ChiCTR2300067517 版本V1.2 版本创建时间2023/07/25 10:09:25 中国临床试验注册中心

审核状态：

Project audit state：

通过审核

Successful

注册号：

Registration number：

 ChiCTR2300067517 

最近更新日期：

Date of Last Refreshed on：

 2023-05-08 20:58:13 

注册时间：

Date of Registration：

 2023-01-10 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

一项芦可替尼联合ACT001治疗芦可替尼单药治疗反应不佳的骨髓纤维化患者的单中心、开放、单臂Ⅱ期研究

Public title：

A single-center, open, single-arm phase II study of ruxolitinib in combination with ACT001 in the treatment of myelofibrosis subjects with poor response to ruxolitinib monotherapy

注册题目简写：

English Acronym：

研究课题的正式科学名称：

一项芦可替尼联合ACT001治疗芦可替尼单药治疗反应不佳的骨髓纤维化患者的单中心、开放、单臂Ⅱ期研究

Scientific title：

A single-center, open, single-arm phase II study of ruxolitinib in combination with ACT001 in the treatment of myelofibrosis subjects with poor response to ruxolitinib monotherapy

研究课题代号(代码)：

Study subject ID：

在二级注册机构或其它机构的注册号：

The registration number of the Partner Registry or other register：

申请注册联系人：

徐泽锋 

研究负责人：

肖志坚 

Applicant：

Xu Zefeng 

Study leader：

Xiao Zhijian 

申请注册联系人电话：

Applicant telephone：

 +86 22 23909046

研究负责人电话：

Study leader's
telephone：

+86 22 23909184

申请注册联系人传真 ：

Applicant Fax：

研究负责人传真：

Study leader's fax：

申请注册联系人电子邮件：

Applicant E-mail：

 gbxzf@163.com

研究负责人电子邮件：

Study leader's E-mail：

 zjxiao@ihcams.ac.cn

申请单位网址(自愿提供)：

Applicant website(voluntary supply)：

研究负责人网址(自愿提供)：

Study leader's website(voluntary supply)：

申请注册联系人通讯地址：

天津市和平区南京路288号

研究负责人通讯地址：

天津市和平区南京路288号

Applicant address：

288 Nanjing Road, Heping District, Tianjin

Study leader's address：

288 Nanjing Road, Heping District, Tianjin

申请注册联系人邮政编码：

Applicant postcode：

研究负责人邮政编码：

Study leader's postcode：

申请人所在单位：

中国医学科学院血液病医院（中国医学科学院血液学研究所）

Applicant's institution：

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

研究负责人所在单位：

中国医学科学院血液病医院（中国医学科学院血液学研究所）

Affiliation of the Leader：

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

是否获伦理委员会批准：

是

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

 IIT2022050-EC-2

伦理委员会批件附件：

Approved file of Ethical Committee：

 查看附件View

批准本研究的伦理委员会名称：

中国医学科学院血液病医院伦理委员会

Name of the ethic committee：

Ethics Committee of Blood Disease Hospital, Chinese Academy of Medical Sciences

伦理委员会批准日期：

Date of approved by ethic committee：

 2022-11-17 00:00:00

伦理委员会联系人：

张雅丽

Contact Name of the ethic committee：

Zhang Yali

伦理委员会联系地址：

天津市和平区南京路288号

Contact Address of the ethic committee：

288 Nanjing Road, Heping District, Tianjin

伦理委员会联系人电话：

Contact phone of the ethic committee：

 +86 22 23909095

伦理委员会联系人邮箱：

Contact email of the ethic committee：

研究实施负责（组长）单位：

中国医学科学院血液病医院(中国医学科学院血液学研究所)

Primary sponsor：

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

研究实施负责（组长）单位地址：

天津市和平区南京路288号

Primary sponsor's address：

288 Nanjing Road, Heping District, Tianjin

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

天津

市(区县)：

Country：

China

Province：

Tianjin

City：

单位(医院)：

中国医学科学院血液病医院(中国医学科学院血液学研究所)

具体地址：

和平区南京路288号

Institution
hospital：

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Address：

288 Nanjing Road, Heping District

经费或物资来源：

中国医学科学院血液病医院(中国医学科学院血液学研究所)

