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在 CCR (ACTIW) 慢性期慢性粒细胞白血病患者中与酪氨酸激酶抑制剂 (TKIs) 联合或序贯治疗 (ACTIW)

2026年9月25日 更新者：Philippe ROUSSELOT、Versailles Hospital

联合或序贯使用酪氨酸激酶抑制剂治疗 CCR 慢性期慢性粒细胞白血病患者的候选疗法未实现深度分子反应：基于滴落设计的适应性试验

Patients will be randomized in phase II trials to continue on the same TKI versus one of the alternative treatment approaches. If a patient is not eligible for one of the treatments, he (she) will be randomized between the options for which he (she) is eligible.

The trial will start with current available treatment options (experimental arms). New available treatment options may be open at any times later on. Authorized TKIs are imatinib, nilotinib, dasatinib, bosutinib and ponatinib.

For all options the treatment duration is for a minimum of 12 months and will be continued in the absence of adverse events following investigator decision. Each therapeutic option will be detailed in term of combination modalities, dose, dose adaptation, specific warnings, specific exclusion and inclusion criteria. The decision to introduce a new option will depend on the general pace of recruitment and on the assessment of the potential efficacy and safety of the new treatment, and will be implemented after scientific review by a protocol amendment.

Primary objective:

A. To select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control.

Secondary objectives:

A. To determine the safety of selected therapies

B. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms

C. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms

D. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms

E. To estimate treatment free remission (TFR) in patients eligible for discontinuation studies

F. To investigate the relationship between biological activity and the clinical efficacy of the selected therapies

G. To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest

H. To estimate duration of response, progression-free survival, event free survival and overall survival.

研究概览

地位

主动，不招人

条件

干预/治疗

详细说明

Patients will be randomised to continue on TKI (same daily dose) versus one of the alternative novel treatment approaches. If a patient is not eligible for one of the treatments, he can be randomised for the options for which he is eligible. All treatment options may be open at all times. Investigators must specify before randomization for which treatment option they want their patient be included and randomized.

Perspectives New treatment options will be introduced over time. The decision to introduce a new option will depend on the general pace of recruitment and the assessment of the potential efficacy and safety of the new treatment in this patient population, and will be implemented after scientific review by a protocol amendment.

The available treatment arms are:

  1. TKI alone same daily dose (control arm)
  2. TKI in combination with pioglitazone
  3. TKI in combination with Avelumab (anti-PD-L1 antibody)

Planned treatment arms for the future may be :

  1. TKI in combination with pegylated interferon
  2. TKI in combination with arsenic trioxide
  3. TKI in combination with Homoharringtonine

Protocol plan:

  1. Control arm (Imatinib, nilotinib, dasatinib, bosutinib or ponatinib):

    Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months

  2. Pioglitazone arm

    • TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months

    • PIOGLITAZONE (Actos®):

      30 mg per day for 12 months. The dose will be increased to 45 mg per day after 2 months in the absence of grade >1 related AE.

    • After 12 Months :

    Continue TKI at the same daily dose and STOP pioglitazone.

  3. AVELUMAB arm

    • TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
    • AVELUMAB: 10mg/kg every 2 weeks, for a maximum of 8 IV infusions over a 4 months' period. (If MR4.5 is acheived by the first 3 months the 7th and 8th infusions will be omitted)
    • After 12 Months :Continue TKI at the same daily dose.

