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)
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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
210
Induction 1: Cytarabine 200 mg/m2 i.v. (continuously) d1-7 + Idarubicin 12mg/m2 d1, 2, 3 i.v (60 min) Induction 2: Cytarabine 1500 mg/m2 i.v. q12h d1-3 Consolidation: Cytarabine 1500 mg/m2 i.v. q12h d1-3
Induction 1:CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine i.v. (90 min) d1,3,5 Induction 2: CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine i.v. (90 min) d1,3 Consolidation therapy:CPX-351 29 mg/m2 daunorubicin / 65 mg/m2 cytarabine i.v. (90 min) d1,3
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
Time frame: 28-56 days
Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method
Time frame: 28-56 days
Analysis of rate of flow-based MRD quantified in the bone marrow according to both the LAIP/DfN method and the LSC method
Time frame: 10-13 weeks
Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods
Time frame: 10-13 weeks
Overall response rate, and CR and CRi rates
Time frame: 28-56 days
Cumulative incidence of allogeneic HSCT
Time frame: 4.5 years
Early mortality at D30, D60, D100
Time frame: day 100
Overall Survival (with and without censoring at allogeneic HSCT)
Time frame: 4.5 years
Relapse-Free Survival (with and without censoring at allo-HSCT)
Time frame: 4.5 years
Event-Free Survival (with and without censoring at allo-HSCT)
Time frame: 4.5 years
Cumulative Incidence of Relapse (with and without censoring at allo-HSCT)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
CHU Amiens Picardie site Sud
Amiens, France
CH Avignon
Avignon, France
RECRUITINGCHRU Jean Minjoz
Besançon, France
RECRUITINGCentre Hospitalier de Béziers
Béziers, France
RECRUITINGHôpital Avicenne APHP
Bobigny, France
RECRUITINGInstitut d'hématologie de Basse Normandie (IHBN)
Caen, France
RECRUITINGHôpital d'Instruction des Armée (HIA)
Clamart, France
RECRUITINGCHU Estaing
Clermont-Ferrand, France
RECRUITINGCentre Hospitalier Sud Francilien (CHSF)
Corbeil-Essonnes, France
RECRUITINGCHU Henri Mondor
Créteil, France
RECRUITING...and 20 more locations
Time frame: 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
Time frame: 4.5 years
Analysis of duration of hospitalization during induction and consolidation cycles
Time frame: 6 months
Analysis of changes of the genomic landscape with the treatment
Time frame: 6 months
Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS
Time frame: 4.5 years
QoL EORTC QLQ-C30 ( core quality of life questionnaire developped by European Organization for Research and treatment of Cancer), Self assessment by patients
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
Time frame: 6 months
Analysis of secondary-type mutational profile at screening as determined by Lindsley et al
Exploratory objectives
Time frame: 6 months
Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate
Exploratory objectives
Time frame: 6 months
Analysis of Flow MRD
Exploratory objectives
Time frame: 6 months