Dose Escalation of Clofarabine in Combination With Cytarabine and Idarubicin as Induction Therapy in High Risk AML (CIARA)
2012年2月17日 更新者：Prof. Dr. Juergen Krauter、Hannover Medical School
Phase I/II Study on Cytarabine and Idarubicin Combined With Escalating Doses of Clofarabine as Induction Therapy in Patients With Acute Myeloid Leukemia and High Risk for Induction Failure (AMLSG 17-10)
With current chemotherapy protocols, in 60-80% of patients with acute myeloid leukemia (AML) the leukemic blasts in the bone marrow can be reduced to < 5%.
This is called "complete remission (CR)" and is the prerequisite for cure of the disease.
During the last years, several genetic and biologic risk factors for the achievement of CR have been defined, and the remission rates vary considerably between patient groups with different risk profiles.
On one hand, patients with certain chromosomal or molecular aberrations have very high CR rates of approximately 90%.
Moreover, in some of these patients, molecularly targeted therapies for specific genetic aberrations are currently evaluated in clinical trials.
However, these genetic aberrations account for only 50-60% of the overall patient population in AML.
The remaining patients have a significantly inferior CR rate of only 50-60% with 30% resistant disease after two cycles of standard induction chemotherapy.
In conclusion, there is need for improved induction regimens in a large number of adult patients with AML.
An improved CR rate in this patient population will increase the number of patients eligible for intensive consolidation such as an allogeneic stem cell transplantation and might thereby be the basis for a better overall outcome.
However, there is no clear evidence that this goal can be achieved with the currently available chemotherapy protocols.
Clofarabine (2-chloro-2-fluoro-deoxy-9-D-arabinofuranosyladenine) is a nucleoside analogon which combines properties of fludarabine and cladribine.
Due to the lack of neurological side effects, clofarabine could be explored in higher doses than other nucleoside analogues and has shown considerable antileukemic activity in patients with relapsed or refractory acute leukemias and elderly AML patients alone or in combination with cytarabine.
In addition, the combination of clofarabine, cytarabine and idarubicin has produced promising results with acceptable toxicity in patients with relapsed or refractory AML.
Based on these initial studies, there is need for a further optimization of the clofarabine dose in this combination.
The aim of the AMLSG 17-10 study is therefore to evaluate the tolerability and safety of increasing doses of clofarabine in combination with idarubicin/cytarabine in patients with high risk AML defined by the genetic and molecular risk profile.
研究概览
研究类型
介入性
注册 (预期的)
60
阶段
- 阶段2
- 阶段1
联系人和位置
本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。
学习地点
-
-
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Düsseldorf、德国、40225
- 尚未招聘
- Universitätsklinikum Düsseldorf
-
接触：
- Andrea Kuendgen, MD
- 邮箱：andrea.kuendgen@med.uni-duesseldorf.de
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首席研究员：
- Andrea Kuendgen, MD
-
Essen、德国、45239
- 招聘中
- Klinikum Essen-Werden
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接触：
- Mohammad Wattad, MD
- 邮箱：m.wattad@kliniken-essen-sued.de
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首席研究员：
- Mohammad Wattad, MD
-
Freiburg、德国、D-79106
- 招聘中
- Universitatsklinikum Freiburg
-
接触：
- Michael Luebbert, MD
- 邮箱：luebbert@mm11.ukl.uni-freiburg.de
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首席研究员：
- Michael Luebbert, MD
-
Hamburg、德国、20246
- 尚未招聘
- Universitätsklinikum Hamburg-Eppendorf
-
接触：
- Walter Fiedler, MD
- 邮箱：fiedler@uke.uni-hamburg.de
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首席研究员：
- Walter Fiedler, MD
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Hannover、德国、D-30625
- 招聘中
- Hannover Medical School
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接触：
- Juergen Krauter, MD
- 电话号码：+49-511-532-3720
- 邮箱：Krauter.Juergen@MH-Hannover.de
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首席研究员：
- Juergen Krauter, MD
-
Muenchen、德国、81675
- 尚未招聘
- Klinikum rechts der Isar
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接触：
- Justus Duyster
- 邮箱：justus.duyster@lrz.tum.de
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首席研究员：
- Justus Duyster, MD
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Ulm、德国、89081
- 尚未招聘
- Universitätsklinikum Ulm
-
接触：
- Richard Schlenk, MD
- 邮箱：Richard.Schlenk@uniklinik-ulm.de
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首席研究员：
- Richard Schlenk, MD
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参与标准
研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。
资格标准
适合学习的年龄
18年 及以上 (成人、年长者)
接受健康志愿者
不
有资格学习的性别
全部
描述
Inclusion Criteria:
Patients with newly diagnosed AML according to WHO classification and aged ≥ 18 years eligible for an intensive induction chemotherapy with with the following characteristics:
- absence of a t(15;17), t(8;21), inv(16)/t(16;16) and the respective fusion transcripts PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11
- absence of an activating FLT3-mutation (FLT3-ITD or TKD-mutation)
- absence of an NPM1 exon12 mutation
- Written informed consent
