutation(s) at inclusion: in case of FLT3-ITD, the ITD/wt ratio must be > 0.05 ; in case of FLT3-TKD, the mutation must be at D835 or I836 position with a VAF > 5% by NGS. Pseudonymized results will be uploaded in the eCRF for review by coordinating investigator or sponsor project manager before validation of the patient inclusion.
3. 3. Subjects must be primary refractory or relapsed (R/R) to 1st line of treatment for AML. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis. 3a. Primary refractory is defined as no CR or CRi after at least one course of ICT (including “7+3”, gemtuzumab ozogamycin (GO)-based and CPX-351, including or not midostaurine) or two courses (maximum 4) of AZA and venetoclax, or AZA and Ivosidenib as per the investigator’s discretion. 3b. Morphological relapse after 1st line ICT for AML is defined as the first hematologic relapse with bone marrow blasts >5% after one line of treatment for AML that includes at least one course of ICT (one line of treatment for AML can include induction, re-induction, consolidation, allogeneic HSCT and maintenance) 3c. Morphological relapse after 1st line non intensive chemotherapy for AML includes the first hematologic relapse with bone marrow blasts >5% after or during treatment by AZA venetoclax regardless of number of cycles. 3d. Morphological relapse after 1st line non intensive chemotherapy for AML is defined asinclude the first hematologic relapse with bone marrow blasts >5% after or during treatment by AZA ivosidenib regardless of number of cycles
4. 4. 1st line treatment may or may not include previous treatment by tyrosine kinase inhibitor (TKI) except gilteritinib.
5. 5. Patients who never received previously oral azacitidine
6. 6. Age ≥ 18 years
7. 7. Adequate baseline organ function defined by the criteria below: - adequate renal function as demonstrated by a creatinine clearance ≥ 50 ml/min; calculated by the Cockcroft gault formula or measured by 24-hours urine collection - aspartate aminotransferase (AST) ≤ 2.5 × ULN - alanine aminotransferase (ALT) ≤ 2.5× ULN - bilirubin ≤ 1.5 × ULN - adequate cardiac function with LVEF ≥45%
8. 8. ECOG < 3
9. 9. Absence of any psychological, familial, sociological, or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule
10. 10. Patient is suitable for oral administration of study drug.
11. 11. A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: - Not a woman of childbearing potential (WOCBP) as defined in post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented as surgically sterile (at least 1 month prior to Screening) - WOCBP agrees to follow the contraceptive treatment starting at screening and continue throughout the study period, and for at least 180 days after the final study drug administration.
12. 12. Patient must be affiliated to the french social security (health insurance)
13. 13. Signed written informed consent for the study
14. 14. 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.
15. 15. Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration
16. 16. A male subject with female partner(s) of childbearing potential must agree to use contraception starting at screening and continue throughout the study period, for at least 120 days after the final study drug administration.
17. 17. Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.

