ChiCTR2500104805 版本V1.0 版本创建时间2025/06/24 09:16:19 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：

ChiCTR2500104805 

最近更新日期：

Date of Last Refreshed on：

2025-06-24 09:16:05 

注册时间：

Date of Registration：

2025-06-24 00:00:00 

注册号状态：

补注册

Registration Status：

Retrospective registration

注册题目：

一项派安普利单抗（AK105）联合化疗±盐酸安罗替尼治疗晚期鼻咽癌的II期临床研究

Public title：

A Phase II clinical study of penpulimab (AK105) in combination with chemotherapy +/- anlotinib hydrochloride in the treatment of advanced nasopharyngeal carcinoma

注册题目简写：

English Acronym：

研究课题的正式科学名称：

一项派安普利单抗（AK105）联合化疗±盐酸安罗替尼治疗晚期鼻咽癌的II期临床研究

Scientific title：

A Phase II clinical study of penpulimab (AK105) in combination with chemotherapy +/- anlotinib hydrochloride in the treatment of advanced nasopharyngeal carcinoma

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：

李悦 

研究负责人：

陈晓钟 

Applicant：

Li Yue 

Study leader：

Chen Xiaozhong 

申请注册联系人电话：

Applicant telephone：

+86 15880909143

研究负责人电话：

Study leader's telephone：

+86 571 88128202

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：

yue.li@akesobio.com

研究负责人电子邮件：

Study leader's E-mail：

chenxz@zjcc.org.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：

广东省中山市火炬开发区神农路6号

研究负责人通讯地址：

杭州市拱墅区半山东路1号

Applicant address：

No. 6 Shennong Road, Zhongshan City, Guangdong Province, China.

Study leader's address：

No. 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang

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：

康方天成（广东）制药有限公司

Applicant's institution：

CanSino Biologics (Guangdong) Co., Ltd.

研究负责人所在单位：

浙江省肿瘤医院

Affiliation of the Leader：

Zhejiang Cancer Hospital

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：

IRB-[2020]920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：

浙江省肿瘤医院医学伦理委员会

Name of the ethic committee：

Medical Ethics Committee of Zhejiang Cancer Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

2020-11-25 00:00:00

伦理委员会联系人：

王丽虹

Contact Name of the ethic committee：

Wang Lihong

伦理委员会联系地址：

杭州市拱墅区半山东路1号

Contact Address of the ethic committee：

No. 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 571 88122564

伦理委员会联系人邮箱：

Contact email of the ethic committee：

ec@zjcc.org.cn

研究实施负责（组长）单位：

浙江省肿瘤医院

Primary sponsor：

Zhejiang Cancer Hospital

研究实施负责（组长）单位地址：

杭州市拱墅区半山东路1号

Primary sponsor's address：

No. 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

浙江省

市(区县)：

Country：

China

Province：

Zhejiang

City：

单位(医院)：

浙江省肿瘤医院

具体地址：

杭州市拱墅区半山东路1号

Institution
hospital：

Zhejiang Cancer Hospital

Address：

No. 1, East Banshan Road, Gongshu District, Hangzhou, Zhejiang

经费或物资来源：

康方天成（广东）制药有限公司

Source(s) of funding：

CanSino Biologics (Guangdong) Co., Ltd.

Target disease：

Histologically or cytologically confirmed nasopharyngeal carcinoma according to the International Union Against Cancer and American Joint Committee on Cancer staging line at the time of enrollment Nasopharyngeal carcinoma stage IVb as defined by the 8th edition.

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：

非随机对照试验 

Study design：

Non randomized control 

研究目的：

研究主要目的:评估派安普利单抗+安罗替尼+吉西他滨一线治疗晚期鼻咽癌的安全性和有效性， 有效性基于RECIST v1.1 评估的客观缓解率（ORR）。 研究次要目的：评估派安普利单抗+安罗替尼+吉西他滨一线治疗晚期鼻咽癌的 DoR、 DCR、 TTR、 TTP、 PFS、OS；评估派安普利单抗+安罗替尼+吉西他的药代动力学（Pharmacokinetics, PK）；评估派安普利单抗+安罗替尼+吉西他的免疫原性； 评估免疫组织化学检测肿瘤样本中 PD-L1 表达与疗效的相关性；评价晚期鼻咽癌受试者血液中 EBV DNA 拷贝数与派安普利单抗联合治疗抗肿瘤活性的相关性； 评估派安普利单抗联合化疗±安罗替尼治疗受试者的健康相关生活质量（HRQoL）。  

