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

Study Overview
=================
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

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

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Cytarabine and Idarubicin
* Drug: CPX-315


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard arm<br> | Drug: Cytarabine and Idarubicin<br>* 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<br>|
| Experimental: Investigational arm<br> | Drug: CPX-315<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CPX-351, Acute Myeloid Leukemia