A Phase II, Multicentre, Open Label Clinical Trial to Assess the Efficacy and Toxicity of Induction and Consolidation With CPX-351 for Patients Aged 60 to 75 Years With Secondary or High-risk Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 59
- 试验地点
- 13
- 主要终点
- To evaluate the CR/CRi rate after induction with CPX-351
研究概览
简要总结
This protocol corresponds to a prospective, multicentre, open label, phase II study designed to evaluate the efficacy of CPX-351 in elderly patients with secondary or high-risk AML. The clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a single arm group. Patients will be enrolled at diagnosis to follow the treatment arm. After that will start induction chemotherapy with CPX-351 regimen (14 days maximum screening period). Once a patient have been evaluated for response and recovered from major complications, he/she will start second course (consolidation 1), unless the bone marrow and peripheral blood assessment is showing less than a complete response, then a second induction may be offered. If a CR or CRi is obtained after the second induction course, patients will start the third course after a rest and recovery period. Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients aged between 65 and 70 years old can be proposed for an allo-SCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis. Patients with CR/CRi who are not considered for an allo-SCT, will follow 6 maintenance cycles with modified courses of CPX-351 schedule. Patients showing unacceptable toxicity along all therapeutic phases that, in consideration of the investigator, will be prematurely discontinued. All patients will be followed-up for survival. The study will be analyzed on an intention to treat basis. Bone marrow and response assessments will be done after each induction and consolidation course, and every 3 months during the first 12 months after starting maintenance therapy. Patients will be followed-up for a minimum period of 1 year after the enrolment of the last patient. Additionally, after the end of the trial, patients will be followed-up for 2 years in order to verify survival and the evolution of the disease. Study design allows a maximum of 59 patients.
详细描述
This is a prospective, multicenter, open-label, phase II study to assess efficacy of CPX-351 in elderly patients (60 to 75 years of age) with newly diagnosed high risk AML. The study includes a single arm group. The primary endpoint of the study is to assess the CR/CRi rate after induction with CPX-351.
Patients will be enrolled at diagnosis to follow the treatment arm. After that they will start induction chemotherapy with CPX-351 regimen (14 days maximum screening period). Once a patient has been evaluated for response and recovered from major complications (minimum 42 days and maximum 80 days after starting the first course), he/she will start second course (consolidation 1), unless the bone marrow and peripheral blood assessment is showing less than a partial response. If a CR or CRi is obtained after the second course, patients will start the third course after a rest and recovery period (minimum 42 days and maximum 80 days after starting the second course). After the third course an assessment of response will be done.
Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients with age less than 65-70 years old can be proposed for an allogeneic HSCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis.
Patients with CR/CRi who are not considered for an allo-SCT, will follow 6 maintenance cycles with modified courses of CPX-351 schedule. Patients showing unacceptable toxicity along all therapeutic phases that, in consideration of the investigator, will be prematurely discontinued. All patients will be followed-up for survival. The study will be analyzed on an intention to treat basis. Bone marrow and response assessments will be done after each induction and consolidation course, and every 3 months after starting maintenance therapy. Patients will be followed-up for a minimum period of 3 years after the enrollment of the last patient in order to know OS, disease-free, and relapse free survival (RFS), as well as on the duration of remission and cumulative incidence of relapse. Patients may be admitted in hospital to receive the experimental treatment.
The clinical trial is divided into pre-treatment (screening), treatment periods (induction, consolidation and maintenance cycles) and follow-up:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. Informed consent form must be signed by the patient and the investigator.
- •Age 60 to 75 years at the time of diagnosis of AML.
- •Newly confirmed diagnosed of AML according to WHO 2008 criteria.
- •Secondary or high risk AML, defined as one of the following:
- •t-AML: documentation of prior cytotoxic therapy or radiation therapy for an unrelated disease in a discharge summary or pharmacy records or radiation therapy records
- •MDSAML: bone marrow documentation of MDS prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
- •CMMoLAML: bone marrow documentation of CMMoL prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
- •de novoAML with FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Ability to adhere to the study visit schedule and other protocol requirements.
- •Laboratory values fulfilling the following:
- •Serum creatinine < 2.0 mg/mL
- •Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin < 3 times the upper limit of normal (ULN, subjects with elevated liver enzymes related to disease were instructed to contact the Sponsor) (subjects with Gilbert's Syndrome were instructed to contact the sponsor).
- •Subjects with second malignancies in remission may have been eligible if there was clinical evidence of disease stability for a period ≥ 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies at screening. Subjects maintained on long-term nonchemotherapy treatment such as hormonal therapy were eligible.
