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注册号： Registration number：	ChiCTR1900027480
最近更新日期： Date of Last Refreshed on：	2019-11-15 14:10:59
注册时间： Date of Registration：	2019-11-15 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	一项高选择性RET抑制剂BLU-667治疗甲状腺癌、非小细胞肺癌（NSCLC）和其他晚期实体瘤患者的I期研究
Public title：	A Phase 1 Study of the Highly-Selective RET Inhibitor, BLU 667, in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors
注册题目简写：	BLU-667-1101
English Acronym：	BLU-667-1101
研究课题的正式科学名称：	一项高选择性RET抑制剂BLU-667治疗甲状腺癌、非小细胞肺癌（NSCLC）和其他晚期实体瘤患者的I期研究
Scientific title：	A Phase 1 Study of the Highly-Selective RET Inhibitor, BLU 667, in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors
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：	王可	研究负责人：	王可
Applicant：	Ke Wang	Study leader：	Ke Wang
申请注册联系人电话： Applicant telephone：	+86 18980602252	研究负责人电话： Study leader's telephone：	+86 18980602252
申请注册联系人传真： Applicant Fax：	+86 028-85423660	研究负责人传真： Study leader's fax：	+86 028-85423660
申请注册联系人电子邮件： Applicant E-mail：	WangKeWK2019@163.com	研究负责人电子邮件： Study leader's E-mail：	WangKeWK2019@163.com
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：	四川省成都市武侯区国学巷37号	研究负责人通讯地址：	四川省成都市武侯区国学巷37号
Applicant address：	37 Guoxue Lane, Wuhou District, Chengdu, Sichuan	Study leader's address：	37 Guoxue Lane, Wuhou District, Chengdu, Sichuan
申请注册联系人邮政编码： Applicant postcode：	610041	研究负责人邮政编码： Study leader's postcode：	610041
申请人所在单位：	四川大学华西医院
Applicant's institution：	West China Hospital, Sichuan University
研究负责人所在单位：	四川大学华西医院
Affiliation of the Leader：	West China Hospital, Sichuan University

是否获伦理委员会批准：	是/Yes
Approved by ethic committee：	Yes
伦理委员会批件文号： Approved No. of ethic committee：	2019年临床试验(西药)审（151）号	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：	四川大学华西医院临床试验伦理委员会
Name of the ethic committee：	Ethics Committee of West China Hospital, Sichuan University
伦理委员会批准日期： Date of approved by ethic committee：	2019-08-20 00:00:00
伦理委员会联系人：	韩玉榕
Contact Name of the ethic committee：	Yurong Han
伦理委员会联系地址：	四川省成都市武侯区国学巷37号
Contact Address of the ethic committee：	37 Guoxue Lane, Wuhou District, Chengdu, Sichuan
伦理委员会联系人电话： Contact phone of the ethic committee：		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：

N/A

Primary sponsor：

N/A

研究实施负责（组长）单位地址：

N/A

Primary sponsor's address：

N/A

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	江苏	市(区县)：	苏州
Country：	China	Province：	Jiangsu	City：	Suzhou
单位(医院)：	基石药业（苏州）有限公司	具体地址：	苏州工业园区星湖街218号生物纳米园A1楼北座二楼E168单元
Institution hospital：	Cstone	Address：	Unit E168, 2nd Floor, Building A1, Biological Nano Park, 218 Xinghu Street, Suzhou Industrial Park

经费或物资来源：

基石药业（苏州）有限公司

Source(s) of funding：

Cstone

Target disease：

Advanced solid tumor

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

I期临床试验

Study phase：

1

研究设计：

单臂

Study design：

Single arm

研究目的：

1. 根据RECIST v1.1（或RANO，如果适用于研究的肿瘤类型），确定ORR。 2. 进一步明确BLU-667的安全性和耐受性。 3. 评估所有患者的其他临床获益指标，包括DOR、CBR、DCR、PFS和总生存期（OS）。 4. 评估基线时的血浆和/或肿瘤组织的RET基因状态，及其与抗肿瘤活性指标的相关性，包括但不限于ORR、DOR和DCR。 5. 描述BLU-667的PK特征以及药物暴露量与安全性评估（包括ECG间期的变化）和疗效的相关性。 6. 描述BLU-667的药效动力学特征，包括但不限于，MTC患者的血降钙素和癌胚抗原（CEA）变化。

Objectives of Study：

1. To determine the ORR by RECIST v1.1 (or RANO, if appropriate for tumor type). 2. To further define the safety and tolerability of BLU-667. 3. To assess additional measures of clinical benefit including DOR, CBR, DCR, PFS, and overall survival (OS) in all patients. 4. To assess baseline RET gene status in plasma and/or tumor tissue and correlate with measures of antineoplastic activity including, but not limited to ORR, DOR, and DCR. 5. To characterize the PK profile of BLU-667 and correlate drug exposure with safety assessments, including changes in ECG intervals, and efficacy. 6. To characterize the pharmacodynamics of BLU-667, including, but not limited to, changes in blood calcitonin and CEA in MTC patients only.