Objectives of Study：

Primary purpose:To evaluate the safety and efficacy of penpulimab, anlotinib, and gemcitabine in the first-line treatment of advanced nasopharyngeal carcinoma based on objective response rate (ORR) as assessed by RECIST v1.1. Secondary purpose:To evaluate the first-line treatment of Penpulimab + Anlotinib + Gemcitabine in the first-line treatment of advanced nasopharyngeal carcinoma in DoR, DCR, TTR, TTP, PFS,OS;To evaluate the pharmacokinetics (PK) of penpulimab + anlotinib + gemcita;To evaluate the immunogenicity of penpulimab + anlotinib + gemcita; To evaluate the correlation between PD-L1 expression and efficacy in tumor samples detected by immunohistochemistry;To evaluate the correlation between EBV DNA copy number in blood and antitumor activity of penpulimab combination therapy in subjects with advanced nasopharyngeal carcinoma Sex;To assess health-related quality of life (HRQoL) in participants treated with penpulimab in combination with chemotherapy +/- anlotinib.

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. 自愿签署书面 ICF。
2. 入组时年龄 ≥ 18 周岁， ≤ 75 周岁， 男女均可。
3. 东部肿瘤协作组织（ECOG） 体能状况评分为 0 或 1。
4. 预期生存期 ≥ 3 个月。
5. 组织学或细胞学确诊的鼻咽癌， 在入组时为根据国际抗癌联盟和美国癌症联合委员会分期系统第 8 版定义的鼻咽癌 IVb 期。
6. 受试者鼻咽癌初诊时无远处转移， 既往接受过含铂化疗（诱导、 同步或辅助化疗）， 且治疗结束后 6 个月以上出现远处转移， 且未针对转移性鼻咽癌接受过系统性治疗。
7. 根据 RECIST v1.1 至少有一个可测量病灶。
8. 同意提供既往存档的肿瘤组织样本（需入组前 3 年内组织样本） 或者进行活检以采集肿瘤病灶组织（至少 3 张未染色的 FFPE 病理切片， 如经中心实验室判定样本不足以进行 PD-L1 IHC检测， 需额外提供 3 张未染色的 FFPE 病理切片） 送往中心实验室进行 PD-L1 免疫组织化学（IHC） 检测（优选新近获得肿瘤组织样本）。 用于活检的肿瘤病灶不得用作评估疾病的靶病灶， 除非没有其他适合活检的病灶。 若活检病灶用作靶病灶， 则必须在筛选期外进行活检。如果没有 3 年内存档的肿瘤组织样本， 经研究者判断活检可能会增加受试者的风险， 在与医学监查员讨论后， 经同意可收集 3 年以外的存档肿瘤组织样本。 9. 通过以下要求确定良好的器官功能： a) 血液学（开始研究治疗前 7 天内未使用任何血液成分及细胞生长因子支持治疗）： i. 中性粒细胞绝对值 ANC ≥ 1.5 ×109/L (1,500/mm3) ； ii. 血小板计数 ≥ 100 × 109/L (100,000/mm3) ； iii. 血红蛋白 ≥ 90 g/L。 b) 肾脏： i. 肌酐清除率* (CrCl) 计算值 ≥ 50 mL/min* 将采用 Cockcroft-Gault 公式计算 CrCl (Cockcroft-Gault 公式)CrCL (mL/min) = {(140 - 年龄) × 体重 (kg) × F}/ (SCr (mg/dL) × 72)其中男性的 F = 1， 女性的 F = 0.85； SCr = 血清肌酐。 ii. 尿蛋白 < 2+ 或 24 小时（h） 尿蛋白定量 < 1.0 g。 c) 肝脏： i. 血清总胆红素（TBil） ≤ 1.5 × ULN ii. AST 和 ALT ≤ 2.5× ULN iii. 血清白蛋白（ALB） ≥28 g/L d) 凝血功能： i. 国际标准化比率（INR） 和活化部分凝血活酶时间（APTT） ≤ 1.5 × ULN。 e) 心功能： i. 左室射血分数（LVEF） ≥50%。 10. 具有生育能力的女性受试者必须在首次用药前 3 天内进行尿液或血清妊娠检查（如尿液妊娠检查结果不能确认为阴性， 需进行血清妊娠检查， 以血清妊娠结果为准）， 且结果为阴性。如具有生育能力的女性受试者与未绝育的男性伴侣发生性行为， 该受试者必须自筛选开始采取可接受的避孕方法， 且必须同意在研究药物末次给药后的120天内持续使用采用避孕方法；关于在此时间点后是否停止避孕， 应与研究者讨论。 11. 如未绝育的男性受试者与具有生育能力的女性伴侣发生性行为， 该受试者必须自筛选开始至 末次给药后的第 120 天采取有效的避孕方法； 关于在此时间点后是否停止避孕， 应与研究者 讨论。
9. 通过以下要求确定良好的器官功能： a) 血液学（开始研究治疗前 7 天内未使用任何血液成分及细胞生长因子支持治疗）： i. 中性粒细胞绝对值 ANC ≥ 1.5 ×109/L (1,500/mm3) ； ii. 血小板计数 ≥ 100 × 109/L (100,000/mm3) ； iii. 血红蛋白 ≥ 90 g/L。 b) 肾脏： i. 肌酐清除率* (CrCl) 计算值 ≥ 50 mL/min* 将采用 Cockcroft-Gault 公式计算 CrCl (Cockcroft-Gault 公式)CrCL (mL/min) = {(140 - 年龄) × 体重 (kg) × F}/ (SCr (mg/dL) × 72)其中男性的 F = 1， 女性的 F = 0.85； SCr = 血清肌酐。 ii. 尿蛋白 < 2+ 或 24 小时（h） 尿蛋白定量 < 1.0 g。 c) 肝脏： i. 血清总胆红素（TBil） ≤ 1.5 × ULN ii. AST 和 ALT ≤ 2.5× ULN iii. 血清白蛋白（ALB） ≥28 g/L d) 凝血功能： i. 国际标准化比率（INR） 和活化部分凝血活酶时间（APTT） ≤ 1.5 × ULN。 e) 心功能： i. 左室射血分数（LVEF） ≥50%。
10. 具有生育能力的女性受试者必须在首次用药前 3 天内进行尿液或血清妊娠检查（如尿液妊娠检查结果不能确认为阴性， 需进行血清妊娠检查， 以血清妊娠结果为准）， 且结果为阴性。如具有生育能力的女性受试者与未绝育的男性伴侣发生性行为， 该受试者必须自筛选开始采取可接受的避孕方法， 且必须同意在研究药物末次给药后的120天内持续使用采用避孕方法；关于在此时间点后是否停止避孕， 应与研究者讨论。
11. 如未绝育的男性受试者与具有生育能力的女性伴侣发生性行为， 该受试者必须自筛选开始至 末次给药后的第 120 天采取有效的避孕方法； 关于在此时间点后是否停止避孕， 应与研究者 讨论。
12. 受试者愿意而且能够遵守日程表规定的访视、 治疗方案、 实验室检查， 及遵守研究的其他要求。

