A Phase III Randomized, Double-blind, Controlled Study Comparing Clofarabine and Cytarabine Versus Cytarabine Alone in Adult Patients 55 Years and Older With Acute Myelogenous Leukemia (AML) Who Have Relapsed or Are Refractory After Receiving up to Two Prior Induction Regimens
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 326
- 试验地点
- 57
- 主要终点
- Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)
研究概览
简要总结
Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed acute or refractory lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens.
There is no recommended standard treatment for relapsed or refractory acute myelogenous leukemia in older patients. Cytarabine is the most commonly used drug to treat these patients. This study will determine if there is benefit by combining clofarabine with cytarabine. Patients will be randomized to receive up to 3 cycles of treatment with either placebo in combination with cytarabine or clofarabine in combination with cytarabine. Randomization was stratified by remission status following the first induction regimen (no remission [i.e., CR1 = refractory] or remission <6 months vs CR1 = remission ≥6 months). CR1 is defined as remission after first pre-study induction regimen. The safety and tolerability of clofarabine in combination with cytarabine and cytarabine alone will be monitored throughout the study.
详细描述
After screening and eligibility assessment, patients were randomized (in a 1:1 ratio) to receive either clofarabine or matching placebo, in addition to cytarabine. Randomization was stratified by remission status following the first induction regimen (CR1): no remission [i.e., CR1 = refractory] or remission <6 months vs remission ≥6 months. During randomization by interactive voice response system (IVRS), there were 10 participants misclassified to the CR1 <6 months stratum and 12 participants misclassified to CR1 ≥6 months stratum. The error did not affect the participants' treatment, only the stratification. Due to the misclassification, outcomes that used strata in their analysis were analyzed twice: once with the 'randomized stratification' which includes the misclassification and once with the 'calculated stratification' in which participants appear in the 'correct' strata.
Two clinical study reports were written for this study.
- Clinical study report dated 7 April 2011 includes the entire treatment period of all participants plus much of the follow-up. At that time, 33 participants in the Clofarabine+cytarabine group and 29 participants in the placebo+cytarabine group were still being follow-up post treatment. Results were reported on clinicaltrials.gov in August 2011. Outcomes that used strata reported the 'calculated strata' on clinicaltrials.gov.
- Clinical study report dated 9 July 2012 includes all patient treatment experience plus all long-term follow-up (a minimum of 2 years from the end of treatment or until the patient died). The study was completed at that time. Outcomes that used strata reported the 'randomized strata' on clinicaltrials.gov. AE records on clinicaltrials.gov reflect the final database.
Outcomes that changed between the two clinical study reports due to the additional long-term follow-up data are reported twice on clinicaltrials.gov (once from each clinical study report) and the appropriate report date is included in the outcome description. Outcomes from the 9 July 2012 report represent more complete data.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have a diagnosis of Acute Myelogenous Leukemia (AML) according to World Health Organization (WHO) classification
- •Relapsed after receiving up to 2 prior induction regimens (i.e. first or second relapse)or are refractory to not more than one prior combination chemotherapy induction regimen
- •Be ≥ 55 years of age
- •Have an Eastern Cooperative Oncology Group (ECOG) score of 0-2
- •Be able to comply with study procedures and follow-up examinations
- •Be nonfertile or agree to use birth control during the study through the end of treatment visit and for at least 90 days after the last dose of study drug
- •Have adequate liver and renal function as indicated by certain laboratory values
排除标准
- •Received previous treatment with clofarabine
- •Received bolus, intermediate or high-dose cytarabine as induction therapy unless certain remission criteria are met
- •Have received a hematopoietic stem cell transplant (HSCT) within the previous 3 months
- •Have moderate or severe graft versus host disease (GVHD), whether acute or chronic
- •Are receiving any other chemotherapy or investigational therapy. Patients must have been off prior AML therapy for at least 2-6 weeks prior to entering study.
- •Have a psychiatric disorder that would interfere with consent, study participation, or follow-up
- •Have an active, uncontrolled infection
- •Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system
- •Have been diagnosed with another malignancy, unless disease-free for at least 5 years; patients with treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed.
- •Have clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless lumbar puncture confirms absence of leukemic blasts in the cerebrospinal fluid(CSF)
- •Known HIV positivity
- •Are pregnant or lactating
研究组 & 干预措施
clofarabine (IV formulation) and cytarabine
Participants received clofarabine (40 mg/m^2) administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Participants could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)
Complete induction cycle = 5 consecutive days of treatment
Re-induction cycle = 5 consecutive days of treatment at the original or modified dose
Consolidation cycle = 4 consecutive days of treatment at the original or modified dose
干预措施: clofarabine (IV formulation) (Drug)
clofarabine (IV formulation) and cytarabine
Participants received clofarabine (40 mg/m^2) administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Participants could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)
Complete induction cycle = 5 consecutive days of treatment
Re-induction cycle = 5 consecutive days of treatment at the original or modified dose
Consolidation cycle = 4 consecutive days of treatment at the original or modified dose
干预措施: cytarabine (Drug)
placebo and cytarabine
Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)
干预措施: placebo (Drug)
placebo and cytarabine
Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)
干预措施: cytarabine (Drug)
结局指标
主要结局
Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)
时间窗: Day 1 (randomization) up to approximately 4 years
Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 calculated strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)
时间窗: Day 1 (randomization) up to approximately 4 years
Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 randomized strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
次要结局
- Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)(Day 12 up to approximately 6 months)
- Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)(Day 12 to approximately 4 years)
- Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)(Day 12 to approximately 4 years)
- Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)(Day 12 to approximately 4 years)
- Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)(Day 12 to approximately 4 years)
- Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)(Day 1 (randomization) up to approximately 4 years)
- Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)(Day 1 (randomization) up to approximately 4 years)
- Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)(Day 1 (randomization) to Day 122)
- Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)(Day 1 (randomization) to Day 122)
- Participants With Adverse Events (CSR 7-April-11)(Day 1 up to a maximum of 4 years (includes up to a maximum of 3 cycles of therapy plus 45 days follow up. Related AEs are followed to resolution.))