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. 患者年龄≥18岁。
2. 剂量扩展部分（第2部分）的诊断 – 所有患者（第3、4和9队列除外）必须有携带致癌性RET融合或突变（不包括同义、移码和无义突变）的实体肿瘤，RET 检测可以在当地或中心实验室通过肿瘤或血液中的循环肿瘤核酸检测确定；详情如下。常见致癌突变列表见附录6。
第1组 – 患者必须有病理学证实和确诊的携带RET融合的局部晚期或转移性NSCLC ，且既往接受过含铂化疗。
第2组 – 患者必须有病理学证实和确诊的携带RET融合的局部晚期或转移性NSCLC，且既往未接受过含铂化疗。
第3组 – 患者必须有病理学证实和确诊的晚期MTC，在筛选访视前14个月内发生进展，且既往接受过卡博替尼和/或凡德他尼治疗。
第4组 – 患者必须有病理学证实和确诊的晚期MTC，在筛选访视前14个月内发生进展，且既往未接受过卡博替尼和/或凡德他尼治疗。
第5组– 患者必须有病理学证实和确诊的携带致癌性RET融合的晚期实体肿瘤，既往接受过针对于该肿瘤类型的标准治疗，且不适合参加其他治疗组。
第6组 – 患者必须有病理学证实和确诊的携带致癌性RET融合或突变的晚期实体肿瘤，且既往接受过选择性RET TKI的治疗，如LOXO-292。
第7组 – 患者必须有病理学证实和确诊的携带致癌性RET突变的晚期实体肿瘤，既往接受过适用于该肿瘤类型的标准治疗，且不适合参加其他治疗组。
第8组 – 患者必须有病理学证实和确诊的携带RET融合的局部晚期或转移性NSCLC，且既往接受过含铂化疗。
第9组 – 患者必须有病理学证实和确诊的晚期MTC，在筛选访视前14个月内发生进展，且既往未接受过治疗。
3. 患者必须患有不可切除的肿瘤且标准治疗后疾病进展或对标准治疗反应不充分，或患者对标准治疗不耐受、或研究者认为患者不适合接受标准治疗，或其肿瘤没有标准治疗。
4. 参加剂量扩展部分（第2部分）的第1、2、3、4、6、8和9组患者必须有根据RECIST v1.1（或RANO，适当）可测量的病灶。
5. 患者同意提供肿瘤组织（存档组织[如有] ，或新鲜活检组织）以进行RET状态确认，并且愿意在治疗期间接受研究者认为安全且医学上可行的肿瘤活检。第2部分第6组的患者必须接受治疗前活检，以确定肿瘤组织中的RET的基线状态。
6. 患者的美国东部肿瘤协作组（ECOG）体能状态（PS）评分为0-1；
7. 患者提供了参加本研究的知情同意书。

Inclusion criteria

1. Patient is >= 18 years of age.
2. Diagnosis during dose escalation (Part 1) – Pathologically documented, definitively diagnosed non-resectable advanced solid tumor. All patients treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood. Part 1 enrichment patients must have MTC or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
3. Diagnosis during dose expansion (Part 2) – All patients (with the exception of Groups 3, 4 and 9) must have an oncogenic RET fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below. For a list of common oncogenic mutation, see Appendix 6.
Group 1: patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.
Group 2: patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy.
Group 3: patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.
Group 4: patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib or vandetanib.
Group 5: patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups.
Group 6: patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, previously treated with a selective TKI that inhibits RET, such as LOXO-292.
Group 7: patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups.
Group 8: patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum-based chemotherapy.
Group 9: patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treatment nave.
4. Patient must have non-resectable disease progressed following standard therapy or have not adequately responded to standard therapy, or the patient must be intolerant to, or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.
5. Dose expansion (Part 2) patients in groups 1, 2, 3, 4, 6, 8, and 9 must have measurable disease per RECIST v1.1 (or RANO, if appropriate for tumor type).
6. Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Part 2, Group 6, patients are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.
7. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
8. Patient provides informed consent to participate in the study.

