肿瘤细胞治疗研究
英文原题：GRACE: A Phase 1/2a Study of VTRU200 in Relapsed/Refractory AML, High-risk MDS, DLBCL Post CART Failure and Advanced Solid Tumors
这是一项 I/II 期注册临床试验，评估细胞治疗用于急性髓系白血病、弥漫大 B 细胞淋巴瘤、骨髓增生异常综合征的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 108 例。登记号：NCT07749976。
不限性别 · ≥ 6 Months
纳入标准：
* 1. 成人（≥18岁），患有
I. 根据WHO 2022标准经病理学确诊的急性髓系白血病（AML）。复发性或难治性AML，定义为以下任一情况：
1. 难治性AML：至少接受2个疗程的强化诱导治疗后未能达到CR、CRh或CRi。
2. 复发性AML：既往达到CR、CRh或CRi后复发，经以下一项或多项证实：形态学评估骨髓原始细胞>5%；形态学评估外周血中原始细胞持续重新出现 II. HR-MDS：根据WHO 2022标准经病理学确诊的骨髓增生异常综合征（MDS），高危疾病定义为IPSS-R高危或极高危（评分>4.5）。不适合接受异基因造血干细胞移植。
III. CAR-T 后 DLBCL：经组织学确诊为符合 WHO 2022 标准的 DLBCL，且既往 CAR-T 治疗后出现复发或难治性疾病。符合条件的 CAR-T 后治疗失败必须在 CAR-T 输注后至少 1 个月记录到，并包括无代谢反应、首次代谢进展性疾病，或既往缓解后首次复发。既往 CAR-T 输注必须在筛选前至少 1 个月进行。受试者在筛选时不得处于部分代谢反应或完全代谢反应，并且必须在 PET/CT（首选）或 CT/MRI 上具有可测量病灶，定义为至少 1 个淋巴结病灶 >1.5 cm 或至少 1 个结外病灶 >1.0 cm；如果使用 PET，病灶必须为 FDG 高摄取，并与活动性淋巴瘤一致 IV. 晚期实体瘤 2. 患有 R/R-AML 的儿童（6 个月-11 岁）和青少年（12-17 岁）。
1. 儿童和青少年难治性 AML：在 2 个周期诱导治疗结束时，通过多参数流式细胞术（MFC）检测骨髓中含有 1% 原始细胞
2. 儿童和青少年复发性AML：单次骨髓样本通过MFC显示5%白血病原始细胞，荧光原位杂交（FISH）检测或其他分子方法，或单次骨髓样本至少两项检测显示1%原始细胞，如通过MFC、核型异常且至少一个中期分裂相与诊断时相似或相同、FISH异常与诊断时存在的异常相同（高于特定FISH探针的灵敏度水平）或聚合酶链反应（PCR）或基于下一代测序（NGS）证明与诊断时相同的白血病致病性病变（例如，融合、突变）且可定量为1% 3. 东部肿瘤协作组（ECOG）体能状态0-2或卡氏体能评分（KPS）≥50% 4. 器官功能充足：I. 肝脏：血清AST/ALT ≤2.5×ULN且总胆红素 ≤1.5×ULN（若为Gilbert综合征则 ≤3×ULN）II. 肾脏：血清肌酐 ≤1.5×ULN；计算CrCl：≥40 mL/min（Cockcroft-Gault[成人]；Schwartz公式[青少年]；若血清肌酐处于临界值则适用）III. 心脏：射血分数 ≥ 50%且ECHO确定无心包积液的证据 IV. 血液学：在首剂研究治疗前及第1周期每次给药前，WBC计数必须 ≤20 × 10⁹/L；WBC >20 × 10⁹/L的患者可接受羟基脲（最多4 g/天）和/或白细胞分离术进行细胞减灭以达到该阈值，羟基脲在每次研究治疗给药前至少停用12-24小时 5. 有生育能力的女性必须血清或尿液妊娠试验阴性 6. 成人：书面知情同意。青少年：书面患者同意书加父母/监护人知情同意书。
7. 既往接受过研究性药物治疗是允许的，前提是至少已过5个半衰期且所有治疗相关毒性已恢复至≤1级（脱发除外）。既往T细胞衔接、检查点抑制剂或细胞治疗需至少8周洗脱期。
排除标准：
* 1. 需要治疗的活动性中枢神经系统（CNS）疾病。2. 未控制或具有临床意义的基线神经系统疾病（例如，未控制的癫痫发作或严重认知障碍/谵妄）、严重精神疾病或活动性物质滥用。
3. 未控制的感染，包括尽管接受适当治疗仍持续存在的菌血症/真菌血症、进行性侵袭性真菌感染，或伴终末器官疾病的未控制病毒感染。活动性结核。
4. 需要积极全身治疗的并发恶性肿瘤。5. 首次给药前14天内接受过细胞毒性化疗。首次给药前7-14天内接受过靶向抗白血病治疗。首次给药前14天内接受过放疗（局限性姑息性放疗除外）。既往接受过CD3衔接治疗。