Exclusion criteria 25

1. 1. Subjects with any of the following current or previous diagnoses: 1.a. AML secondary to prior myeloproliferative syndrome (MPN) 1.b AML secondary to chronic myelomonocytic leukemia (CMML) 1.c Acute promyelocytic leukemia (APL) and core binding factor (CBF) AML 1.d. DNA fragility or bone marrow (BM) failure syndromes 1.e. Blastic plasmacytoid dendritic cell neoplasm 1.e. Acute lymphoblastic leukemia including ambiguous lineage
2. 10. Severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis or hyperbilirubinemia)
3. 11. Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC).
4. 12. Subject exhibiting evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
5. 13. Isolated extramedullary leukemia relapse
6. 14. History of another malignancy within the past 3 years except basal cell carcinoma of the skin or cervix in situ carcinoma
7. 15. Any other serious medical condition, laboratory abnormalities or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent
8. 16. Severe medical or mental condition precluding the administration of protocol treatments
9. 17. Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrolment
10. 18. Subject with Positive HIV test (due to potential drug-drug interactions). HIV testing will be performed at screening, if required per local guidelines or institutional standards. Subject known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status with undetectable PCR viral load on antivirals (non-exclusionary medications) are not excluded
11. 19. Known hypersensitivity to the study medication
12. 2. Subjects that have been previously treated by gilteritinib
13. 20. Subject has congestive heart failure classified as New York Heart Association Class III and IV unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
14. 21. Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at screening
15. 22. Subject with a history of Long QT Syndrome at screening
16. 3. Subjects that have been previously treated by oral azacitidine
17. 4. Clinically active central nervous system (CNS) leukemia
18. 5. Subjects who have received more than 1 prior allogeneic HSCT
19. 6. Subjects who have relapsed within 100 days after allogeneic HSCT
20. 7. Presence of Grade 2 or above graft-versus-host disease (GVHD), including acute, chronic, or overlap; or escalation of therapy for GVHD within 14 days prior to inclusion
21. 8. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A
22. 9. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the subject
23. 23. Patients ≥ 2nd line of treatment, HSCT being not considered as a line of treatment. Venetoclax-Azacitidine as preemptive treatment for molecular relapse (before morphological relapse) is not considered as 2nd line of treatment.
24. 24. Patients previously treated by AZA as single agent for AML are not allowed
25. persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. CRc is defined by addition of best response during the first 3-months treatment
2. CR is defined by presence of regenerating hematopoietic cells in the bone marrow and achievement of a morphologic leukemia-free state (MLFS) with absolute neutrophil count (ANC) ≥1 × 109/l, platelet count ≥100 × 109/l, normal bone marrow differential with <5% blasts, and red blood cell (RBC)/platelet transfusion independence with no evidence of extramedullary AML according to Döhner et al. 1
3. CRi defined by achievement of all CR criteria except for hematologic recovery with residual neutropenia (ANC <1 × 109/l) with or without RBC/platelet transfusion independence according to Perl et al. 2
4. CRp defined by achievement of all CR criteria except for platelet recovery (platelet count <100 × 109/l) according to Perl et al. 2

Secondary endpoints 6

1. Safety and tolerability will be defined by: • % of early deaths (ED) at Day 30 • incidence and relatedness of adverse events (AE) according to CTCAE v5.0
2. Best response during the first 6-months treatment among: • CRh is defined by bone marrow blasts <5% with partial hematologic recovery defined as ANC ≥0.5 × 109/l and platelet count ≥50 × 109/l, with no evidence of extramedullary leukemia and cannot be classified as CR, according to Perl et al. 2
3. Best response during the first 6-months treatment among:• PR is defined by presence of regenerating normal hematopoietic cells in bone marrow with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a ≥50% decrease in the number of blasts in the bone marrow aspirate with total marrow blasts between 5% and 25%. A value of ≤5% blasts is also considered a PR if Auer rods are present according to Döhner et al. 1
4. Best response during the first 6-months treatment among: • MLFS is defined by a bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required according to Döhner et al. 1
5. Best response during the first 6-months treatment among: • SD is defined as absence of CR, CRi, CRp, CRh, PR or MLFS without progressive disease for at least 3 months according to Döhner et al. 1 • CR/CRi/CRp/CRh/MLFSMRD- is defined as a CR/CRi/CRp/CRh/MLFS with negativity for a genetic marker by RT-qPCR, or CR/CRi/CRp/CRh/MLFS with <10-3 AML cells by MFC according to Döhner et al. 3
6. Analysis of: • % of per protocol HSCT, % of HSCT in CRc, % of patients receiving gilteritinib at day +100 post HSCT • OS, EFS, RFS, CIR and NRM will be defined according to Cheson et al. 4

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

French Innovative Leukemia Organization

Sponsor organisation

French Innovative Leukemia Organization

Address

2 Boulevard Tonnelle

City

Tours

Postcode

37000

Country

France

Scientific contact point

Organisation

French Innovative Leukemia Organization

Contact name

Pr DUMAS Pierre-Yves

Public contact point

Organisation

French Innovative Leukemia Organization

Contact name

FILO Desk Officer

Third parties 9

Locations

1 EU/EEA country · 21 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 13 files

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

Application history

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