  4. Other experimental arm TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months

    • Arsenic trioxide : to be determined after amendment
    • Pegylated Interferon : to be determined after amendment
    • Homoharringtonine : to be determined after amendment
    • Drug X
    • Drug Y

研究类型

介入性

注册 (估计的)

100

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

  • 法国
      • Angers、法国
        • Martine GARDEMBAS
      • Annecy、法国
        • Pascale CONY.MAKHOUL
      • Bobigny、法国
        • Thorsten BRAUN
      • Bordeaux、法国
        • Etienne
      • Caen、法国
        • CHU Côte de Nacre
      • Clermont-Ferrand、法国
        • CHU Estaing
      • Créteil、法国
        • CH Henri Mondor
      • Le Chesnay、法国
        • Rousselot
      • Lille、法国
        • CHU Lille
      • Limoges、法国
        • CHU de LIMOGES
      • Lyon、法国
        • Franck NICOLINI
      • Marseille、法国
        • Institut P Calmette
      • Nantes、法国
        • Viviane DUBRUILLE
      • Nice、法国
        • Hopital l'Archet
      • Nîmes、法国
        • Eric JOURDAN
      • Orléans、法国
        • Hôpital La Source
      • Paris、法国
        • Delphine REA _St louis
      • Paris、法国
        • Simona LAPUSAN_St Antoine
      • Poitiers、法国
        • Cayssials
      • Rennes、法国
        • CHU de Rennes - Pontchaillou
      • Saint-Cloud、法国
        • Hôpital René Huguenin
      • Toulouse、法国
        • Institut Universitaire contre le Cancer
      • Tours、法国
        • CHU Tours

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

Common Inclusion Criteria:

  1. Patient aged 18y or more
  2. Signed informed consent
  3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1 transcript positivity at diagnosis
  4. Treatment with imatinib, nilotinib, dasatinib or bosutinib for more than 2 years overall
  5. No switch between tyrosine kinase inhibitors within the last 3 months
  6. No dose modification within the last 3 months
  7. Complete cytogenetic response or BCR-ABL1IS ≤ 1%
  8. Detectable BCR-ABL1 with BCR-ABL1IS > 0.0032% (less than MR4.5)
  9. ECOG grade 0 to 2
  10. ASAT and ALAT ≤ 2.5 N
  11. Bilirubin in serum ≤ 2.5 N
  12. Men and Women of childbearing potential must be using an adequate method of contraception

These specific inclusion criteria will apply for the Avelumab arm in addition to the common criteria.

  1. Hematologic:

    1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
    2. Platelet count ≥ 100 × 109/L,
    3. Hemoglobin ≥ 9 g/dL. (may have been transfused).

  2. Hepatic:

    a. Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range.

  3. Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)

  4. Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential.

  5. Contraception: Highly effective contraception for both male and female subjects throughout the study and for at least 30 days after last Avelumab treatment administration if the risk of conception exists.

Common Exclusion Criteria:

  1. Pregnant or lactating women,

  2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,

  3. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)

  4. Cardiovascular disease:

    • Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
    • Myocardial infarction within the previous 6 months
    • Symptomatic cardiac arrhythmia requiring treatment

  5. Grade III or IV fluid retention

  6. Known BCR-ABL kinase domain mutation

  7. CML patient not in chronic phase at diagnosis

  8. Individuals with an active malignancy

  9. Known HIV-positivity

These specific exclusion criteria will apply for the pioglitazone arm in addition to the common criteria.

  1. Known osteoporosis with curative therapy (prophylactic therapy is not an exclusion criteria)
  2. Patient requiring anti-diabetic medication

These specific exclusion criteria will apply for the Avelumab arm in addition to the common criteria:

  1. IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the following:

    1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
    2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

  2. AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.

  3. ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell transplantation.

  4. INFECTIONS: Active infection requiring systemic therapy.

  5. HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency syndrome.

  6. HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

  7. VACCINATION: Vaccination within 4 weeks of the first dose of Avelumab and while on trials is prohibited except for administration of inactivated vaccines

  8. HYPERSENSITIIVTY TO STUDY DRUG: Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions tomonoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)

  9. CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia equiring medication.

  10. OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.

  11. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

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：随机化
  • 介入模型：并行分配
  • 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：Experimental Arm_ACTOS

TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months

PIOGLITAZONE (Actos®):

30 mg per day for 12 months. The dose will be increased to 45 mg per day after 2 months in the absence of grade >1 related AE.
药品：Pioglitazone