Source(s) of funding：

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

研究疾病：

骨髓纤维化  

Target disease：

myelofibrosis

研究疾病代码：

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

 II期临床试验 

Study phase：

2

研究设计：

单臂 

Study design：

Single arm 

研究目的：

研究主要目的：1）评估芦可替尼联合ACT001对芦可替尼反应不佳的MF患者在第24周的脾脏体积变化。2）评价芦可替尼联合ACT001中受试者报告的MF症状负荷疗效。次要目的：1)评价芦可替尼联合ACT001的安全性和耐受性。2)评估芦可替尼联合ACT001患者的至脾脏体积反应出现时间和缓解持续时间。3)评价芦可替尼联合ACT001对贫血和输血频率的影响。探索性目的：1)评价芦可替尼联合ACT001的受试者的OS。2)评价芦可替尼联合ACT001的受试者的无疾病进展生存期。3)评价芦可替尼联合ACT001的受试者的总体有效率（ORR）。4)评价芦可替尼联合ACT001的受试者的骨髓纤维化分级、体细胞突变和MF相关等位基因突变负荷。5)探索芦可替尼联合ACT001治疗前后生物标志物变化，并探索其与疗效的相关性。  

Objectives of Study：

Primary Objectives: 1) To assess spleen volume changes at week 24 in patients with MF who have poor efficacy to ruxolitinib in combination with ACT001. 2) To assess the efficacy of patient-reported myelofibrosis-related symptom burden in ruxolitinib in combination with ACT001. Secondary Objectives: 1) To assess the safety and tolerability of ruxolitinib in combination with ACT001. 2) To assess the time to onset of spleen response and duration of remission in patients with ruxolitinib in combination with ACT001. 3) To assess the effect of ruxolitinib in combination with ACT001 on anemia and the frequency of transfusion. Exploratory objectives: 1) To assess subjects overall survival (OS) on ruxolitinib in combination with ACT001. 2) To assess the progression free survival (PFS) of subjects on ruxolitinib in combination with ACT001. 3) To assess subjects overall response rate (ORR) on ruxolitinib in combination with ACT001. 4) To assess the fibrosis grade, somatic mutations and MF related allele mutation burden in subjects on ruxolitinib in combination with ACT001. 5) To explore changes in biomarkers before and after treatment with ruxolitinib in combination with ACT001 and to explore their correlation with efficacy.

药物成份或治疗方案详述：

 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

1.筛选时年龄为18-65岁的男性或女性患者，并提供书面知情同意书；2.根据2016年世界卫生组织的标准，诊断为DIPSS中危-1，中危-2、高危的PMF、PPV-MF或PET-MF患者；3.接受芦可替尼治疗≥3个月，在第1天前至少8周内接受稳定剂量治疗(可接受剂量为5mg/次×2次/日至25mg/次×2次/日，允许分次给药[每日总剂量至少10mg]，不允许1次/日给药)；4.芦可替尼疗效不佳的证据(必须同时满足a和b): a.筛选访视时体格检查时可触及左肋缘下脾脏≥5cm，且 b.筛选访视时存在活动性MF症状，使用筛选症状表评估的TSS≥10；5.受试者在筛选时的东部肿瘤协作组织（ECOG）体能状态评分为0、1或2；6.在过去2个月内获得筛选骨髓活检标本和病理学报告，或愿意在筛选/基线时接受骨髓活检;愿意在第24周和此后每24周接受骨髓活检。筛选/基线活检标本必须显示MF诊断（骨髓活检和穿刺评价标准见附录9）；7.预期寿命至少为24周；8.根据以下标准，愿意避免妊娠或生育。a.无生育能力(即经子宫切除术和/或双侧卵巢切除术手术绝育或闭经≥12个月且年龄≥50岁)的女性受试者有资格参加研究。b.有生育能力的女性受试者在筛选时的血清妊娠试验结果必须为阴性，在第1天首次给药前的尿妊娠试验结果必须为阴性，并且必须同意从筛选至安全性随访期间采取有效的避孕措施。c.有生育能力的男性受试者必须同意从筛选至研究药物末次给药后6个月内天采取有效的避孕措施，并在此期间不得捐献精子。

Inclusion criteria

1.Male or female patients aged 18-65 years at the time of screening who provide written informed consent.2.Patients with a diagnosis of DIPSS intermediate-1, intermediate-2, high-risk PMF, PPV-MF, or PET-MF according to the 2016 World Health Organization criteria.3.Treated with ruxolitinib for >=3 months, receiving a stable dose for at least 8 weeks prior to day 1 (may receive a dose of 5 mg twice daily to 25 mg twice daily, split dosing [total daily dose of at least 10 mg] is allowed, once daily is not allowed). 4.Evidence of poor efficacy of ruxolitinib [both (1) and (2) must be met]: (1) The spleen is palpable ≥ 5 cm below the left costal margin on physical examination at the screening visit, and (2) MF-related active symptoms are present at the screening visit, and the total symptom score (TSS)>=10 as assessed using Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). 5.Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 ,or 2 at Screening. 6.Screening bone marrow biopsy specimen and pathology report obtained within the past 2 months or willingness to undergo bone marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at week 24 and every 24 weeks thereafter. Screening/baseline bone marrow biopsy specimens must show the diagnosis of MF.7.Life expectancy for at least 24 weeks.8.Subjects are willing to avoid pregnancy or childbirth based on the following criteria. (1) Infertile female subjects (i.e. surgically sterilized by hysterectomy and/or bilateral oophorectomy or amenorrhea for >= 12 months and >= 50 years of age) are eligible to participate in the study. (2) Fertile female subjects must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result prior to the first dose of study drug on Day 1 and must agree to use effective contraception measures from screening to safety follow-up. (3) Fertile male subjects must agree to use effective contraception measures from screening to 6 months after the last dose of study drug and during this period no sperm donation is allowed.

