Phase 3 trial aimed at improving the overall survival of AML in adults aged 18 to 60 by comparing high-dose idarubicin with daunorubicin at induction, high-dose and intermediate-dose cytarabine at consolidation and mycophenolic acid as standard prophylaxis in the prevention of graft versus host disease in allograft patients in first complete remission after reduced conditioning: Backbone Inter-Group-1 (BIG-1) trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire D'Angers

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

13 Jan 2026 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516873-57-00

EudraCT number

2014-000699-24

ClinicalTrials.gov

NCT02416388

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

- For R1 and R2 randomisations:
Overall survival at 3 years, both for the comparison idarubicin versus daunorubicin at induction (R1), and for the comparison cytarabine 1.5 g/m2 versus cytarabine 3.0 g/m2 by bolus post-induction (R2)

- For R3 randomization:
Cumulative incidence of grade II to IV acute GvHD at D100

- For R4 randomisation(s):
Leukemia-free survival at 18 months

Conditions and MedDRA coding

Acute myeloid leukemia in adults aged 18 to 60

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Diagnosis: • Patients aged 18 and over but under 61 years old • Patients with AML, de novo or secondary to myelodysplastic syndrome or cancer therapy ("therapy-related" AML) • Not previously treated for AML (except hydroxyurea) or MDS (except with EPO) • General condition maintained (ECOG performance scale ≤ 3) • No severe uncontrolled infection • No cardiac contraindications from the use of anthracyclines (decompensated or uncontrolled coronary insufficiency, recent myocardial infarction, current manifestations of cardiac insufficiency, uncontrolled rhythm disorders, ventricular ejection fraction < 50%) • AST and ALAT ≤ 2.5 times upper limit of normal (ULN), total bilirubin ≤ 2 times ULN, creatinine < 150 μmol/L unless these biological abnormalities are related to leukemia • Search for FLT3 gene mutations(FLT3-ITD or FLT3-TKD), in a local or centralized laboratory • Use of an effective contraceptive method For patients treated with midostaurin: - Women of childbearing potential should use an effective method of contraception for the duration of treatment and up to 5 months after discontinuation of treatment - Men should use condoms during sexual intercourse, for the duration of treatment and up to 5 months after stopping midostaurin. • Patients who are members or beneficiaries of a social security scheme • Having read and understood the information letter and signed the informed consent form Post-induction: R4-VOS randomization for cytarabine and vosaroxine combination R4-VOS randomization is stopped as of 05/02/2019. Post-induction: R4-VOS randomization for cytarabine and dexamethasone combination R4-DEX randomization is discontinued as of 04/27/2021. Post-induction: R4-VEN randomization for cytarabine and venetoclax combination • Patient included in the BIG-1 protocol • Patient with AML in CR or CRp/CRi after induction or salvage therapy for randomized phase 2 (confirmed within 15 days prior to R4-VEN randomization) • Patient classified in the favorable or intermediate risk group according to the prognostic classification of the BIG-1 protocol • General condition maintained (ECOG performance scale ≤ 2) • Creatinine ≤ 150 μmol/L, total bilirubin ≤ 1.5 X ULN; AST and ALAT ≤ 2.5 times upper limit of normal (ULN) • Signed the specific consent for the venetoclax study • LVEF ≥ 40% 4 • No severe uncontrolled infection • Women of childbearing potential must have uninterrupted effective contraception during the study and for at least 3 months after the end of treatment Prior to CSH allograft: R3 randomization for GvHD prophylaxis study (R3-RIC) R3-RIC randomization is discontinued as of 10/09/2023.

Exclusion criteria 1

1. With Diagnosis: • Patients with acute promyelocytic leukemia (AML3) with either t(15;17) or a positive test for the PML-RARA transcript, or AML in the CBF group with either t(8;21), t(16,16) or inv(16), or a positive test for the transcripts associated with these cytogenetic abnormalities (RUNX1-RUNX1T1, CBFB-MYH11). • Patients with AML secondary to a previously known myeloproliferative syndrome according to 2008 WHO classification • Patients with previous Philadelphia chromosome (Ph1+) AML or chronic myeloid leukemia • Patients with severe organic or psychiatric pathology presumed to be independent of AML and contra-indicating treatment, including allogeneic transplantation • Patients who, for psychological, family, social or geographical reasons, are unable to receive regular consultation services • Previous cancer, if uncontrolled for at least two years, with the exception of basal cell skin carcinoma and carcinoma in situ of the uterine cervix • No severe uncontrolled infection at the time of inclusion • Positive serology for HIV 1 or 2 or HTLV 1 or 2, or active hepatitis B or C infection • Pregnant (beta-hCG positive) or breast-feeding women • Looked-after adult patients who are under guardianship • Patient on State Medical Aid Post-induction: R4-VOS randomization for cytarabine and vosaroxine combination R4-VOS randomization is stopped as of 05/02/2019. Post-induction: R4-VOS randomization for cytarabine and dexamethasone combination R4-DEX randomization is discontinued as of 04/27/2021. Post-induction: R4-VEN randomization for cytarabine and venetoclax combination • Patient classified in the unfavorable risk group according to BIG-1 protocol classification • Patient included in R4-DEX • Uncontrolled severe infection such as sepsis, or multi-organ failure syndrome, uncontrolled fever • Documented, uncontrolled fungal infection (positive blood and cultures) • Previous myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA) within 3 months prior to randomization • Patient on hemodialysis (HD) or peritoneal dialysis (PD) • Any severe, uncontrolled condition including diabetes, hypertension, gastric ulcer, psychiatric disorders, myasthenia gravis or glaucoma 5 • Pregnant (beta-hCG positive) or breast-feeding women • Patients previously treated with venetoclax • Active hepatitis B viral infection • Patient known to be HIV positive • Known hypersensitivity to any of the study drugs. • Concomitant treatment with a CYP3A4 inhibitor that cannot be stopped during phase 1 administration of venetoclax only. • During the randomized phase 2, in the case of IDAC + venetoclax randomized paients, if concomitant treatment with a CYP3A4 inhibitor cannot be stopped, the venetoclax dose will need to be reduced by 75%. Prior to CSH allograft: R3 randomization for GvHD prophylaxis study, R3-RIC • R3-RIC randomization is discontinued as of 10/09/2023.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. For R1 and R2 randomizations: The primary endpoint will be a comparison of overall survival (OS) at 3 years according to the treatment considered (idarubicin vs. daunorubicin for randomization 1, and high-dose cytarabine 3.0 g/m2 vs. intermediate-dose cytarabine 1.5 g/m2 for randomization 2). For R3 randomization: The primary endpoint will be the cumulative incidence of grade II to IV acute GvHD at D100, compared according to the GvHD prophylaxis regimen considered (standard regimen or mycopheno

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire D'Angers

Sponsor organisation

Centre Hospitalier Universitaire D'Angers

Address

4 Rue Larrey

City

Angers

Postcode

49100

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire D'Angers

Contact name

Prof. Mathilde Hunault

Public contact point

Organisation

Centre Hospitalier Universitaire D'Angers

Contact name

Issam BILAL

Locations

1 EU/EEA country · 59 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 16 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