Inclusion criteria

1. Sign a written ICF voluntarily. 2. Age >= 18 years old, <= 75 years old, male and female can be enrolled. 3. The Eastern Cancer Collaboration (ECOG) Physical Fitness score is 0 or 1. 4. Expected survival >= 3 months. 5. Nasopharyngeal carcinoma diagnosed histologically or cytologically was stage IVb nasopharyngeal carcinoma as defined by the International Union against Cancer and the American Joint Committee on Cancer Staging System, Edition 8, at the time of enrollment. 6. The subjects had no distant metastasis at first diagnosis of nasopharyngeal carcinoma, had previously received platinum-containing chemotherapy (induction, synchronous or adjuvant chemotherapy), had developed distant metastasis more than 6 months after the end of treatment, and had not received systematic treatment for metastatic nasopharyngeal carcinoma. 7. Have at least one measurable lesion according to RECIST v1.1. 8. Agree to provide previously archived tumor tissue samples (tissue samples within 3 years prior to enrollment) or conduct biopsy to collect tumor lesion tissues (at least 3 unstained FFPE pathological sections). If the samples are determined by the central laboratory to be insufficient for PD-L1 IHC detection, An additional 3 unstained FFPE pathological sections are required to be sent to the central laboratory for PD-L1 immunohistochemical (IHC) testing (preferably recently acquired tumor tissue samples). A tumor lesion intended for biopsy should not be used as a target for disease assessment unless there are no other lesions suitable for biopsy. If the biopsy lesion is used as a target lesion, the biopsy must be performed outside the screening period. If there are no tumor tissue samples on file within 3 years, the investigator determines that biopsy may increase the risk of the subject, and after discussion with the medical monitor, it is agreed that archived tumor tissue samples beyond 3 years may be collected. 9. Good organ function is determined by the following requirements: a) Hematology (no use of blood components and cell growth factors to support therapy within 7 days prior to initiation of study therapy) : i. Neutrophil absolute value ANC >= 1.5 ×10^9/L (1,500/mm^3); ii. Platelet count >= 100 × 10^9/L (100,000/mm^3); iii. Hemoglobin >= 90 g/L. b) Kidney: i. Creatinine clearance * (CrCl) calculated value >= 50 mL/min* The Cockcroft-Gault formula will be used to calculate CrCl (Cockcroft-Gault formula)CrCL (mL/min) = {(140 - age) × body weight (kg) × F}/ (SCr (mg/dL) × 72) where F = 1 for males and F = 0.85 for females; SCr = serum creatinine. ii. Urinary protein < 2+ or 24-hour (h) urinary protein quantity < 1.0 g. c) Liver: i. Serum total bilirubin (TBil) <= 1.5 × ULN ii. AST and ALT <= 2.5× ULN iii. Serum albumin (ALB) >=28 g/L d) Coagulation function: i. International Standardized ratio (INR) and activated partial thromboplastin time (APTT) <= 1.5 × ULN. e) Cardiac function: i. Left ventricular ejection fraction (LVEF) >=50%. 10. Female subjects with fertility must undergo urine or serum pregnancy test within 3 days before the first medication (if the urine pregnancy test result is not confirmed negative, serum pregnancy test is required, the serum pregnancy result shall prevail), and the result is negative. If a fertile female subject has sex with an unsterilized male partner, the subject must use an acceptable contraceptive method since screening and must consent to continued use of the contraceptive method for 120 days after the last administration of the study drug; Whether to stop contraception after this time point should be discussed with the investigator. 11. If an unsterilized male subject has sex with a fertile female partner, the subject must use an effective contraceptive method from the beginning of screening until the 120th day after the last dose; Whether to stop contraception after this time point should be discussed with the investigator. 12. Subject is willing and able to comply with scheduled visits, treatment protocols, laboratory tests, and other requirements of the study.