6. 入组前6个月内接受过T细胞清除治疗（ATG、阿仑单抗或等效药物）7. 严重未控制的心血管疾病（例如，NYHA III/IV级心力衰竭、6个月内不稳定型心绞痛或MI、未控制的心律失常）。严重未控制的肺部疾病（例如，需要高流量吸氧或通气支持）。
8. 首次给药前7天内使用系统性皮质类固醇 >10 mg/天泼尼松等效剂量。
9. 过去12个月内需要系统性免疫抑制的活动性自身免疫性疾病。
10. 3个月内接受过异基因移植或存在活动性移植物抗宿主病（GVHD）。
11. 原发性免疫缺陷（需要持续医疗管理的先天性免疫缺陷病）。
12. 已知HIV感染。乙型肝炎：HBsAg阳性（慢性HBV感染）。丙型肝炎：抗-HCV阳性（HCV暴露）。
13. 妊娠或哺乳期 14. 已知先天性或获得性出血性疾病，包括血友病A/B或血管性血友病，或其他具有临床意义的凝血病 15. 对免疫治疗有严重过敏反应史
Inclusion Criteria:
* 1\. Adults (≥18 years) with
I. Pathologically confirmed acute myeloid leukemia (AML) according to WHO 2022 criteria. Relapsed or refractory AML, defined as either:
1. Refractory AML: Failure to achieve CR, CRh, or CRi after at least 2 courses of intensive induction therapy.
2. Relapsed AML: Recurrence after prior CR, CRh, or CRi, documented by one or more of the following: Bone marrow blasts \>5% by morphologic assessment; persistent reappearance of blasts in peripheral blood by morphologic assessment II. HR-MDS: Pathologically confirmed myelodysplastic syndrome (MDS) according to WHO 2022 criteria, with high-risk disease defined as IPSS-R high-risk or very high-risk (score \>4.5). Ineligible for allogeneic hematopoietic stem cell transplantation.
III. DLBCL post-CAR T: histologically confirmed DLBCL per WHO 2022 criteria and relapsed or refractory disease after prior CART therapy. Qualifying post-CAR T treatment failure must be documented at least 1 month after CAR T infusion and include no metabolic response, first metabolic progressive disease, or first relapse after prior response. Prior CART infusion must have occurred at least 1 month before screening. Participants must not be in partial metabolic response or complete metabolic response at screening and must have measurable disease on PET/CT (preferred) or CT/MRI, defined as at least 1 nodal lesion \>1.5 cm or at least 1 extranodal lesion \>1.0 cm; if PET is used, lesions must be FDG-avid and consistent with active lymphoma IV. Advanced solid tumors 2. Children (6 months-11 years) and adolescents (12-17 years) with R/R-AML.