排除标准：

1.已知对芦可替尼或对ACT001或其他任何辅料过敏；2.既往接受过芦可替尼以外的其他JAK抑制剂治疗；3.受试者先前或计划进行造血干细胞移植；4.在开始研究药物治疗前3个月内使用针对MF的试验性药物或用于MF的任何其他标准药物（例如，达那唑、羟基脲）（芦可替尼除外）治疗，和/或既往治疗（芦可替尼除外）的所有毒性未恢复至1级或更好；5.无法吞咽食物或上消化道存在任何妨碍口服药物给药的状况；6.骨髓储备不足的近期病史，证据如下：a筛选前4周内血小板计数＜100×109/L或筛选前8周内输注血小板。b. 筛选前4周内中性粒细胞绝对计数＜0.5 × 109/L。c. 筛选或基线血液学检查时外周血原始细胞计数＞10%。d. 不愿意接受RBC输注治疗低血红蛋白水平；7.筛选访视时肝功能不全，证据如下：a. 直接胆红素≥2.0×正常值上限（Upper Limit of Normal, ULN）（注：仅在总胆红素≥2.0×ULN时测定直接胆红素）；b. 丙氨酸氨基转移酶（Alanine Aminotransferase, ALT）或天冬氨酸氨基转移酶（Aspartate Aminotransferase, AST）＞2.5×ULN；8.筛选时肾功能不全，根据Cockcroft-Gault公式估计肌酐清除率≤50mL/min。基于Cockcroft-Gault公式的轻度、中度和重度肾功能不全的肌酐清除率临界值分别为60～90 mL/min、30～59 mL/min和0～29 mL/min。如果研究者偏好，他/她可以使用测量的肌酐清除率而不是估计值；9.需要治疗的活动性细菌、真菌、寄生虫或病毒感染。需要治疗的急性感染受试者应延迟筛选/入组，直至治疗过程完成且认为事件消退。允许使用预防性抗生素。需要治疗的活动性HBV或HCV感染，或存在HBV再激活风险。检测时，必须检测不到HBV DNA和HCV RNA。HBV再激活风险定义为乙型肝炎表面抗原阳性或抗乙型肝炎核心抗体阳性。10.已知HIV感染；11.研究者认为可能危及受试者安全或方案依从性的不受控制的重度或不稳定心脏疾病；12.在过去2年内患有活动性侵袭性恶性肿瘤，已治疗的皮肤基底或鳞状细胞癌、完全切除的宫颈上皮内癌以及完全切除的甲状腺乳头状癌和滤泡状癌除外。患有惰性恶性肿瘤（如接受放疗或手术治疗的前列腺癌）的受试者治愈后可入组；13.接受研究药物首次给药前6个月内接受过脾放疗；14.可能干扰研究要求依从性的活动性酒精或药物成瘾；15.在研究药物首次给药前14天或5个半衰期内（以较长者为准）或预期在研究期间使用任何强效CYP3A4抑制剂或诱导剂；16.在开始治疗前，重大手术的毒性和/或并发症尚未充分恢复；17.目前在哺乳期或妊娠期；18.存在研究者判断会干扰研究全程参与（包括研究药物给药和参加必须的研究访视）的情况；对受试者有重大风险的情况；或对研究数据解读造成干扰的情况；19.无法理解或不愿意签署ICF；20.在研究药物首次给药前30天内接受过任何活疫苗。