排除标准：

1. 除鼻咽癌以外， 受试者在入组前 2 年内患有其他恶性肿瘤。 不排除患有通过局部治疗其他肿瘤已治愈的受试者， 例如基底或皮肤鳞状细胞癌、 浅表膀胱癌、 宫颈或乳腺原位癌。
2. 在首次研究给药前 4 周内参加过试验性药物的治疗或使用过试验性器械。
3. 首次给药前 2 周内针对非靶病灶进行了姑息性局部治疗； 首次给药前 2 周内接受过非特异性免疫调节治疗（如白介素、 干扰素、 胸腺肽等， 不包括用于治疗血小板减少的 IL-11）； 首次给药前 1 周内曾接受具有抗肿瘤适应症的中草药或中成药。
4. 鼻咽病灶经过放疗后复发，接受过二次放疗的受试者。
5. 既往接受过免疫治疗，包括免疫检查点抑制剂（如：抗 PD-1 抗体、 抗 PD-L1、 抗 CTLA-4 抗体等）、免疫检查点激动剂（如： ICOS、 CD40、 CD137、 GITR、 OX40 抗体等）、免疫细胞治疗等任何针对肿瘤免疫作用机制的治疗； 既往接受过抗血管生成治疗（除外贝伐珠单抗和恩度）。
6. 患有在过去两年内需要系统性治疗的活动性自身免疫性疾病（如使用改善病情药物，皮质类固醇， 免疫抑制剂治疗），替代治疗（如甲状腺素、胰岛素、或针对肾上腺或垂体功能不全的生理性皮质类固醇替代治疗） 不认为是一种系统性治疗。
7.不能吞咽药片、 吸收不良综合症、 或任何影响胃肠吸收的状况； 活动性或既往有明确的炎症 性肠病（如克罗恩病、 溃疡性结肠炎或慢性腹泻） 病史。
8.存在免疫缺陷病史； HIV 抗体检测阳性者； 当前正在长期使用系统性皮质类固醇激素或其他 免疫抑制剂。
9.已知存在活动性肺结核（TB）， 怀疑有活动性 TB 的受试者， 需检查胸部 X 线、 痰液以及通 过临床症状和体征排除； 已知的活动性梅毒感染。
10.已知异体器官移植史和异体造血干细胞移植史。
11.存在需要系统性糖皮质激素治疗的非感染性肺炎/间质性肺疾病病史或当前存在非感染性肺 炎。
12.首次给药前 4 周内发生严重感染， 包括但不局限于伴有需要住院治疗的合并症、 败血症或严 重肺炎； 在首次给药前两周内接受过全身抗感染治疗的活动性感染（不包括乙型肝炎或丙型 肝炎的抗病毒治疗）。
13.未经治疗的活动性乙型肝炎受试者（HBsAg 阳性且 HBV-DNA 超过 1000 拷贝/m（l 200 IU/ml） 或高于检测下限， 以高者为准）， 对于患有乙型肝炎的受试者， 要求在研究治疗期间接受抗 乙肝病毒治疗； 活动性的丙型肝炎受试者（HCV 抗体阳性且 HCV-RNA 水平高于检测下限）。
14.在首次给药前 30 天内进行过重大外科手术或发生严重外伤， 或在首次给药后的 30 天内有重 大外科手术计划者（由研究者决定）； 在首次给药前 3 天内进行过较小的局部手术（不包括 经外周静脉穿刺中心静脉置管术）。
15.入组前存在脑膜转移、 脊髓压迫、 软脑膜疾病或活动性脑转移。 有中枢神经系统 (CNS) 转 移受试者 AK105 首次给药前必须已经接受治疗并达到无症状（如无神经功能障碍， 癫痫或 其它典型中枢神经系统转移症状和体征） 并且符合以下要求的受试者可以纳入： a) 无同时进行的治疗（包括但不限于手术、 放疗和/或皮质类固醇） b) 在接受最后治疗后， 有影像学证据显示在 AK105 首次给药前至少 4 周内无 CNS 转移进 展 c) 已经停止全身性激素治疗大于 2 周；