1. Children and adolescent refractory AML: Bone marrow contains 1% blasts by multiparametic flow cytometry (MFC) at the end of 2 cycles of induction therapy
2. Children and adolescent relapsed AML: A single bone marrow sample showing 5% leukemic blasts by MFC, fluorescence in situ hybridization (FISH) testing or other molecular method, or a single bone marrow sample with at least two tests showing 1% blasts such as by MFC, karyotypic abnormality with at least one metaphase similar or identical to diagnosis, FISH abnormality identical to one present at diagnosis (above level of sensitivity of specific FISH probe) or polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion (e.g., fusion, mutation) identical to diagnosis and is quantifiably 1% 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or Karnofsky Performance Score (KPS) ≥50% 4. Adequate organ function: I. Hepatic: Serum AST/ALT ≤2.5×ULN and total bilirubin ≤1.5×ULN (≤3×ULN if Gilbert's syndrome) II. Renal: Serum creatinine ≤1.5×ULN; Calculated CrCl: ≥40 mL/min (Cockcroft-Gault \[adults\]; Schwartz formula \[adolescents\]; apply if serum creatinine is borderline) III. Cardiac: ejection fraction ≥ 50% and no evidence of pericardial effusion as determined by ECHO IV. Hematologic: WBC count must be ≤20 × 10⁹/L prior to the first dose of study treatment and before each dose in Cycle 1; patients with WBC \>20 × 10⁹/L may receive cytoreduction with hydroxyurea (up to 4 g/day) and/or leukapheresis per protocol to achieve this threshold, with hydroxyurea held ≥12-24 hours before each study treatment dose 5. Females of childbearing potential must have a negative serum or urine pregnancy test 6. Adults: written informed consent. Adolescents: written patient assent plus parental/guardian informed consent.
7\. Prior treatment with an investigational agent is permitted provided that at least 5 half-lives have elapsed and all treatment-related toxicities have resolved to Grade ≤1 (except alopecia). Prior T-cell engaging, checkpoint inhibitor, or cellular therapies require a minimum washout of 8 weeks.
Exclusion Criteria:
* 1\. Active central nervous system (CNS) disease requiring treatment. 2. Uncontrolled or clinically significant baseline neurologic disorder (e.g., uncontrolled seizures or severe cognitive impairment/delirium), significant psychiatric illness or active substance abuse.
3\. Uncontrolled infections including persistent bacteremia/fungemia despite appropriate therapy, progressive invasive fungal infection, or uncontrolled viral infection with end-organ disease. Active tuberculosis.
4\. Concurrent malignancy requiring active systemic therapy. 5. Cytotoxic chemotherapy within 14 days prior to first dose. Targeted anti-leukemic therapy within 7-14 days prior to first dose. Radiotherapy within 14 days prior to first dose (except limited-field palliative radiotherapy). Prior CD3-engaging therapy.
6\. T-cell depleting therapy (ATG, alemtuzumab, or equivalent) within 6 months prior to enrollment 7. Severe uncontrolled cardiovascular disease (e.g., NYHA class III/IV heart failure, unstable angina or MI within 6 months, uncontrolled arrhythmia). Severe uncontrolled pulmonary disease (e.g., requiring high-flow oxygen or ventilatory support).
8\. Systemic corticosteroids \>10 mg/day prednisone equivalent within 7 days prior to first dose.
9\. Active autoimmune disease requiring systemic immunosuppression within the past 12 months.
10\. Prior allogeneic transplant within 3 months or active graft-versus-host disease (GVHD).
11\. Primary immunodeficiency (congenital immunodeficiency disorder requiring ongoing medical management).
12\. Known HIV infection. Hepatitis B: HBsAg positive (chronic HBV infection). Hepatitis C: anti-HCV positive (HCV exposure).
