CPX-351 vs Intensive Chemotherapy in Patients With de Novo Intermediate or Adverse Risk AML Stratified by Genomics (ALFA2101)

An ALFA 2101 Multicenter Randomized Phase II Study: CPX-351 Versus Intensive Chemotherapy in Patients With de Novo Intermediate or Adverse Risk AML Stratified by Genomics

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

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Cytarabine and Idarubicin; Drug: CPX-315

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.

• Study Type: Interventional
• Enrollment (Estimated): 248
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: valerie Foussat; Phone Number: +33492034011; Email: foussat.v@chu-nice.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • CHU Amiens Picardie Site Sud
    • Principal Investigator: Delphine Lebon
    • Contact: Delphine Lebon
  • Angers, France
    • Not yet recruiting
    • CHU d'Angers
    • Contact: Mathilde Hunault
    • Principal Investigator: Mathilde Hunault, MD
  • Avignon, France
    • Recruiting
    • Ch Avignon
    • Contact: Safia Chebrek
    • Principal Investigator: Safia Chebrek
  • Besançon, France
    • Recruiting
    • CHRU Jean Minjoz
    • Contact: Yohan Desbrosses
    • Principal Investigator: Yohan Desbrosses
  • Bobigny, France
    • Recruiting
    • Hôpital Avicenne APHP
    • Principal Investigator: Thorsten Braun
    • Contact: Thorsten Braun
  • Béziers, France
    • Recruiting
    • Centre Hospitalier de Beziers
    • Contact: Alain Saad
    • Principal Investigator: Alain Saad
  • Caen, France
    • Recruiting
    • Institut d'hématologie de Basse Normandie (IHBN)
    • Contact: Sylvain Chantepie
    • Principal Investigator: Sylvain Chantepie
  • Clamart, France
    • Recruiting
    • Hôpital d'Instruction des Armée (HIA)
    • Contact: Pierre Arnautou
    • Principal Investigator: Pierre Arnautou
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Estaing
    • Contact: Romain Guieze
    • Principal Investigator: Romain Guieze
  • Corbeil-Essonnes, France
    • Recruiting
    • Centre Hospitalier Sud Francilien (CHSF)
    • Contact: Célia Salanouba
    • Principal Investigator: Célia Salanouba
  • Créteil, France
    • Recruiting
    • CHU Henri Mondor
    • Contact: Cécile Pautas
    • Principal Investigator: Cécile Pautas
  • Le Chesnay, France
    • Recruiting
    • Centre Hospitalier de Versailles, Site André Mignot
    • Contact: Juliette Lambert
    • Principal Investigator: Juliette Lambert
  • Lille, France
    • Recruiting
    • Hôpital Claude HURIEZ, CHU Lille
    • Principal Investigator: Celine Berthon
    • Contact: Celine Berthon
  • Limoges, France
    • Recruiting
    • CHU de LImoges
    • Contact: Pascal Turlure
    • Principal Investigator: Pascal Turlure
  • Marseille, France
    • Recruiting
    • Institut Paoli Calmettes
    • Contact: Yosr Hicheri, MD
    • Principal Investigator: Yosr Hicheri
  • Marseille, France
    • Recruiting
    • Hoptial de la Conception APHM
    • Principal Investigator: Regis Costello
    • Contact: Regis Costello
  • Metz, France
    • Recruiting
    • CHR Metz-Thionville Site Mercy
    • Contact: Houria Debarri
    • Principal Investigator: Houria Debarri
  • Mulhouse, France
    • Recruiting
    • Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Hôpital Emile Muller
    • Contact: Mario Ojeda-Uribe
    • Principal Investigator: Mario Ojeda-Uribe
  • Nantes, France
    • Not yet recruiting
    • CHU de NANTES
    • Contact: Pierre Peterlin
    • Principal Investigator: Pierre Peterlin, MD
  • Nice, France
    • Not yet recruiting
    • Centre Antoine Lacassagne
    • Contact: Lauris Gastaud
    • Principal Investigator: Lauris Gastaud
  • Nice, France
    • Recruiting
    • CHU de Nice
    • Principal Investigator: Thomas Cluzeau
    • Contact: Thomas Cluzeau, MD
  • Nîmes, France
    • Recruiting
    • Institut de Cancérologie du Gard
    • Contact: Samy Chraibi
    • Principal Investigator: Samy Chraibi
  • Orléans, France
    • Recruiting
    • CHR Orléans
    • Contact: Diana Carp
    • Principal Investigator: Diana Carp
  • Paris, France
    • Recruiting
    • Hopital Saint-Antoine
    • Contact: Ollivier Legrand
    • Principal Investigator: Ollivier Legrand
  • Paris, France
    • Recruiting
    • Hôpital Saint-Louis
    • Contact: Florence Rabian
    • Principal Investigator: Florence Rabian
  • Paris, France
    • Recruiting
    • Hôpital Necker
    • Principal Investigator: Ambroise Marcais
    • Contact: Ambroise Marcais
  • Paris, France
    • Recruiting
    • Hôpital de la Pitié Salpétrière
    • Contact: Madalina Uzunov
    • Principal Investigator: Madalina Uzunov
  • Pessac, France
    • Recruiting
    • CHU de Bordeaux
    • Contact: Arnaud Pigneux, MD
    • Principal Investigator: Arnaud Pigneux, MD
  • Pierre-Bénite, France
    • Recruiting
    • Hôpital Lyon Sud
    • Principal Investigator: Mael Heiblig
    • Contact: Mael Heiblig
  • Roubaix, France
    • Recruiting
    • CH de Roubaix
    • Principal Investigator: Julia Hieulle
    • Contact: Julia Hieulle
  • Rouen, France
    • Recruiting
    • Centre Henri Becquerel
    • Contact: Emilie Lemasle-Hue
    • Principal Investigator: Emilie Lemasle-Hue
  • Saint-Priest-en-Jarez, France
    • Recruiting
    • Chu de Saint Etienne
    • Contact: Emmanuelle Tavernier
    • Principal Investigator: Emmanuelle Tavernier
  • Toulouse, France
    • Recruiting
    • CHU de Toulouse
    • Contact: Sarah Bertoli
    • Principal Investigator: Sarah Bertoli, MD
  • Tours, France
    • Recruiting
    • Hopital Bretonneau
    • Contact: Alban Villate
    • Principal Investigator: Alban Villate
  • Villejuif, France
    • Recruiting
    • Institut Gustave Roussy
    • Principal Investigator: Stéphane De Botton
    • Contact: Sephane De Botton