排除标准：

1. 患者所患癌症存在除RET以外的已知的主要驱动基因改变。例如，携带EGFR、ALK、ROS1或 BRAF等靶向突变的NSCLC；携带致癌性KRAS、NRAS或BRAF等突变的结直肠癌。如果患者存在共突变，研究者应与申办方讨论该患者是否可以入组。
2. 患者在研究药物首次给药前14天内满足以下任何一项标准。
a. 血小板计数< 75 × 10^9/L。
b. 绝对中性粒细胞计数（ANC）< 1.0 × 10^9/L。
c. 血红蛋白 < 9.0 g/dL，可通过输注红细胞和使用促红细胞生成素使血红蛋白升高至9.0 g/dL或以上水平，但是，该类治疗必须在研究药物首次给药前至少2周前完成。
d. 无肝转移时，天门冬氨酸氨基转移酶（AST）或丙氨酸氨基转移酶（ALT）> 3×正常值上限（ULN）；有肝转移时，> 5 × ULN。
e. 总胆红素> 1.5 × ULN；患有吉尔伯特（Gilbert’s）病时，> 3 × ULN，直接胆红素> 1.5 × ULN。
f. 估计的（Cockroft-Gault公式）或测量的肌酐清除率 < 40 mL/min。
g. 总血清磷> 5.5 mg/dL。
3. 患者的QTcF > 470 msec。患者有QT延长综合征或尖端扭转性室性心动过速病史。患者有QT延长综合征家族病史。
4. 患者有具有临床意义的、无法控制的、心血管疾病，包括根据纽约心脏协会（NYHA）标准分类的III或IV级充血性心脏衰竭；既往6个月内出现过心肌梗死或不稳定型心绞痛、无法控制性的高血压或有临床意义的无法控制的心律失常，包括可能导致QT延长的缓慢型心律失常（例如，II型二度心传导阻滞或三度心传导阻滞）。
5. 患者患有转移性中枢神经系统（CNS）肿瘤或原发性CNS肿瘤，且表现有进行性神经系统症状或需要增加皮质类固醇剂量以控制其CNS疾病。如果患者需要使用皮质类固醇治疗CNS疾病，那么，给药剂量必须在C1D1前两周内保持稳定。
6. 有临床症状的间质性肺疾病或间质性肺炎，包括放射性肺炎（即，影响日常活动或需要治疗干预）
7. 患者在研究药物首次给药前14天或其5个半衰期内接受过抗癌治疗（包括全身治疗和放疗，但不包括免疫治疗或其他抗体治疗）。在28天内接受过免疫治疗或其他抗体治疗的患者（开始BLU-667治疗前免疫相关毒性必须消退至<2级）。如果研究者认为安全且符合患者的最佳利益，并且获得了申办方的事先批准，患者也可以在上述洗脱期内开始BLU-667治疗。
8. 对于进入剂量扩展部分（第2部分）第1-5组和第7、8和9组的患者：既往接受过选择性RET抑制剂（如LOXO-292）治疗。
9. 患者在研究药物首次给药前14天内接受过中性粒细胞生长因子支持治疗。
10. 患者需要使用禁用药物或草药治疗（详见附录2），且在研究药物给药前至少2周内不能中止该治疗。如果研究者认为安全且符合患者的最佳利益，并且获得了申办方的事先批准，患者也可以在14天内或既往治疗的5个半衰期内开始BLU-667治疗。
11. 患者在研究药物首次给药前14天内接受过重大外科手术（中心静脉导管置入、肿瘤穿刺活检和胃管置入等操作不属于重大外科手术）。
12. 在过去一年内，患者被诊断为或有需要治疗的其他原发性恶性肿瘤，以下恶性肿瘤除外：已完全切除的皮肤基底细胞和鳞状细胞癌、接受过治愈性治疗的局部前列腺癌、接受过治愈性治疗的局部甲状腺癌和已完全切除的任何部位的原位癌。
13. 患者不愿意或无法依从计划访视、给药计划、实验室检查或其他研究步骤和研究限制。
14. 非绝经后或已手术绝育的女性受试者，不愿意在研究药物给药期间和研究药物末次给药后至少30天内采用禁欲或高效避孕措施；未进行手术绝育的男性受试者，不愿意在研究药物给药期间和研究药物末次给药后至少90天内采用禁欲或高效避孕措施。可接受的避孕方法参见第9.6.1 节。
15. 在研究药物首次给药前7天内，经血清β人绒毛膜促性腺激素（β-hCG）妊娠试验证实女性受试者妊娠。β-hCG值在妊娠范围内但未妊娠（假阳性）的女性受试者可在获得申办方书面同意后且已排除妊娠后入组。无生育能力的女性受试者（绝经期超过1年；双侧输卵管结扎；双侧卵巢切除术；子宫切除术）无需进行血清β-hCG检查。
16. 正处于哺乳期的女性患者。
17. 经研究者判断，患者既往或现在患有具有临床意义的疾病、医疗状况、手术史、体格检查结果或实验室检查异常，可能会影响患者的安全性，改变研究药物的吸收、分布、代谢或排泄，或影响研究结果的评估。