PIOGLITAZONE (Actos®): 30 mg per day for 12 months. The dose will be increased to 45 mg per day after 2 months in the absence of grade >1 related AE.
无干预：controled Arm

TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
实验性的：Experimental Arm_AVELUMAB

TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months AVELUMAB: 10mg/kg every 2 weeks, for a maximum of 8 IV infusions over a 4 months' period.(If MR4.5 is acheived by the first 3 months the 7th and 8th infusions will be omitted)
药品：Avelumab

10mg/kg every 2 weeks, for a maximum of 8 IV infusions over a 4 months' period. (If MR4.5 is acheived by the first 3 months the 7th and 8th infusions will be omitted)

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
Cumulative incidence of patients achieving a deep molecular response
大体时间：12 months

The cumulative incidence of patients achieving a deep molecular response defined by MR4.5 or deeper (BCR-ABLIS ≤ 0.0032 %) by 12 months
12 months

次要结果测量

结果测量
措施说明
大体时间
通过克隆形成测定和 RTQ-PCR 对骨髓中 CML 和正常 CFU 进行定量
大体时间：12个月
12个月
Adverse events
大体时间：12 Months

Adverse events
12 Months
The cumulative rate of patients achieving MR4.5 by 24months in experimental and control arms
大体时间：24 months

The cumulative rate of patients achieving MR4.5 by 24months in experimental and control arms
24 months
The cumulative rate of patients achieving MR4.5 by 36 months in experimental and control arms
大体时间：36 months

The cumulative rate of patients achieving MR4.5 by 36 months in experimental and control arms
36 months
The cumulative rate of patients achieving MR4.5 by 48 months in experimental and control arms
大体时间：48 months

The cumulative rate of patients achieving MR4.5 by 48months in experimental and control arms
48 months
The cumulative rate of patients achieving MR4 by 12months in experimental and control arms
大体时间：12 months

The cumulative rate of patients achieving MR4 by 12,months in experimental and control arms
12 months
The cumulative rate of patients achieving MR4 by 24 months in experimental and control arms
大体时间：24 months

The cumulative rate of patients achieving MR4 by 24 months in experimental and control arms
24 months
The cumulative rate of patients achieving MR4 by 36 months in experimental and control arms
大体时间：36 months

The cumulative rate of patients achieving MR4 by 36 months in experimental and control arms
36 months
The cumulative rate of patients achieving MR4 by 48 months in experimental and control arms
大体时间：48 months

The cumulative rate of patients achieving MR4 by 48 months in experimental and control arms
48 months
The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12months in experimental and control arms
大体时间：12 months

The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12months in experimental and control arms
12 months
The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 24months in experimental and control arms
大体时间：24 months

The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 24, months in experimental and control arms
24 months
The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 36 months in experimental and control arms
大体时间：36 months

The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 36 months in experimental and control arms
36 months
The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 48 months in experimental and control arms
大体时间：48 months

The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 48 months in experimental and control arms
48 months
The rate of patients in treatment free remission during follow-up
大体时间：48 months

The rate of patients in treatment free remission during follow-up
48 months
Survival
大体时间：48 months

Survival
48 months
duration of response
大体时间：48 months

duration of response
48 months
event free survival
大体时间：48 months

event free survival
48 months
progression free survival
大体时间：48 months

progression free survival
48 months

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。

赞助

Versailles Hospital

调查人员

  • 首席研究员：Philippe ROUSSELOT、CH Versailles

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 (实际的)

2016年7月1日

初级完成 (估计的)

2027年12月1日

研究完成 (估计的)

2028年6月1日

研究注册日期

首次提交

2016年3月16日

首先提交符合 QC 标准的

2016年5月6日

首次发布 (估计的)

2016年5月10日

研究记录更新

最后更新发布 (实际的)

2026年9月28日

上次提交的符合 QC 标准的更新

2026年9月25日

最后验证

2026年9月1日

更多信息

与本研究相关的术语

其他相关的 MeSH 术语

其他研究编号

  • P13/12_ACTIW

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.

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