Clinical trial NCT05260528: CPX-351 vs Intensive Chemotherapy in Patients With de Novo Intermediate or Adverse Risk AML Stratified by Genomics
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: CPX-351
Acute Myeloid Leukemia
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
Collaborators: name: Jazz Pharmaceuticals
name: Acute Leukemia French Association
First posted: 2022-03-02
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: 28-56 days
Secondary outcomes:
measure: Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method
timeFrame: 28-56 days
measure: Analysis of rate of flow-based MRD quantified in the bone marrow according to both the LAIP/DfN method and the LSC method
timeFrame: 10-13 weeks
measure: Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods
timeFrame: 10-13 weeks
measure: Overall response rate, and CR and CRi rates
timeFrame: 28-56 days
measure: Cumulative incidence of allogeneic HSCT
timeFrame: 4.5 years
measure: Early mortality at D30, D60, D100
timeFrame: day 100
measure: Overall Survival (with and without censoring at allogeneic HSCT)
timeFrame: 4.5 years
measure: Relapse-Free Survival (with and without censoring at allo-HSCT)
timeFrame: 4.5 years
measure: Event-Free Survival (with and without censoring at allo-HSCT)
timeFrame: 4.5 years
measure: Cumulative Incidence of Relapse (with and without censoring at allo-HSCT)
timeFrame: 4.5 years
measure: Analysis of Hematological and non-hematological toxicity profile and safety using the NCI- common toxicity criteria (CTCAE) version 5.0 of November 2017
timeFrame: 4.5 years
measure: Analysis of duration of hospitalization during induction and consolidation cycles
timeFrame: 6 months
measure: Analysis of changes of the genomic landscape with the treatment
timeFrame: 6 months
measure: Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS
timeFrame: 4.5 years
measure: QoL EORTC QLQ-C30 ( core quality of life questionnaire developped by European Organization for Research and treatment of Cancer), Self assessment by patients
timeFrame: 6 months
measure: Analysis of secondary-type mutational profile at screening as determined by Lindsley et al
timeFrame: 6 months
measure: Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate
timeFrame: 6 months
measure: Analysis of Flow MRD
timeFrame: 6 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens Picardie site Sud
city: Avignon
country: France
facility: CH Avignon
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Bobigny
country: France
facility: Hôpital Avicenne APHP
city: Béziers
country: France
facility: Centre Hospitalier de Béziers
city: Caen
country: France
facility: Institut d'hématologie de Basse Normandie (IHBN)
city: Clamart
country: France
facility: Hôpital d'Instruction des Armée (HIA)
city: Clermont Ferrand
country: France
facility: CHU Estaing
city: Corbeil-Essonnes
country: France
facility: Centre Hospitalier Sud Francilien (CHSF)
city: Créteil
country: France
facility: CHU Henri Mondor
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles, Site André Mignot
city: Lille
country: France
facility: Hôpital Claude HURIEZ, CHU Lille
city: Limoges
country: France
facility: CHU de Limoges
city: Marseille
country: France
facility: Hoptial de la Conception APHM
city: Metz
country: France
facility: CHR Metz-Thionville Site Mercy
city: Mulhouse
country: France
facility: Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Hôpital Emile Muller
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nice
country: France
facility: CHU de Nice
city: Nîmes
country: France
facility: Institut de cancérologie du Gard
city: Orléans
country: France
facility: CHR Orléans
city: Paris
country: France
facility: Hopital Necker
city: Paris
country: France
facility: Hôpital de la Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre-Bénite
country: France
facility: Hopital Lyon Sud
city: Roubaix
country: France
facility: CH de Roubaix
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Priest-en-Jarez
country: France
facility: CHU de Saint Etienne
city: Tours
country: France
facility: Hopital Bretonneau
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
References: