CPX-351 vs Intensive Chemotherapy in Patients With de Novo Intermediate or Adverse Risk AML Stratified by Genomics
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Drug: CPX-315
- Registration Number
- NCT05260528
- Lead Sponsor
- Centre Hospitalier Universitaire de Nice
- Brief Summary
The trial is a randomized, open-label phase II study comparing CPX-351 vs conventional intensivechemotherapy in patients with newly diagnosed de novo AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria)
- Detailed Description
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal expansion of myeloid blasts.
Interestingly comparing de novo and stringently defined secondary AMLs occurring after a documented phase of MDS, Lindsley et al. could identify among de novo AMLs a molecular subgroup, termed 'secondary-type AML', defined by mutations in either SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR and/or STAG2 genes. Among de novo AML patients, 33.3% had secondary-type mutations.
It has been shown that patients older than 60 years of age harboring secondary-type AML, as defined by this 8-gene molecular signature, had inferior outcome to those without 'secondary-type' mutations when treated with conventional 7+3 chemotherapy, combining cytarabine and an anthracycline (ALFA 1200 study). This was notably true among patients with 'intermediate-risk' disease per European LeukemiaNet criteria.
The incidence of 'secondary-type' AML mutations increases with age and with cytogenetic risk category. Notably, roughly 50% of de novo AML patients with intermediate risk older than 50 years of age harbor such secondary-type mutations, New therapeutic options are thus necessary in patients older than 50 years with de novo AML classified adverse risk but also intermediate risk and associated to secondary-type mutation
This study will evaluate the rate of MRD negative remissions with CPX-351 used as induction and consolidation therapy according to its marketing authorization (AMM), as compared to intensive chemotherapy in a population of non-MRC AMLs enriched in secondary-like mutations. In addition,P-gp activity will be explore as a putative biomarker.
Duration of the enrollment period: 36 months Duration of treatment: 6 months Duration of the participation for a patient: 18 months (post randomization) (including approximately 6 months treatment, and 12 months of post-treatment follow up) Overall duration of the study: 58 months including the analysis of the results
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 210
- De novo AML
- No MRC-defining cytogenetic lesion
- No t(15;17), t(8;21), inv(16) or t(16;16)
- No NPM1 gene mutation
- No FLT3 mutated AML (FLT3 ITD or TKD)
- Not previously treated except for short course hydroxyurea in patients presenting with high WBC count and/or tumor symptoms,
- Age ≥ 50 years,
- Performance status ≤ 2 (ECOG grading),
- Patient must have adequate organ function as indicated detailed with laboratory values in the section IV of the protocol
- Female patient of childbearing potential with a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of CPX-351 or 7+3. Female patient who is not actively breastfeeding at the time of study entry.
- Female patient is either post-menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy, or agrees to not become pregnant throughout the study, starting with study screening
- Male patient agrees to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving CPX-351 or 7+3 and for 3 months after the last dose of study treatment .
- Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
- Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
- Patient registered to the French Social Security.
- Prior history of documented MDS, MPN or MDS/MPN, tAML
- Prior history of radiation therapy or chemotherapy for a solid tumor or lymphoma (exceptions to be considered: local radiotherapy for prostate cancer)
- Patient has active and uncontrolled infection.
- Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
- Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.
- Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
- Patient has clinically active hepatitis B or hepatitis C infection.
- Patient has a known allergy or hypersensitivity to any component of CPX-351, idarubicin or cytarabine.
- Patient with a "currently active" second malignancy, other than nonmelanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for >1 year or are considered by their physician to be at less than 30% risk of relapse.
- Patients with clinical evidence of CNS leukemia.
- Cardiac ejection fraction <50% or considered as abnormal by echocardiography or multi-gated acquisition (MUGA) scan.
