Phase 3 Study of Idarubicin, Daunorubicin, Cytarabine, and Mycophenolic Acid in Acute Myeloid Leukemia Patients Aged 18-60

Trial ID: 2024-516873-57-00
Protocol: BIG-1
Sponsor: Centre Hospitalier Universitaire D'Angers

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Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this Phase 3 trial is to evaluate the **overall survival** at 3 years in adults aged 18 to 60 with **acute myeloid leukemia** (AML). This is assessed through two comparisons: high-dose **idarubicin** versus **daunorubicin** during induction (R1), and high-dose versus intermediate-dose **cytarabine** during consolidation (R2). Additionally, the trial aims to assess the cumulative incidence of grade II to IV acute graft versus host disease (GvHD) at day 100 post-transplantation (R3), and leukemia-free survival at 18 months (R4). These objectives are clinically relevant as they address critical aspects of AML treatment, including the effectiveness of induction and consolidation therapies, and the management of GvHD, which are pivotal in improving patient outcomes.

Participants

The clinical trial involves participants diagnosed with **acute myeloid leukemia** (AML), specifically targeting adults aged 18 to 60 years. The study population includes both male and female subjects, with no vulnerable populations selected. Participants are required to have a maintained general health status, as indicated by an ECOG performance scale of 3 or less, and must not have severe uncontrolled infections or cardiac contraindications related to anthracycline use. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. Key inclusion criteria include a confirmed diagnosis of AML, either de novo or secondary to myelodysplastic syndrome or cancer therapy, and no prior treatment for AML or MDS, except for hydroxyurea or EPO, respectively. Participants must also have certain laboratory values within specified limits unless abnormalities are related to leukemia. The selection process for the trial population is not explicitly described in the provided data.

Plans and Procedures

The clinical trial is a **Phase 3** study designed to evaluate the efficacy of different treatment regimens in improving overall survival in adults aged 18 to 60 with **acute myeloid leukemia (AML)**. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The study is expected to span from its recruitment start date in January 2015 to its estimated end date in January 2032, providing a comprehensive evaluation over several years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, diagnosis of AML, and general health status. Following successful screening, participants will be randomized into different treatment arms. The trial includes multiple follow-up visits to monitor the participants' response to treatment and any adverse effects. These visits are crucial for collecting data on primary endpoints, such as overall survival at three years and the incidence of acute graft-versus-host disease (GvHD) at day 100. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to gather comprehensive data on the long-term effects of the treatments.

The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of 42 days for some regimens. Conditions that may lead to early termination from the study include severe adverse reactions, withdrawal of consent, or any significant protocol deviations. The trial's methodology ensures that all data collected is robust and contributes to the understanding of effective treatment strategies for AML.

Treatment

The clinical trial involves the administration of **Cytarabine**, a chemical compound known for its role as an **antimetabolite**. Cytarabine is utilized in the study in its pharmaceutical form coded as PHF00230MIG. The medication is administered intravenously, with a maximum daily dose of 3 gm/m² and a total maximum dose of 27 gm/m² over a treatment period of 9 days. The primary objective of using Cytarabine in this trial is to evaluate its efficacy in the consolidation phase of treatment for acute myeloid leukemia (AML) in adults. The trial compares high-dose (3.0 g/m²) and intermediate-dose (1.5 g/m²) regimens to determine the optimal dosing strategy for improving overall survival.

**Venetoclax** is also employed in this trial as a test medication. It is a chemical compound formulated as a film-coated tablet, with the sponsor product code ABT-199. Venetoclax is administered orally, with a maximum daily dose of 400 mg and a total maximum dose of 16,800 mg over a 42-day treatment period. This medication functions as a **Bcl-2 family protein inhibitor**, and its role in the trial is to assess its potential in enhancing treatment outcomes for AML patients. Venetoclax is provided by ABBVIE DEUTSCHLAND GMBH & CO. KG and is not a pediatric formulation.

In addition to the experimental medications, the trial includes standard-of-care therapies such as high-dose idarubicin and daunorubicin during the induction phase, as well as mycophenolic acid for the prevention of graft versus host disease in allograft patients. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to improve overall survival rates and assess the cumulative incidence of acute graft versus host disease, as well as leukemia-free survival in the specified patient population.

Efficacy

Efficacy in this clinical trial will be assessed through several key endpoints. The primary endpoint for the R1 and R2 randomizations is the comparison of **overall survival (OS)** at 3 years. This will be evaluated based on the treatment administered, specifically comparing idarubicin versus daunorubicin for randomization 1, and high-dose cytarabine 3.0 g/m² versus intermediate-dose cytarabine 1.5 g/m² for randomization 2. For the R3 randomization, the primary endpoint is the cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) at day 100, assessed according to the GvHD prophylaxis regimen used.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.

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Exclusion Criteria

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.