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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 210
- 试验地点
- 30
- 主要终点
- 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
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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+
- •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.
排除标准
- •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.
研究组 & 干预措施
Standard arm
干预措施: Cytarabine and Idarubicin (Drug)
Investigational arm
干预措施: CPX-315 (Drug)
结局指标
主要结局
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
时间窗: 28-56 days
次要结局
- Event-Free Survival (with and without censoring at allo-HSCT)(4.5 years)
- Analysis of changes of the genomic landscape with the treatment(6 months)
- Analysis of duration of hospitalization during induction and consolidation cycles(6 months)
- 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)
- Overall response rate, and CR and CRi rates(28-56 days)
- Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods(10-13 weeks)
- Cumulative incidence of allogeneic HSCT(4.5 years)
- 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)
- 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 Flow MRD(6 months)
- Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method(28-56 days)
- Early mortality at D30, D60, D100(day 100)
- Analysis of the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS(4.5 years)
- Analysis of secondary-type mutational profile at screening as determined by Lindsley et al(6 months)
- Analysis of entralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate(6 months)
- QoL EORTC QLQ-C30 ( core quality of life questionnaire developped by European Organization for Research and treatment of Cancer), Self assessment by patients(6 months)