13\. Pregnant or breastfeeding 14. Known congenital or acquired bleeding disorder, including hemophilia A/B or von Willebrand disease, or other clinically significant coagulopathy 15. History of severe allergic reaction to immunotherapy以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Phase 1: Safety and tolerability · Incidence and severity of treatment-emergent AEs (number and percentage) · 28 days；Phase 1: Safety and tolerability · Incidence of serious adverse events (number and percentage) · 28 days；Phase 1: Pharmacokinetics · 6 months；Phase 1: Safety and tolerability · Incidence of dose-limiting toxicities · 28 days；Phase 1: Determination of RP2D · Integrated assessment of safety, PK, PD and preliminary disease-specific evidence of biological activity (e.g., reduction in bone marrow blast percentage, peripheral blood blast clearance, hematologic recovery, or reduction in measurable tumor burden · 6 months；Phase 2a: Efficacy · Adult AML: Durable CR and durable CR+CRh (ELN criteria) · 12 months
次要终点：Phase 2a: Safety and tolerability；Phase 1: Preliminary Efficacy；Phase 1- Preliminary Efficacy；Phase 1- Preliminary Efficacy；Phase 1- Preliminary Efficacy；Phase 1- Preliminary Efficacy；Phase 1- Preliminary Efficacy；Phase 1- Preliminary Efficacy
A组：成人R/R AML和HR-MDS；VTRU200输注
成人DLBCL CAR-T治疗失败后；VTRU200输注
无治愈选择的青少年R/R AML（12-17岁）；VTRU200输注
RP2D扩展-成人R/R AML和HR-MDS；VTRU200输注
RP2D扩展：成人DLBCL CAR-T治疗失败后
RP2D扩展：无治愈选择的青少年R/R AML；VTRU200输注
RP2D扩展：成人实体瘤；VTRU200输注
RP2D扩展：儿童R/R AML（6个月-11岁）；VTRU200输注
关于本研究 这是VTRU200首次在人体中进行的研究。本研究的主要目的是找到VTRU200的安全剂量，并了解该药物在体内的表现。研究人员还将寻找其可能有助于治疗癌症的早期迹象。 VTRU200是一种实验性免疫疗法。它旨在帮助人体免疫系统发现并摧毁癌细胞，同时限制对健康细胞的影响。 与许多靶向单一蛋白的癌症治疗不同，VTRU200识别癌细胞上常见的应激信号。这些信号包括某些糖类（称为聚糖）和脂质（称为磷脂），它们存在于多种类型的癌细胞上，但在正常健康细胞上不常见。VTRU200还可附着于称为T细胞的免疫细胞，并帮助引导它们攻击癌细胞。 由于VTRU200靶向许多癌症共有的特征，即使癌细胞丢失或改变其他治疗所依赖的单个蛋白，它也可能继续发挥作用。 谁可以参加？ 本研究适用于患有某些血液癌症且在接受治疗后复发或对现有治疗无应答的人群。这些包括： 急性髓系白血病（AML） 较高危骨髓增生异常综合征（HR-MDS） 在CAR T细胞治疗后复发的弥漫性大B细胞淋巴瘤（DLBCL） 研究的后续部分也可能纳入患有AML的青少年和儿童。 研究期间会发生什么？ 参与者将通过静脉（静脉输注）接受VTRU200。 研究将首先给予小剂量，以帮助确定未来参与者的最安全剂量。如果这些剂量耐受良好，后续参与者可能接受更高剂量。 研究人员将： 密切监测参与者的副作用。 进行血液检测，以测量VTRU200如何在体内移动和排出。 测量免疫系统对治疗的反应。 检查癌症是否缩小、消失或保持受控。 如果参与者继续获益且未出现不可接受的副作用，他们可能接受多个治疗周期。 可能的获益是什么？ VTRU200可能对参与者有帮助，也可能没有帮助。从本研究中获得的信息可能有助于未来为患有这些癌症的人群开发新疗法。 可能的风险是什么？ 由于VTRU200是首次在人体中进行测试，并非所有副作用都已知。 可能的风险包括与免疫系统激活相关的反应、输注相关反应、实验室检查变化以及其他副作用。参与者将在整个研究期间受到密切监测，如果出现副作用，将可获得医疗照护。 简要研究描述 这是一项首次人体、开放标签的1/2a期研究，将评估VTRU200在复发或难治性急性髓系白血病（AML）、较高危骨髓增生异常综合征（HR-MDS）或弥漫性大B细胞淋巴瘤（DLBCL）患者接受CAR T细胞治疗后的安全性、耐受性、药代动力学、药效学、免疫原性和初步抗肿瘤活性。VTRU200是一种在研三特异性T细胞衔接器，可结合应激相关聚糖、磷脂酰丝氨酸和CD3，从而将T细胞重定向至癌细胞。1期剂量递增部分将确定推荐的2期剂量（RP2D），随后进行疾病特异性扩展队列，以进一步评估安全性和初步抗肿瘤活性。 为什么这项研究很重要？ 许多血液癌症最终会对现有治疗不再产生应答。癌细胞可以通过改变或丢失许多当前药物所靶向的蛋白质来逃逸治疗。 VTRU200旨在识别许多癌细胞共有的应激相关特征，而不是依赖单一蛋白质靶点。研究人员希望这种方法可能降低治疗耐药的机会，同时限制对健康细胞的损害。这项研究将有助于确定VTRU200是否可以安全给药，以及它是否显示出帮助难以治疗的血癌患者的早期迹象。