- No previous cytotoxic chemotherapy for the treatment of AML (exception: oral hydroxyurea for up to 5 days during screening/baseline to control hyperleukocytosis)
Adequate renal and hepatic functions as indicated by the following laboratory values:
- Serum creatinine > upper limit of normal (ULN) or glomerular filtration rate (GFR) > 60 mL/min/1.73 m2, respectively
- Serum bilirubin < 1.5 x ULN
- Aspartate aminotransferase (AST/SGOT)/ alanine aminotransferase (ALT/SGPT) < 2.5 x ULN
- Alkaline phosphatase (ALP) < 2.5 x ULN
- Capable of understanding the investigational nature, potential risks and benefits of the study
- Women of childbearing potential must have a negative serum pregnancy test with a sensitivity of at least 25 MIU/ml within 72 hours prior to start of IMP treatment
Female patients must meet one of the following criteria:
- For female patients > 50 years of age at the day of inclusion: Menopause since at least 1 year
Female patients < 50 years of age at the day of inclusion who meet all of the following criteria:
- menopause since at least 1 year
- serum FSH levels > 40 MIU/mL
- serum estrogen levels < 30 pg/ml or negative estrogen test
- 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy
- Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide. In case the patient takes hormone preparations for suppression of menstruation during the period of aplasia, a suitable and effective method of contraception has to be discussed with the investigator and used by the patient
- General sexual abstinence from the time of screening/baseline, during the study until a minimum of 90 days after the last administration of study medication
- Having only female sexual partners
- Monogamous relationship with sterile male partner
Male patients must meet one of the following criteria:
- 6 weeks after surgical sterilization by vasectomy
- Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an IUD with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide.
- General sexual abstinence from the time of screening/baseline, during the study until a minimum of 90 days after the last administration of study medication
- Having only male sexual partners
- Monogamous relationship with sterile female partner
Exclusion Criteria:
- Current concomitant chemotherapy, radiation therapy or immunotherapy not defined in the study protocol
- Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of oral hydroxyurea. The patient must have recovered from all non-hematological acute toxicities from any previous therapy
- Participation in a clinical trial within 30 days before inclusion in this study or concurrent to this study.
- Bleeding disorder independent of AML
- Patients with uncontrolled systemic fungal, bacterial, viral or other infection (defined as persistent disease signs/symptoms without improvement despite appropriate antibiotics or other treatment)
- HIV Infection
- Pregnant or lactating women
- Any significant concurrent disease, illness, psychiatric disorder or history of serious organ dysfunction that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
Diagnosis of another malignancy, unless the patient is disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions:
- Myelodysplastic syndrome (MDS) in patients with AML after MDS according to the WHO classification
- Patients with treated non-melanoma 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.
- Known hypersensitivity to any of the investigational medical products
学习计划
本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
实验性的：治疗
|
Treatment is stratified according to patients age (< 60 years vs. ≥ 60 years). Medication: Patients < 60 years:
Patients ≥ 60 years:
Clofarabine will be given in escalating doses to cohorts of at least three patients: Clofarabine:
Patients will be recruited according to a 3+3 design. New cohorts will be initiated depending on toxicity of the previous cohort during the first induction cycle. Enrollment will begin with dose level 1. |
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin
大体时间：six weeks
|
maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin in the therapy of previously untreated AML and high risk for induction failure
|
six weeks
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
complete remission rate
大体时间：12 weeks
|
complete remission rate after two cycles of induction therapy
|
12 weeks
|
|
relapse-free, event-free and overall survival
大体时间：4 years
|
4 years
|
|
|
blast reduction in the bone marrow after the first induction cycle
大体时间：15 days
|
15 days
|
|
|
duration of aplasia
大体时间：12 weeks
|
12 weeks
|
|
|
therapy-associated morbidity and mortality
大体时间：12 weeks
|
12 weeks
|
|
|
course of molecular and cytogenetic markers during chemotherapy
大体时间：four years
|
molecular and cytogenetic markers will be evaluated by cytognetic analysis and molecular techniuques (e.g.
RT-PCR)
|
four years
|
|
fraction of patients who receive an allogeneic stem cell transplantation in first complete remission
大体时间：four years
|
four years
|
合作者和调查者
在这里您可以找到参与这项研究的人员和组织。
调查人员
- 首席研究员：Juergen Krauter, MD、Hannover Medical School
研究记录日期
这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。
研究主要日期
学习开始
2012年1月1日
初级完成 (预期的)
2013年4月1日
研究完成 (预期的)
2015年9月1日
研究注册日期
首次提交
2012年2月14日
首先提交符合 QC 标准的
2012年2月16日
首次发布 (估计)
2012年2月17日
研究记录更新
最后更新发布 (估计)
2012年2月20日
上次提交的符合 QC 标准的更新
2012年2月17日
最后验证
2012年2月1日
更多信息
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.