A Phase II Randomized Study to Assess the Efficacy on Outcome of Venetoclax Combined With Cytarabine Versus Idarubicin Combined With Cytarabine Administered as Post-remission Therapy to Elderly Patients With Acute Myeloid Leukemia in First Remission
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 134
- 试验地点
- 26
- 主要终点
- Relapse Free Survival (RFS)
研究概览
简要总结
For the FILO group, the standard of care for induction chemotherapy of elderly fit patients with AML is represented by the combination of Cytarabine, Idarubicin and Lomustine. The superiority of this combination was confirmed in a larger prospective study the LAMSA-2007. This induction treatment, followed by six courses of consolidation (Idarubicin and Cytarabine) followed then by a period of 6-month maintenance therapy, allows up to 80 % of remission, and a RFS of 46 % at 2 years.
The aim of the study is to assess the efficacy on outcome of Venetoclax combined with Cytarabine versus Idarubicin combined with Cytarabine administered as post-remission therapy to elderly patients with acute myeloid leukemia in first complete remission (CR) following induction chemotherapy.
详细描述
Acute myeloid leukemia is characterized by the clonal expansion of myeloid blasts in the bone marrow, peripheral blood and extramedullary tissues which disrupts normal hematopoiesis.
It is the most common form of acute leukemia in adults with an estimated 19,950 new cases and 10,430 deaths in 2016 in the United States. The prevalence is approximately 36,000 in the US alone. The median age of diagnosis is 67 years, with 55 % of the patients diagnosed at 65 years or older, and approximately a third of them are diagnosed over the age of 75.
Due to a higher frequency of poor prognosis factors such as adverse cytogenetics, previous history of myelodysplastic syndrome (MDS) or therapy-related AML (t-AML), the prognosis of elderly AML remains dismal in patients > 60 years.
The complete remission rate achieved after induction chemotherapy is lower than in young adults, and the remission duration is seldom longer than a year. Consequently, the overall survival of these patients rarely excesses 10-15 % beyond 5 years from diagnosis. For this group of patients, improving the efficacy of post induction chemotherapy and preventing relapse, without increasing the treatment-related mortality, remain a challenge.
For the FILO group, the standard of care for induction chemotherapy of elderly fit patients with AML is represented by the combination of Cytarabine, Idarubicin and Lomustine (ICL: Idarubicin 8 mg per square meter per day, IV on days 1-5, Cytarabine 100 mg per square meter per day on days 1-7 IV continuously, Lomustine 200 mg per square meter orally at day 1). This induction treatment, followed by six courses of consolidation, consisting of reduced doses of Idarubicin 8 mg per square meter per day IV on day 1 and Cytarabine 50 mg per square meter/12h/d subcutaneously on days 1-5 followed then by a period of 6-month maintenance therapy, allows up to 80 % of remission, an improvement in 2-year Event Free Survival from 26 % to 41 %, and a 2 year relapse free survival improvement from of 33 % to 46 % for patients without unfavorable cytogenetics.
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
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Diagnosis of Acute Promyelocytic Leukemia (APL)
- •AML with adverse cytogenetics according to ELN 2017
- •AML with BCR-ABL1 translocation
- •Subject with an antecedent of myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia (CML) with or without BCR-ABL1 translocation
- •Clinical symptoms suggesting active central nervous system leukemia, or presence of isolated extramedullary leukemia
- •Previous exposure of anthracycline ≥ 550 mg/m² (Daunorubicin equivalence)
- •Previous AML treatment other than Hydroxyurea
- •Treatment with an investigational drug within 30 days or 5 half-life whichever is longer, preceding the initiation study and/or previous treatment with Venetoclax
- •History of another malignancy within the past 3 years except basal cell carcinoma of the skin or cervix in situ carcinoma
- •Any serious medical condition, laboratory abnormalities or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent or precluding the administration of protocol treatments
- •Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrolment
- •Subject with known HIV infection (due to potential drug-drug interactions between antiretroviral medications and Venetoclax). HIV testing will be performed at Screening. Subject known to be positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status with undetectable Polymerase Chain Reaction (PCR) viral load on antivirals (non-exclusionary medications) are not excluded.
- •Randomization criteria:
- •Subjects must have been registered at diagnosis
- •Subjects must have received intensive induction by Idarubicin, Cytarabine and Lomustine
- •Patients in Complete Response / Complete Response with incomplete hematologic recovery (CR/CRi) post induction according to ELN 2017 criteria
- •Randomization should be performed no more than D+60 after induction
- •ECOG < 3 (appendix 1)
- •Adequate baseline organ function defined by the criteria below:
- •Adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
- •Aspartate aminotransferase (AST) ≤ 3.0 × ULN
- •Alanine aminotransferase (ALT) ≤ 3.0 × ULN
- •Bilirubin ≤ 1.5 × ULN
- •Adequate cardiac function with LVEF ≥ 50 %
- •Male subjects who are sexually active must agree, from study Day 1 through at least 180 days after the last dose of study drug, to practice protocol-specified methods of contraception
- •Female subjects must be postmenopausal defined as with no menses for 12 or more months without an alternative medical cause
- •Non randomization criteria
- •Patient in Partial Remission (PR) or failure following one induction course by Idarubicin, Cytarabine and Lomustine (according ELN 2017 criteria)
- •Uncontrolled infection
- •Subject with cardiovascular disability status as per New York Heart Association Class >
- •Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain. Class 3 is defined as cardiac disease in which subjects are comfortable at rest but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class 4 is defined as cardiac disease in which subjects have an inability to carry on any physical activity without discomfort, symptoms of heart failure at rest, and if any physical activity is undertaken then discomfort increases.
- •Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
- •Any serious medical condition, laboratory abnormality, or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent.
- •Treatment with any of the following within 7 days prior to the first dose of study drug :
- •Strong or moderate CYP3A inducers
- •Steroid therapy for anti-neoplastic intent
- •Subject having consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
- •Subject having chronic respiratory disease that requires continuous oxygen, or a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
- •Previous treatment with Venetoclax and/or current participation in any other research study with investigational products.
- •Known hypersensitivity to the study medication
研究组 & 干预措施
VEN-CYTA
Venetoclax 600mg/day, Per Os (PO), D1 to D14 / 28 days cycle Cytarabine 50 mg/m2/12h Subcutaneous (SC), D1 to D5 / 28 days cycle
干预措施: Cytarabine-Venetoclax Association (Drug)
IDA-CYTA
Idarubicin 8mg/m2, Intravenous (IV), at D1 / 28 days cycle Cytarabine 50 mg/m2/12h, SC, D1 to D5 / 28 days cycle
干预措施: Cytarabine-Idarubicin Association (Drug)
结局指标
主要结局
Relapse Free Survival (RFS)
时间窗: from randomization to last follow-up (up to 5 years)
RFS measured from the date of achievement of a remission until the date of relapse or death from any cause
次要结局
- Overall survival at 2 years(from date of randomization to 2 years after last administration of experimental treatment)