- •Cardiac ejection fraction ≥ 50% assessed by echocardiography or MUGA.
- •Eligible to receive intensive chemotherapy.
- •Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception for three months after their last dose of medication. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential).
- •Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
排除标准
- •Patients with genetic diagnosis of acute promyelocytic leukemia.
- •Age <60 years or >75 years.
- •Blastic phase of bcr/abl chronic myeloid leukemia.
- •Patients with de novo AML without FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
- •Clinical evidence of active central nervous system (CNS) leukemia.
- •Subjects with active (uncontrolled, metastatic) second malignancies.
- •Any major surgery or radiation therapy in 4 weeks.
- •Subjects with myocardial impairment of any cause (eg, cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging).
- •Uncontrolled infection; subjects with an infection receiving treatment (antibiotic, antifungal, or antiviral treatment) could be entered into the study provided the subject was respiratory and hemodynamically stable for ≥ 72 hours.
- •Current evidence of invasive fungal infection (blood or tissue culture); subjects with recent fungal infection must have had subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values).
- •Hypersensitivity to cytarabine, daunorubicin or liposomal products.
- •Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
- •Serum creatinine ≥ 20 mg/dL (unless it is attributable to AML activity).
- •Bilirubin, alkaline phosphatase, or SGOT > 3 times the ULN (unless it is attributable to AML activity).
- •Subjects with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
- •History of Wilson's disease or other copper-metabolism disorder.
- •Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.
研究组 & 干预措施
CPX-351
干预措施: CPX-351 (Drug)
结局指标
主要结局
To evaluate the CR/CRi rate after induction with CPX-351
时间窗: After 1 or 2 cycles of induction (between 12 and 16 weeks approximately)
The primary endpoint of the study is to evaluate the CR/CRi rate after induction with CPX-351. The responses for CR, CRi, PR, therapeutic failure, and disease recurrence are defined for this study based on the revised recommendations of the International Working Group for response criteria.
次要结局
- Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 consolidation regimen(Safety/toxicity assessments will be done in day 1, 8, 15, 22, 29 and 36 of the consolidation cycles)
- Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 induction regimen.(The induction cycles (up to 2 cycles) will have a mean estimated duration of 6 weeks per cycle. Safety/toxicity assessments will be done in day 1, 8, 15, 22, 29 and 36 of the induction cycles.)
- To evaluate the effect of priming with G-CSF with the CPX-351 regimen(Priming with G-CSF will be done in the induction cycles (up to 2 cycles) and in the consolidation cycles (up to 2 cycles) that will have an an estimated duration of 6 weeks per cycle.)
- To evaluate the impact on the quality of life, using the European Quality of Life-5 Dimensions (EQ5D) form, in patients treated with CPX-351(The cycles will have a mean estimated duration of 6 weeks and Quality of life questionnaire following EQ-5D will be performed at screening, after induction (day 36), after consolidation 2 ( day 36 of cycle 3) and/or prior to allo-SCT)
- To evaluate the impact on the use of medical resources during induction and consolidation phase.(The cycles will have a mean estimated duration of 6 weeks and patients may have up to 2 cycles of induction and up to 2 cycles of consolidation.)
- To evaluate early mortality (first 60 days) in patients initially treated with CPX-351(Day 60)
- Incidence of hematologic and non-hematologic adverse events occurred during the study.(At 9 months, which is approximately the estimated mean treatment time.)
- To assess the rate of allo-SCT(After consolidation 1 (aprox 12 weeks) or after consolidation 2 (aprox 18 weeks))
- Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 maintenance regimen(Safety/toxicity assessments will be done every 2 weeks during the manteinance cycles (24 to 40 weeks of maintenance).)
- Overall survival(Estimated 1, 2 and 3 year OS)
- Event-free, disease-free, and relapse free survival (RFS), as well as on the duration of remission and cumulative incidence of relapse(1, 2 and 3 years)
- To evaluate the quality of CR (by study of minimal residual disease percentages in the bone marrow using multiparametric flow cytometry)(After first cycle of induction (6 weeks) and after consolidation 1 (cycle 2: 6 weeks after consolidation 1 onset) only in patients achieving CR/CRi after consolidation 1)
- To compare the results with a matched-paired historical cohort of the PETHEMA registry(Once the study is completed ( an average of 30 months through study completion))
- To evaluate 100 day mortality after allo-SCT(100 day after allo-SCT)
- To assess compliance of the maintenance schedule(After maintenance (aprox 36 weeks))