评估 GEN1055 单药治疗和联合治疗对恶性实体瘤的安全性和初步疗效的试验
首次人体、开放标签、剂量递增试验并扩大队列，以评估 GEN1055 作为单一疗法和联合疗法在恶性实体瘤受试者中的安全性和初步疗效
该试验的目的是了解抗体 GEN1055 单独使用时以及与另一种抗体癌症药物派姆单抗（联合或不联合化疗）一起使用时，用于治疗患有某些类型癌症的参与者。 参与者将接受单独的 GEN1055、GEN1055 联合派姆单抗、或 GEN1055 联合派姆单抗和化疗。 所有参与者都将接受活性药物；没有人会接受安慰剂。
该试验有 2 个部分。 第一部分的目的是确定 GEN1055 是否安全，并确定 GEN1055 单独使用和与派姆单抗一起使用的剂量。 第二部分的目的是向更多参与者提供 GEN1055，以了解第一部分中选择的 GEN1055 剂量单独对抗癌症的效果如何，以及与派姆单抗（联合或不联合其他化疗）联合使用的效果如何。
参与者将接受最长 24 个月的含派姆单抗治疗方案的试验治疗，或直到：
- 癌症进展。
- 存在需要停止治疗的副作用。
- 参与者决定不再参与本次试验。
- 医生认为停止治疗符合参与者的最大利益。
参与试验需要访问现场。 前 12 周每周进行一次探视，之后每 3 周进行一次探视。 在现场访问时，将进行各种测试（例如抽血）和程序（例如记录心脏活动、计算机断层扫描（CT））以监测治疗是否安全有效。 每个参与者的试验持续时间（包括筛查、治疗和随访）约为 39 个月。
研究概览
详细说明
这是一项多中心试验，将分两部分进行：剂量递增（1a/1b 期）和扩展（2a 期）。
该试验的剂量递增部分将评估剂量限制毒性 (DLT)，以确定推荐的 2 期剂量 (RP2D)，如果达到，则确定局部晚期或转移性实体瘤参与者的最大耐受剂量 (MTD)。
扩展部分将评估选定剂量和方案在选定肿瘤适应症中的安全性、耐受性、作用机制 (MoA)、免疫原性、药代动力学 (PK) 和初始抗肿瘤活性。
研究类型
注册 (实际的)
阶段
- 阶段2
- 阶段1
联系人和位置
参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
纳入标准：
所有队列：
- 年满 18 岁。
- 根据 RECIST v1.1 患有可测量的疾病。
- 如果有的话，提供自上次先前治疗失败以来的所有基线前扫描（即记录的放射学进展性疾病 [PD]）。
- 筛选时和 C1D1 预处理时东部肿瘤合作组体能状态 (ECOG PS) 评分为 0 到 1。
- 提供活检（即福尔马林固定石蜡包埋的载玻片/块）。 除非在医学上不可行并且经过申办者审查和批准后，优选在筛选期间进行新鲜活检。 如果无法提供，可以提供上次治疗失败/停止后、C1D1 之前 6 个月内进行的活检。
阶段 1a 和 1b - 剂量递增：
- 患有经组织学或细胞学证实患有转移性或晚期疾病的非中枢神经系统 (CNS) 原发性实体瘤。
- 在标准护理 (SoC) 治疗方面取得进展，其中应包括铂类化疗和抗 PD/PD-L1 疗法（如果适用于肿瘤类型），或者没有可能提供临床益处的可用标准疗法，并且研究者认为，使用 GEN1055 或 GEN1055+pembrolizumab 进行实验性治疗可能有益。
第 2a 阶段 - 扩展：
可能适用特定于所选肿瘤适应症的纳入标准。
排除标准：
患有不受控制的并发疾病，包括但不限于：
- 持续或活动性感染需要在首次给药前 2 周内进行静脉注射抗感染治疗（包括 2019 年冠状病毒病 [COVID-19] 感染）。
严重的心血管损害包括：
i) 有症状的充血性心力衰竭（纽约心脏协会分类为 III 级或 IV 级）、不稳定型心绞痛或心律失常。
ii) 不受控制的高血压定义为尽管采取了最佳的医疗管理，但收缩压≥160 毫米 (mm) Hg 和/或舒张压≥100 mm Hg。
iii) 使用Fridericia 的QT 校正公式，延长校正QT 间期基线≥470 毫秒。
- 持续或最近（筛查后 1 年内）证据表明存在需要全身免疫抑制治疗的重大自身免疫性疾病，这可能提示发生免疫相关不良事件 (irAE) 的风险。
- 导致检查点抑制剂 (CPI) 治疗停止的 3 级或以上 irAE 病史。 因 irAE 低于 3 级而导致停药的参与者应与申办者进行讨论。 也可以讨论已完全恢复的 3 级 irAE。
- 慢性肝病史（例如酒精性肝炎或非酒精性脂肪性肝炎）、药物相关性或自身免疫性肝炎，或肝硬化的证据。
- 间质性肺疾病的证据。
持续性肺炎（任何级别），包括基线时持续性肺炎的任何放射学变化或需要类固醇的非传染性药物、免疫或辐射相关肺炎病史。
- 在指定时间范围内曾接受过以下任何先前治疗/治疗：
- 在试验治疗给药前 4 周内接受抗癌药物治疗，或在药物 5 个半衰期内接受全身治疗，以较短者为准。
- 首次治疗后 14 天内需要使用皮质类固醇（>10 mg 每日泼尼松当量）或其他免疫抑制药物进行全身治疗的病症。 在没有活动性自身免疫性疾病的情况下，允许吸入或局部类固醇，以及肾上腺或垂体替代类固醇>10 mg每日泼尼松当量。
- 在首次试验治疗前 2 周内接受过粒细胞或粒细胞/巨噬细胞集落刺激因子支持或长期依赖输血。
在计划的第一剂试验治疗前 14 天内进行 RT。 允许在 C1D1 之前最多 7 天对骨转移进行姑息性放疗。
- 肝炎（除非当地卫生当局强制要求，否则不需要进行乙型或丙型肝炎检测）：
乙型肝炎病毒 (HBV)：有 HBV 病史或血清学阳性（定义为乙型肝炎表面抗原或 HBV 脱氧核糖核酸 [DNA] 阳性）。
i) 如果认为是由于疫苗接种、自然感染得到解决或由于免疫球蛋白治疗而被动免疫，则上述内容并不排除。
- 丙型肝炎病毒 (HCV)：已知的活动性 HCV 感染（定义为 HCV 核糖核酸 [RNA] [定性] 阳性）。
注意：其他协议定义的纳入和排除标准可能适用。
学习计划
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：顺序分配
- 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：剂量递增
GEN1055 将作为单一疗法并与固定剂量的派姆单抗联合用药。
|
静脉（IV）给药。
静脉注射给药
|
|
实验性的：扩张
GEN1055 将作为单一疗法或与派姆单抗联合给药，或在单独的扩展队列中与派姆单抗和标准化疗联合给药，剂量水平选自剂量递增部分。
|
静脉（IV）给药。
静脉注射给药
静脉注射给药
|
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 |
|---|---|---|
|
Dose Escalation: Number of Participants With Adverse Events (AEs)
大体时间：Up to approximately 1.5 years
|
An AE was defined as any untoward medical occurrence in a clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
|
Up to approximately 1.5 years
|
|
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
大体时间：21 days
|
A DLT was defined as any of the following events during the DLT evaluation period (21 days).
All grade 5 events, anaphylaxis, grade ≥3 infusion-related reaction (IRR), hematological events (grade 4 neutropenia lasting more than 7 days, grade 4 thrombocytopenia for ≥7 consecutive days, grade 3/4 febrile neutropenia for more than 1 hour, grade 3/4 hemorrhage associated with thrombocytopenia of ≥ grade 3 requiring platelet transfusion, grade 4 anemia), nonhematological events (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] elevations ≥ grade 2 with concomitant bilirubin >2.0×upper limit of normal [ULN] with no signs of cholestasis and no other reason can be found to explain the combination of increased ALT/AST and total bilirubin, ie, a Hy's law case, all nonhematological toxicities of grade ≥3 (severe or life-threatening), with exclusions per protocol).
Toxicities were graded for severity according to National Cancer Institute Common Terminology Criteria