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. De novo AML
2. No MRC-defining cytogenetic lesion
3. No t(15;17), t(8;21), inv(16) or t(16;16)
4. No NPM1 gene mutation
5. No FLT3 mutated AML (FLT3 ITD or TKD)
6. Not previously treated except for short course hydroxyurea in patients presenting with high WBC count and/or tumor symptoms,
7. Age ≥ 50 years,
8. Performance status ≤ 2 (ECOG grading),
9. Patient must have adequate organ function as indicated detailed with laboratory values in the section IV of the protocol
10. 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.
11. 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
12. 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 .
13. Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
14. Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
15. Patient registered to the French Social Security.

Exclusion Criteria:

1. Prior history of documented MDS, MPN or MDS/MPN, tAML
2. Prior history of radiation therapy or chemotherapy for a solid tumor or lymphoma (exceptions to be considered: local radiotherapy for prostate cancer)
3. Patient has active and uncontrolled infection.
4. 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.
5. 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.
6. Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
7. Patient has clinically active hepatitis B or hepatitis C infection.
8. Patient has a known allergy or hypersensitivity to any component of CPX-351, idarubicin or cytarabine.
9. 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.
10. Patients with clinical evidence of CNS leukemia.
11. Cardiac ejection fraction <50% or considered as abnormal by echocardiography or multi-gated acquisition (MUGA) scan.
12. Patient is pregnant or breastfeeding within the projected duration of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard arm; conventional 7+3 chemotherapy	Drug: Cytarabine and Idarubicin; 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; Other Names: Standard arm
Experimental: Investigational arm; CPX-351	Drug: CPX-315; 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; Other Names: Investigational arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method		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		10-13 weeks
Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods		10-13 weeks
Overall response rate, and CR and CRi rates		28-56 days
Cumulative incidence of allogeneic HSCT		4.5 years
Early mortality at D30, D60, D100		day 100
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
Event-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 duration of hospitalization during induction and consolidation cycles		6 months
Analysis of changes of the genomic landscape with the treatment		6 months
Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS		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	6 months
Analysis of secondary-type mutational profile at screening as determined by Lindsley et al	Exploratory objectives	6 months
Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate	Exploratory objectives	6 months
Analysis of Flow MRD	Exploratory objectives	6 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice
• Collaborators: Jazz Pharmaceuticals; Acute Leukemia French Association
• Investigators: Principal Investigator: Thomas Cluzeau, MD, Centre Hospitalier Universitaire de Nice

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2023
• Primary Completion (Estimated): August 2, 2028
• Study Completion (Estimated): February 2, 2030

Study Registration Dates

• First Submitted: February 7, 2022
• First Submitted That Met QC Criteria: February 17, 2022
• First Posted (Actual): March 2, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; CPX-351
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Cytarabine; Idarubicin
• Other Study ID Numbers: 21-PP-26

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No