- Patient is pregnant or breastfeeding within the projected duration of the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard arm Cytarabine and Idarubicin - Investigational arm CPX-315 -
- Primary Outcome Measures
Name Time Method Improvement in the proportion of patients achieving deep remission (CR)/(CRi) with a standardized flow based MRD in the BM aspirate using the LAIP/Dfn method after the 1st induction 28-56 days
- Secondary Outcome Measures
Name Time Method Analysis of duration of hospitalization during induction and consolidation cycles 6 months Analysis of rate of flow-based MRD quantified in the bone marrow according to both the LAIP/DfN method and the LSC method 10-13 weeks Overall response rate, and CR and CRi rates 28-56 days Event-Free Survival (with and without censoring at allo-HSCT) 4.5 years Analysis of changes of the genomic landscape with the treatment 6 months Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods 10-13 weeks Cumulative incidence of allogeneic HSCT 4.5 years Overall Survival (with and without censoring at allogeneic HSCT) 4.5 years Relapse-Free Survival (with and without censoring at allo-HSCT) 4.5 years Cumulative Incidence of Relapse (with and without censoring at allo-HSCT) 4.5 years Analysis of Hematological and non-hematological toxicity profile and safety using the NCI- common toxicity criteria (CTCAE) version 5.0 of November 2017 4.5 years Analysis of Flow MRD 6 months Exploratory objectives
Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method 28-56 days Early mortality at D30, D60, D100 day 100 Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS 4.5 years Analysis of secondary-type mutational profile at screening as determined by Lindsley et al 6 months Exploratory objectives
Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate 6 months Exploratory objectives
QoL EORTC QLQ-C30 ( core quality of life questionnaire developped by European Organization for Research and treatment of Cancer), Self assessment by patients 6 months The EORTC QLQ-C30nsubscales scores are tranformed to a 0 to 100 scale, with higher score on functionnal scales indicating better function and higher scores on sumptom scales indicating worse symptoms
Trial Locations
- Locations (30)
CHR Orléans
🇫🇷Orléans, France
Centre Hospitalier de Versailles, Site André Mignot
🇫🇷Le Chesnay, France
Hôpital Claude HURIEZ, CHU Lille
🇫🇷Lille, France
Hoptial de la Conception APHM
🇫🇷Marseille, France
Hopital Necker
🇫🇷Paris, France
Hôpital Saint-Antoine
🇫🇷Paris, France
CHU de Saint Etienne
🇫🇷Saint-Priest-en-Jarez, France
Hôpital d'Instruction des Armée (HIA)
🇫🇷Clamart, France
Hopital Lyon Sud
🇫🇷Pierre-Bénite, France
CHRU Jean Minjoz
🇫🇷Besançon, France
Centre Hospitalier Sud Francilien (CHSF)
🇫🇷Corbeil-Essonnes, France
Hôpital Saint-Louis
🇫🇷Paris, France
Hôpital Avicenne APHP
🇫🇷Bobigny, France
CHU de Limoges
🇫🇷Limoges, France
Centre Henri Becquerel
🇫🇷Rouen, France
Hopital Bretonneau
🇫🇷Tours, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Hôpital de la Pitié Salpêtrière
🇫🇷Paris, France
CHR Metz-Thionville Site Mercy
🇫🇷Metz, France
Centre Antoine Lacassagne
🇫🇷Nice, France
CH de Roubaix
🇫🇷Roubaix, France
CHU Amiens Picardie site Sud
🇫🇷Amiens, France
CH Avignon
🇫🇷Avignon, France
Centre Hospitalier de Béziers
🇫🇷Béziers, France
Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Hôpital Emile Muller
🇫🇷Mulhouse, France
Institut d'hématologie de Basse Normandie (IHBN)
🇫🇷Caen, France
CHU Estaing
🇫🇷Clermont Ferrand, France
CHU Henri Mondor
🇫🇷Créteil, France
CHU de Nice
🇫🇷Nice, France
Institut de cancérologie du Gard
🇫🇷Nîmes, France