|
21 days
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Dose Escalation: Maximum (Peak) Plasma Concentration (Cmax) of GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma to evaluate the pharmacokinetics (PK) of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Time to Reach Cmax (Tmax) for GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma, to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Plasma Trough (Pre-dose) Concentrations (Ctrough) of GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma, to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Sample (AUC0-tlast) for GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma, to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) for GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma, to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Half-life (t½) of GEN1055
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma, to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Clearance (CL) of GEN1055 From the Plasma
大体时间：Cycle 1 and Cycle 2 (cycles were 21 days)
|
Blood samples were collected and processed to obtain plasma to evaluate the PK of GEN1055.
|
Cycle 1 and Cycle 2 (cycles were 21 days)
|
|
Dose Escalation: Number of Participants With Anti-Drug Antibodies (ADA)
大体时间：Up to approximately 1.5 years
|
Venous blood samples were drawn for analysis of ADAs.
|
Up to approximately 1.5 years
|
|
Dose Escalation: Overall Response Rate (ORR)
大体时间：Up to approximately 1.5 years
|
ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as assessed by investigator.
CR was defined as disappearance of all target and non-target tumor lesions, reduction in short axis to <10 millimeters (mm) in all pathological target and non-target lymph nodes and normalization of tumor marker level (if applicable).
PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
|
Up to approximately 1.5 years
|
|
Dose Escalation: Duration of Response (DOR)
大体时间：Up to approximately 1.5 years
|
DOR based on investigator assessment was defined as the time from the first documentation of response (CR or PR) to the date of progressive disease (PD) or death, whichever occurred earlier according to RECIST v1.1. CR was defined as disappearance of all target and non-target tumor lesions, reduction in short axis to <10 mm in all pathological target and non-target lymph nodes and normalization of tumor marker level (if applicable). PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 1 of the following: ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of ≥5 mm in the sum of diameters, or unequivocal appearance of 1 or more new lesion(s), or unequivocal progression of non-target lesions. |
Up to approximately 1.5 years
|
|
Dose Escalation: Time to Response (TTR)
大体时间：Up to approximately 1.5 years
|
TTR based on investigator assessment was defined as the time from Cycle 1 Day 1 (C1D1) to first documentation of objective response (CR or PR) in participants achieving PR or CR according to RECIST v1.1.
CR was defined as disappearance of all target and non-target tumor lesions, reduction in short axis to <10 mm in all pathological target and non-target lymph nodes and normalization of tumor marker level (if applicable).
PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
|
Up to approximately 1.5 years
|
|
Dose Escalation: Disease Control Rate (DCR)
大体时间：Up to approximately 1.5 years
|
DCR was defined as the percentage of participants with BOR of CR, PR, or stable disease (SD) according to RECIST v1.1 as assessed by investigator.
CR was defined as disappearance of all target and non-target tumor lesions, reduction in short axis to <10 mm in all pathological target and non-target lymph nodes and normalization of tumor marker level (if applicable).
PR was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters (nadir) while on trial.
|
Up to approximately 1.5 years
|
合作者和调查者
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (实际的)
研究完成 (实际的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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