16.存在有临床症状或需要引流的心包积液或腹水， 或需要反复引流的胸腔积液的受试者。
17.当前存在未得到控制的合并疾病， 包括但不限于症状性充血性心力衰竭（按照纽约心脏病协 会功能分级确定的 2 级及以上）、 不稳定型心绞痛、 急性心肌缺血、 控制不佳的心律失常、 失代偿性肝硬化、 肾病综合征、 未控制的代谢紊乱、 重度活动性消化性溃疡病或胃炎， 或会 限制受试者依从研究要求或影响受试者提供书面知情同意能力的精神疾病/社会状况。
18.既往存在心肌炎、 心肌病、 恶性心律失常病史。 首次给药前 12 个月内存在需住院治疗的不 稳定性心绞痛、 充血性心力衰竭或血管疾病（如需手术修复的主动脉瘤或外周静脉血栓）， 或可能影响研究药物安全性评价的其他心脏损害（如控制不佳的心律失常， 心肌梗塞或缺 血）； 首次给药前 6 个月内存在食管胃底静脉曲张， 严重溃疡， 伤口未愈， 胃肠穿孔， 腹瘘， 胃肠梗阻， 腹腔内脓肿或急性胃肠道出血病史； 首次给药前 6 个月内发生过任何动脉血栓栓塞事件， NCI CTCAE 5.0 版 3 级及以上的静脉血栓栓塞， 短暂性脑缺血发作， 脑血管意外， 高血压危象或高血压脑病； 首次给药前 1 个月内发生慢性阻塞性肺病急性加重； 当前存在高 血压且经口服降压药物治疗后收缩压≥160mmHg 或舒张压≥100mmHg。
19.有严重出血倾向或凝血功能障碍病史； 首次给药前 1 个月内存在具有显著临床意义的出血症 状， 包括但不限于消化道出血、 咳血（定义为咳出或咯出≥1 茶匙鲜血或小血块或只咳血无 痰液， 允许痰中带血者入组）、 鼻腔出血（不包括鼻衄出血及回缩性涕血）； 筛选期影像学显 示肿瘤包绕重要血管或存在明显坏死、 空洞， 且研究者认为参与研究可能会引起出血风险； 首给药前 10 天内接受过持续的抗血小板或抗凝治疗。
20.既往抗肿瘤治疗毒性未缓解， 定义为毒性未恢复至 NCI CTCAE 5.0 版 0 级或 1 级， 或入选/ 排除标准中规定的水平， 但脱发、 既往铂类治疗相关神经毒性的后遗症除外。 对于发生不可 逆毒性且预期研究药物给药后不会加重的受试者（例如听力损失）， 在与医学监查员协商后， 可能会被纳入研究。 放疗引起的远期毒性， 经研究者判断不能恢复的受试者， 在与医学监查 员协商后， 可能会被纳入研究。
21.在首次给药前的 30 天内接种了活疫苗， 或计划在研究期间接种活疫苗。
22.已知对任何研究药物的任何成分过敏； 已知对其他单克隆抗体产生严重超敏反应的病史。
23.已知有精神疾病、 药物滥用、 酗酒或吸毒史。
24.妊娠期或哺乳期女性。
25.既往或当前存在任何疾病、 治疗、 实验室检查异常， 可能会混淆研究结果， 影响受试者全程 参与研究， 或参与研究可能不符合受试者的最佳利益。
26.非恶性肿瘤导致的局部或全身性疾病， 或肿瘤继发的疾病或症状， 并可导致较高医学风险和 /或生存期评价的不确定性， 如肿瘤类白血病反应（白细胞计数>20× 109 / L）、 恶液质表现（如 已知的筛选前 3 个月体重减轻超过 10%） 等。

