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

Acute Myeloid Leukemia Clinical Trial

— ALFA2101  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05260528
• Other study ID #: 21-PP-26
• Status: Recruiting
• Phase: Phase 2
• Start date: May 3, 2023
• Est. completion date: October 2027

Study information

• Verified date: January 2024
• Source: Centre Hospitalier Universitaire de Nice
• Contact: valerie Foussat
• Phone: 04 92 03 63 77
• Email: foussat.v[@]chu-nice.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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 information / eligibility

• Status: Recruiting
• Enrollment: 210
• Est. completion date: October 2027
• Est. primary completion date: October 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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
• 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

Locations

Country	Name	City	State
France	CHU Amiens Picardie site Sud	Amiens
France	CH Avignon	Avignon
France	CHRU Jean Minjoz	Besançon
France	Centre Hospitalier de Béziers	Béziers
France	Hôpital Avicenne APHP	Bobigny
France	Institut d'hématologie de Basse Normandie (IHBN)	Caen
France	Hôpital d'Instruction des Armée (HIA)	Clamart
France	CHU Estaing	Clermont Ferrand
France	Centre Hospitalier Sud Francilien (CHSF)	Corbeil-Essonnes
France	CHU Henri Mondor	Créteil
France	Centre Hospitalier de Versailles, Site André Mignot	Le Chesnay
France	Hôpital Claude HURIEZ, CHU Lille	Lille
France	CHU de Limoges	Limoges
France	Hoptial de la Conception APHM	Marseille
France	CHR Metz-Thionville Site Mercy	Metz
France	Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Hôpital Emile Muller	Mulhouse
France	Centre Antoine Lacassagne	Nice
France	CHU de Nice	Nice
France	Institut de cancérologie du Gard	Nîmes
France	CHR Orléans	Orléans
France	Hôpital de la Pitié Salpêtrière	Paris
France	Hopital Necker	Paris
France	Hôpital Saint-Antoine	Paris
France	Hôpital Saint-Louis	Paris
France	Hopital Lyon Sud	Pierre-Bénite
France	CH de Roubaix	Roubaix
France	Centre Henri Becquerel	Rouen
France	CHU de Saint Etienne	Saint-Priest-en-Jarez
France	Hopital Bretonneau	Tours
France	Institut Gustave Roussy	Villejuif

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nice	Acute Leukemia French Association, Jazz Pharmaceuticals

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method		28-56 days
Secondary	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
Secondary	Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods		10-13 weeks
Secondary	Overall response rate, and CR and CRi rates		28-56 days
Secondary	Cumulative incidence of allogeneic HSCT		4.5 years
Secondary	Early mortality at D30, D60, D100		day 100
Secondary	Overall Survival (with and without censoring at allogeneic HSCT)		4.5 years
Secondary	Relapse-Free Survival (with and without censoring at allo-HSCT)		4.5 years
Secondary	Event-Free Survival (with and without censoring at allo-HSCT)		4.5 years
Secondary	Cumulative Incidence of Relapse (with and without censoring at allo-HSCT)		4.5 years
Secondary	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
Secondary	Analysis of duration of hospitalization during induction and consolidation cycles		6 months
Secondary	Analysis of changes of the genomic landscape with the treatment		6 months
Secondary	Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS		4.5 years
Secondary	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
Secondary	Analysis of secondary-type mutational profile at screening as determined by Lindsley et al	Exploratory objectives	6 months
Secondary	Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate	Exploratory objectives	6 months
Secondary	Analysis of Flow MRD	Exploratory objectives	6 months