Exclusion criteria：

1. Patients cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1, or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. Investigators should discuss enrollment with Sponsor regarding co-mutations.
2. Patient has any of the following within 14 days prior to the first dose of study drug:
a. Platelet count < 75 x 10^9/L.
b. Absolute neutrophil count (ANC) < 1.0 x 10^9/L.
formula) or measured creatinine clearance < 40 mL/min.
g. Total serum phosphorous > 5.5 mg/dL.
3. Patient has a QTcF > 470 msec. Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a familial history of prolonged QT syndrome.
4. Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second degree heart block or third degree heart block).
5. Patient has central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding C1D1.
6. Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (ie, affecting activities of daily living or requiring therapeutic intervention).
7. Patient received anticancer therapy (including both systemic therapy and radiotherapy, but not including immunotherapy or other antibody therapies) within 14 days or 5 half-lives prior to the first dose of study drug. Patients who received previous immunotherapy or other antibody therapy, within 28 days (immune related toxicities must have resolved to < Grade 2 prior to starting BLU-667). BLU-667 may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
8. Dose expansion patients in Groups 1-5 and 7-9 (Part 2): patient has previously received treatment with a selective RET inhibitor such as LOXO-292.
9. Patient received neutrophil growth factor support within 14 days of the first dose of study drug.
10. Patient requires treatment with a prohibited medication or herbal remedy (as specified in Appendix 2) that cannot be discontinued at least 2 weeks before the start of study drug administration. BLU-667 may be started within 14 days or 5 half-lives of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
11. Patient has had a major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
12. Patient has a history of another primary malignancy that has been diagnosed or required therapy within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site.
13. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
14. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 90 days after the last dose of study drug. Refer to Section 9.6.1 for acceptable methods of contraception.
15. Pregnant females, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of study drug. Females with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor, after pregnancy has been ruled out. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test.
16. If female, patient is breastfeeding.
17. Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigators opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.

研究实施时间：

Study execute time：

从 From 2019-11-14 00:00:00至 To 2021-06-30 00:00:00

征募观察对象时间：

Recruiting time：

从From 2019-11-14 00:00:00 至 To 2020-05-31 00:00:00

干预措施：

Interventions：

组别：	剂量递增组	样本量：	62
Group：	dose escalation group	Sample size：	62
干预措施：	BLU-667	干预措施代码：
Intervention：	BLU-667	Intervention code：

组别：	剂量扩展组	样本量：	360
Group：	dose expansion group	Sample size：	360
干预措施：	BLU-667	干预措施代码：
Intervention：	BLU-667	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	四川	市(区县)：	成都
Country：	China	Province：	Sichuan	City：	Chengdu
单位(医院)：	四川大学华西医院	单位级别：	三级甲等
Institution hospital：	West China Hospital, Sichuan University	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	每个瘤肿和每个扩展组的ORR	指标类型：	主要指标
Outcome：	ORR by tumor type and by each expansion group	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	BLU-667总体安全性特征：通过任何AE和严重不良事件（SAE）的类型、频率、严重程度、发生时间、与研究药物的关系，以及生命体征、ECG结果和安全性实验室检查结果的变化进行评估。	指标类型：	主要指标
Outcome：	Overall safety profile of BLU-667, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs, SAEs, changes in vital signs, ECGs, and safety laboratory tests.	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	使用后保存	说明
Fate of sample：	Preservation after use	Note：

标本中文名：	尿液	组织：
Sample Name：	Urine	Tissue：
人体标本去向	使用后销毁	说明
Fate of sample：	Destruction after use	Note：

征募研究对象情况：

Recruiting status：

正在进行

Recruiting

年龄范围：

Participant age：

最小 Min age	18	岁 years
最大 Max age		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）：

未使用

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

Not stated

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：	N/A
Blinding：	N/A

是否共享原始数据： IPD sharing	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）：	不公开原始数据
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	Don't public source data
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：	CRF
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	CRF
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2019-11-15 14:10:59