Exclusion criteria：

1. In addition to nasopharyngeal carcinoma, subjects had other malignant tumors within 2 years prior to enrollment. Subjects who have been cured by local treatment of other tumors, such as basal or skin squamous cell carcinoma, superficial bladder cancer, cervical or breast carcinoma in situ, are not excluded. 2. Participated in the treatment of the investigational drug or used the investigational device within 4 weeks prior to the initial study administration. 3. Palliative local treatment was performed for non-target lesions within 2 weeks before the first administration; Received non-specific immunomodulatory therapy (e.g., interleukin, interferon, thymosin, etc., excluding IL-11 for the treatment of thrombocytopenia) within 2 weeks prior to initial administration; Received Chinese herbal medicine or proprietary Chinese medicine with anti-tumor indications within 1 week prior to the first administration. 4. Subjects whose nasopharyngeal lesions recurred after radiotherapy and received secondary radiotherapy. 5. Previously received immunotherapy, including immune checkpoint inhibitors (such as anti-PD-1 antibody, anti-PD-L1, anti-CTLA-4 antibody, etc.), immune checkpoint agonists (such as: ICOS, CD40, CD137, GITR, OX40 antibody, etc.), immune cell therapy, and any treatment targeting the immune mechanism of tumor; Previously received antiangiogenic therapy (except bevacizumab and Endol). 6. Patients with active autoimmune disease that has required systemic treatment within the past two years (e.g., treatment with disease-modifying drugs, corticosteroids, immunosuppressants) and replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a systemic treatment. 7. Inability to swallow tablets, malabsorption syndrome, or any condition affecting gastrointestinal absorption; Be active or have a clear past history of inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, or chronic diarrhea. 8. History of immune deficiency; HIV antibody test positive; Systemic corticosteroid hormones or other immunosuppressants are currently being used on a long-term basis. 9. Subjects with known active tuberculosis (TB) and suspected active TB should be examined by chest X-ray, sputum, and excluded through clinical signs and symptoms; Known active syphilis infection. 10. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation. 11. There is a history or current presence of non-infectious pneumonia/interstitial lung disease requiring systemic glucocorticoid therapy. 12. Severe infection occurring within 4 weeks prior to initial dosing, including but not limited to comorbidification requiring hospitalization, sepsis, or severe pneumonia; Active infections that have received systemic anti-infective therapy (excluding antiviral therapy for hepatitis B or C) within two weeks prior to initial dosing. 13. Subjects with untreated active hepatitis B (HBsAg positive with more than 1000 copies /m of HBV-DNA (l 200 IU/ml) or higher than the lower limit of detection, whichever is higher), for subjects with hepatitis B, are required to receive anti-hepatitis B therapy during the study treatment; Active hepatitis C subjects (HCV antibody positive with HCV-RNA levels above the lower limit of detection). 14. Had a major surgical procedure or severe trauma within 30 days prior to the first dose, or had a major surgical procedure planned within 30 days after the first dose (as determined by the investigator); Minor local surgery (excluding central venous catheterization by peripheral venipentesis) was performed within 3 days prior to initial dosing. 15. Meningeal metastasis, spinal cord compression, pia disease, or active brain metastasis were present before enrollment. Subjects with central nervous system (CNS) transfer AK105 must have been treated prior to initial administration and be asymptomatic (e.g., free of neurological dysfunction, epilepsy, or other typical CNS transfer symptoms and signs) and meet the following requirements may be included: a) no concurrent therapy (including but not limited to surgery, radiation, and/or corticosteroids) b) imaging evidence of no CNS metastasis for at least 4 weeks prior to the first administration of AK105 after receiving final therapy c) systemic sex hormone therapy has been discontinued for more than 2 weeks; 16. Subjects with clinical symptoms or pericardial effusion or ascites requiring drainage, or pleural effusion requiring repeated drainage. 17. There are currently uncontrolled co-diseases, Including, but not limited to, symptomatic congestive heart failure (grade 2 and above as determined by the New York Heart Association Functional Scale), unstable angina pectoris, acute myocardial ischemia, poorly controlled arrhythmias, decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis, Mental illness/social condition that may limit the subject's compliance with study requirements or affect the subject's ability to provide written informed consent. 18. Previous history of myocarditis, cardiomyopathy and malignant arrhythmia. Unstable angina, congestive heart failure, or vascular disease requiring hospitalization (such as aortic aneurysms requiring surgical repair or peripheral venous thrombosis), or other cardiac impairment that may affect the safety evaluation of the study drug (such as poorly controlled arrhythmias, myocardial infarction, or lack of blood) in the 12 months prior to initial administration; History of esophageal and gastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months before first administration; Any arterial thromboembolism event, NCI CTCAE 5.0 grade 3 or above venous thromboembolism, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy occurred within 6 months prior to initial administration; Acute exacerbation of chronic obstructive pulmonary disease occurred within 1 month before first administration; Currently high blood pressure is present and the systolic blood pressure is ≥160mmHg or the diastolic blood pressure is ≥100mmHg after oral antihypertensive medication. 19. History of severe bleeding tendency or coagulopathy; Clinically significant bleeding symptoms, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing up or spitting up ≥1 TSP of blood or small blood clots or only coughing up blood with no sputum, allowing inclusion of blood in the sputum), and nasal bleeding (excluding nosebleed and retractile rhinorrhea) within 1 month before first administration; During the screening period, imaging showed that the tumor surrounded important blood vessels or had obvious necrosis and voids, and the investigators believed that participating in the study might cause bleeding risk. Received continuous antiplatelet or anticoagulant therapy within 10 days prior to first administration. 20. No remission of toxicity from previous antitumor therapy, defined as toxicity not returning to NCI CTCAE 5.0 level 0 or 1, or to the level specified in the inclusion/exclusion criteria, except for hair loss and sequelae of previous platinum treaty-related neurotoxicity. Subjects who develop irreversible toxicity and are not expected to worsen with administration of the study drug (e.g. hearing loss) may be enrolled in the study after consultation with the medical monitor. Subjects with long-term toxicity from radiation therapy that the investigator determines will not recover may be enrolled in the study after consultation with the medical monitor. 21. Live vaccine was administered within 30 days prior to the first dose or was planned to be administered during the study period. 22. Known allergy to any component of any investigational drug; There is a known history of severe hypersensitivity to other monoclonal antibodies. 23. A known history of mental illness, substance abuse, alcohol or drug abuse. 24. Pregnant or lactating women. 25. The presence of any past or current medical conditions, treatments, or laboratory abnormalities that may confuse the study results, interfere with the subject's full participation in the study, or that participation in the study may not be in the subject's best interest. 26. Local or systemic disease caused by non-malignant neoplasms, or disease or symptoms secondary to neoplasms, that can lead to higher medical risk and/or uncertainty in the assessment of survival, Such as tumor leukemoid reaction (white blood cell count >20× 10^9 / L), bad fluid manifestations (such as known weight loss of more than 10% in the 3 months before screening).

