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

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат 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

Первичные конечные точки

• 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 [Срок оценки: 28-56 days]

Вторичные конечные точки (12)

• Rate of CR/CRi with a flow based MRD in the BM aspirate using the LAIP/Dfn method [Срок оценки: 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 [Срок оценки: 10-13 weeks]
• Analysis of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods [Срок оценки: 10-13 weeks]
• Overall response rate, and CR and CRi rates [Срок оценки: 28-56 days]
• Cumulative incidence of allogeneic HSCT [Срок оценки: 4.5 years]
• Early mortality at D30, D60, D100 [Срок оценки: day 100]
• Overall Survival (with and without censoring at allogeneic HSCT) [Срок оценки: 4.5 years]
• Relapse-Free Survival (with and without censoring at allo-HSCT) [Срок оценки: 4.5 years]
• Event-Free Survival (with and without censoring at allo-HSCT) [Срок оценки: 4.5 years]
• Cumulative Incidence of Relapse (with and without censoring at allo-HSCT) [Срок оценки: 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 [Срок оценки: 4.5 years]
• Analysis of duration of hospitalization during induction and consolidation cycles [Срок оценки: 6 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 35 центров

• CHU Amiens Picardie site Sud — Amiens
• CHU d'Angers — Angers
• CH Avignon — Avignon
• CHRU Jean Minjoz — Besançon
• Centre Hospitalier de Béziers — Béziers
• Hôpital Avicenne APHP — Bobigny
• Institut d'hématologie de Basse Normandie (IHBN) — Caen
• Hôpital d'Instruction des Armée (HIA) — Clamart
• … и ещё 27 центров

Идентификаторы

NCT: NCT05260528 · 21-PP-26

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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