Exclusion criteria：

1. Known hypersensitivity to ruxolitinib or to ACT001 or any other excipient. 2. Subjects who have previously received treatment with a JAK inhibitor other than ruxolitinib. 3. Subjects with prior or planned hematopoietic stem cell transplantation (HSCT). 4. Treatment with an experimental drug against MF or any other standard drug used for MF (e.g., danazol, hydroxyurea) (except ruxolitinib) within 3 months prior to initiation of study drug therapy and/or all toxicity from prior therapy (except ruxolitinib) has not returned to Grade 1 or better; 5. Inability to swallow food or any condition in the upper gastrointestinal tract that prevents the administration of oral drugs. 6. Recent history of inadequate bone marrow reserve as evidenced by: (1) Platelet count <100 x 10^9/L within 4 weeks prior to screening or platelet transfusion within 8 weeks prior to screening. (2) Absolute neutrophil count (ANC) <0.5 * 10^9/L within 4 weeks prior to screening. (3) Peripheral blood blast >10% at screening or baseline hematology. (4) Reluctance to receive RBC transfusions for low hemoglobin levels. 7. Subjects with inadequate liver function, as evidenced by: (1) Direct bilirubin >=2.0 * Upper Limit of Normal (ULN) (Note: direct bilirubin is measured only if total bilirubin is >=2.0*ULN). (2) Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) >2.5*ULN. 8. Subjects with inadequate renal function, with estimated creatinine clearance rate ≤50mL/min. Based on the Cockcroft-Gault formula, the threshold creatinine clearance rate for mild, moderate, and severe renal insufficiency are 60 to 90 mL/min, 30 to 59 mL/min, and 0 to 29 mL/min, respectively. If the investigator prefers, he/she may use the measured creatinine clearance rate instead of the estimated value. 9. Subjects with a clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute infections requiring treatment should delay screening/enrollment until the treatment is completed and the event is considered to have subsided. Prophylactic antibiotics are allowed. Active HBV, HCV infection, or at risk of HBV reactivation requiring treatment. HBV DNA and HCV RNA must be undetectable. The risk of HBV reactivation is defined as a positive Hepatitis B surface antigen (HBsAg) or positive anti-hepatitis B core antibody (HBcAb). 10. HIV antibody positivity. 11. Uncontrolled severe or unstable cardiac disease that the investigator believes may jeopardize the safety of the subject or compliance with the protocol. 12. Active aggressive malignancy within the past 2 years except for treated basal or squamous cell carcinoma of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary and follicular carcinoma of the thyroid. Subjects with cured inert tumors (e.g., prostate cancer treated with radiation therapy or surgery) may be enrolled. 13. Received splenic radiotherapy within 6 months prior to the first dose of the study drug. 14. Active alcohol or drug addiction that may interfere with compliance with study requirements. 15. Use of any potent CYP3A4 inhibitor or inducer within 14 days or 5 half-lives (whichever is longer) prior to the first dose of the study drug or expected during the study period. 16. Has not recovered sufficiently from the toxicity and/or complications of major surgery prior to initiation of treatment. 17. Currently breastfeeding or pregnant. 18. There are circumstances that, in the judgment of the investigator, would interfere with full study participation (including study drug administration and participation in required study visits); pose a significant risk to the subject; or interfere with the interpretation of study data. 19. Subjects are unable to understand or unwilling to sign an Informed Consent Form (ICF). 20. Received any live vaccine within 30 days prior to the first dose of the study drug.

研究实施时间：

Study execute time：

从 From 2022-11-30 00:00:00至 To 2024-11-30 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2023-02-01 00:00:00 至 To 2025-01-31 00:00:00

干预措施：

Interventions：

组别：

1

样本量：

 10

Group：

Single arm

Sample size：

干预措施：

口服ACT001联合芦可替尼

干预措施代码：

Intervention：

1

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 天津 

市(区县)：

  

Country：

China

Province：

Tianjin

City：

单位(医院)：

 中国医学科学院血液病医院（血液学研究所) 

单位级别：

 三级甲等医院 

Institution
hospital：

Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences

Level of the institution：

Tertiary A hospital

测量指标：

Outcomes：

指标中文名：

脾脏大小评估

指标类型：

主要指标

Outcome：

Spleen size assessment

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

骨髓增殖性肿瘤总症状评估

指标类型：

主要指标

Outcome：

Myeloproliferative Neoplasm-SAF (MPN-SAF TSS) Assessment

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

血液

组织：

Sample Name：

Blood

Tissue：

人体标本去向

 使用后销毁  

说明

Fate of sample：

Destruction after use  

Note：

标本中文名：

骨髓组织切片

组织：

Sample Name：

Bone marrow biopsy

Tissue：

人体标本去向

 使用后保存  

说明

Fate of sample：

Preservation after use  

Note：

征募研究对象情况：

Recruiting status：

尚未开始

Not yet recruiting

年龄范围：

Participant age：
最小 Min age 18 岁 years
最大 Max age 65 岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

无

Randomization Procedure (please state who generates the random number sequence and by what method)：

No

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：

N/A

Blinding：

N/A

试验完成后的统计结果（上传文件）：

Calculated Results after
the Study Completed(upload file)：

是否共享原始数据：

IPD sharing

是Yes

共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：

联系项目申办方负责人 请阅读网页注册指南中关于 原始数据共享 的内容。

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：

Contact the responsible person of the project sponsor

数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：

病例记录表,电子采集和管理系统

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：

Case Record Form,Electronic Data Capture

数据与安全监察委员会：

Data and Safety Monitoring Committee：

暂未确定/Not yet

注册人：

Name of Registration：

  2023-01-10 15:10:32