研究实施时间：

Study execute time：

从 From 2020-09-01 00:00:00至 To 2023-12-30 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2021-03-18 00:00:00 至 To 2022-06-02 00:00:00  

干预措施：

Interventions：

组别：

A

样本量：

30

Group：

A

Sample size：

干预措施：

派安普利单抗(200 mg,每周期第1天给药，Q3W,直至不再有临床获益)+顺铂(80mg/m2,每周期第1天给药，Q3W,46周期)+吉西他滨(100mg/m2,每周期第1、8天给药，Q3W,4-6周期》+盐酸安罗替尼(12mg QD,连用2周后停1周，直至不再有临床获益),每3周(21天)为一治疗周期。 先入组约6例晚期鼻咽癌受试者，如安全性和耐受性良好，并观察到初步疗效信号，将进入扩展入组期。入选约15例受试者时，将进行有效性分析。如果15例受试者中≤6例受试者疗效评估为PR或CR,或者毒副反应大患者不能耐受则将可能停止该组受试者入组。其他各组继续入组，直至该组达到约30例转移性鼻咽癌受试者。

干预措施代码：

Intervention：

Penpulimab (200 mg on the first day of each cycle, Q3W until no longer clinically beneficial) Cisplatin (80 mg/m^2, administered on the first day of each cycle, Q3W, 46 cycles) Gemcitabine (100 mg/m^2, administered on days 1 and 8 of each cycle, Q3W, 4-6 cycles) Anlotinib hydrochloride (12 mg QD, 2 weeks for 2 weeks and then stopped for 1 week until no longer clinically beneficial), every 3 weeks (21 days) is a treatment cycle. About 6 subjects with advanced nasopharyngeal carcinoma will enter the expansion enrollment period if the safety and tolerability are good, and preliminary efficacy signals are observed. Effectiveness analyses will be performed when approximately 15 subjects are enrolled. If <= 6 of the 15 participants have a PR or CR efficacy assessment, or if the toxicity is not tolerated by patients with high toxicity or side effects, enrollment in this group may be discontinued. The other groups continued to be enrolled until approximately 30 subjects with metastatic nasopharyngeal carcinoma were reached in this group.

Intervention code：

组别：

B

样本量：

30

Group：

B

Sample size：

干预措施：

派安普利单抗(200 mg,每周期第1天给药，Q3W,直至不再有临床获益)+顺铂(80mg/m2,每周期第1天给药，Q3W,4-6周期)+吉西他滨(1000mg/m2,每周期第1、8天给药，Q3W,4-6周期),每3周(21天)为一治疗周期。 先入组约6例晚期鼻咽癌受试者，如安全性和耐受性良好，并观察到初步疗效信号，将进入扩展入组期。入选约15例受试者时，将进行有效性分析。如果15例受试者中≤6例受试者疗效评估为PR或CR,或者毒副反应大患者不能耐受则将可能停止该组受试者入组。其他各组继续入组，直至该组达到约30例转移性鼻咽癌受试者。

干预措施代码：

Intervention：

Penpulimab (200 mg on day 1 of each cycle, Q3W until no longer clinically beneficial) Cisplatin (80 mg/m^2 on day 1 of each cycle, Q3W, 4-6 cycles) Gemcitabine (1000 mg/m^2, given on days 1 and 8 of each cycle, Q3W, 4-6 cycles) every 3 weeks (21 days) as a treatment cycle. About 6 subjects with advanced nasopharyngeal carcinoma will enter the expansion enrollment period if the safety and tolerability are good, and preliminary efficacy signals are observed. Effectiveness analyses will be performed when approximately 15 subjects are enrolled. If <= 6 of the 15 participants have a PR or CR efficacy assessment, or if the toxicity is not tolerated by patients with high toxicity or side effects, enrollment in this group may be discontinued. The other groups continued to be enrolled until approximately 30 subjects with metastatic nasopharyngeal carcinoma were reached in this group.

Intervention code：

组别：

C

样本量：

30

Group：

C

Sample size：

干预措施：

派安普利单抗(200mg,每周期第1天给药，Q3W,直至不再有临床获益)+吉西他滨(1000mg/m2,每周期第1、8天给药，Q3W,4-6周期)+盐酸安罗替尼(12mg QD,连用2周后停1周，直至不再有临床获益),每3周(21天)为一治疗周期。 先入组约6例晚期鼻咽癌受试者，如安全性和耐受性良好，并观察到初步疗效信号，将进入扩展入组期。入选约15例受试者时，将进行有效性分析。如果15例受试者中≤6例受试者疗效评估为PR或CR,或者毒副反应大患者不能耐受则将可能停止该组受试者入组。其他各组继续入组，直至该组达到约30例转移性鼻咽癌受试者。

干预措施代码：

Intervention：

Penpulimab (200 mg, administered on the first day of each cycle, Q3W, until there is no longer clinical benefit) Gemcitabine (1000mg/m^2, administered on days 1 and 8 of each cycle, Q3W, 4-6 cycles) Anlotinib hydrochloride (12 mg QD, 2 weeks in a row and then stopped for 1 week until there is no longer clinical benefit), every 3 weeks (21 days) as a treatment cycle. About 6 subjects with advanced nasopharyngeal carcinoma will enter the expansion enrollment period if the safety and tolerability are good, and preliminary efficacy signals are observed. Effectiveness analyses will be performed when approximately 15 subjects are enrolled. If <= 6 of the 15 participants have a PR or CR efficacy assessment, or if the toxicity is not tolerated by patients with high toxicity or side effects, enrollment in this group may be discontinued. The other groups continued to be enrolled until approximately 30 subjects with metastatic nasopharyngeal carcinoma were reached in this group.

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 浙江省 

市(区县)：

  

Country：

China 

Province：

Zhejiang 

City：

 

单位(医院)：

浙江省肿瘤医院 

单位级别：

三级甲等 

Institution
hospital：

Zhejiang Cancer Hospital

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 广西壮族自治区 

市(区县)：

  

Country：

China 

Province：

Guangxi Zhuang Autonomous Region 

City：

 

单位(医院)：

广西壮族自治区人民医院 

单位级别：

三级甲等 

Institution
hospital：

The People’s Hospital of Guangxi Zhuang Autonomous Region

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 湖南省 

市(区县)：

  

Country：

China 

Province：

Hunan 

City：

 

单位(医院)：

湖南省肿瘤医院 

单位级别：

三级甲等 

Institution
hospital：

Hunan Cancer Hospital

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 湖北省 

市(区县)：

  

Country：

China 

Province：

Hubei 

City：

 

单位(医院)：

华中科技大学同济医学院附属协和医院 

单位级别：

三级甲等 

Institution
hospital：

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 广西壮族自治区 

市(区县)：

  

Country：

China 

Province：

Guangxi Zhuang Autonomous Region 

City：

 

单位(医院)：

广西壮族自治区肿瘤医院 

单位级别：

三级甲等 

Institution
hospital：

Guangxi Medical University Cancer Hospital

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

客观缓解率

指标类型：

主要指标

Outcome：

ORR

Type：

Primary indicator

测量时间点：

受试者在首次用 药后 24 周内每 6 周， 24 周后每 9 周 ， 51 周后每 12 周进行一次肿瘤评估.

测量方法：

影像检测

Measure time point of outcome：

Participants were evaluated for tumors every 6 weeks for 24 weeks, every 9 weeks after 24 weeks, and

Measure method：

Imageological examination

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：

肿瘤组织

组织：

Sample Name：

Tumor tissue

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：

结束

/Completed

年龄范围：

Participant age：
最小 Min age 18 岁 years
最大 Max age 75 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)：

None

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：

无

Blinding：

None

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）：

论文发表后一年内通过邮箱共享，邮箱：mingying.liu@akesobio.com 。

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

Within one year of publication through the E-mail,mail address: mingying.liu@akesobio.com.

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：

EDC

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

Electronic data capture

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2025-06-24 09:16:05