About this study This is the first study of VTRU200 in people. The main purpose of this study is to find a safe dose of VTRU200 and learn how the medicine behaves in the body. Researchers will also look for early signs that it may help treat cancer. VTRU200 is an experimental immunotherapy. It is designed to help the body's immune system find and destroy cancer cells while limiting effects on healthy cells. Unlike many cancer treatments that target a single protein, VTRU200 recognizes stress signals that are commonly found on cancer cells. These signals include certain sugars (called glycans) and fats (called phospholipids) that are present on many types of cancer cells but are uncommon on normal healthy cells. VTRU200 also attaches to immune cells called T cells and helps direct them to attack cancer cells. Because VTRU200 targets features that are shared by many cancers, it may continue to work even if cancer cells lose or change individual proteins that other treatments depend on. Who can take part? This study is for people with certain blood cancers that have come back after treatment or have not responded to available treatments. These include: Acute myeloid leukemia (AML) Higher-risk myelodysplastic syndromes (HR-MDS) Diffuse large B-cell lymphoma (DLBCL) that has returned after CAR T-cell therapy Later parts of the study may also include adolescents and children with AML. What will happen during the study? Participants will receive VTRU200 through a vein (intravenous infusion). The study will begin by giving small doses to help determine the safest dose for future participants. If those doses are well tolerated, later participants may receive higher doses. Researchers will: Monitor participants closely for side effects. Perform blood tests to measure how VTRU200 moves through and leaves the body. Measure how the immune system responds to treatment. Check whether the cancer shrinks, disappears, or remains under control. Participants may receive multiple treatment cycles if they continue to benefit and do not have unacceptable side effects. What are the possible benefits? VTRU200 may or may not help participants. Information learned from this study may help develop new treatments for people with these cancers in the future. What are the possible risks? Because VTRU200 is being tested in humans for the first time, not all side effects are known. Possible risks include reactions related to activation of the immune system, infusion-related reactions, laboratory test changes, and other side effects. Participants will be monitored closely throughout the study, and medical care will be available if side effects occur. Brief Study Description This first-in-human, open-label, Phase 1/2a study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of VTRU200 in participants with relapsed or refractory acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (HR-MDS), or diffuse large B-cell lymphoma (DLBCL) following CAR T-cell therapy. VTRU200 is an investigational trispecific T-cell engager that binds stress-associated glycans, phosphatidylserine, and CD3 to redirect T cells toward cancer cells. The Phase 1 dose-escalation portion will determine the recommended Phase 2 dose (RP2D), followed by disease-specific expansion cohorts to further evaluate safety and preliminary antitumor activity. Why is this research important? Many blood cancers eventually stop responding to available treatments. Cancer cells can escape therapy by changing or losing the proteins that many current medicines target. VTRU200 is designed to recognize stress-related features that many cancer cells share rather than relying on a single protein target. Researchers hope this approach may reduce the chance of treatment resistance while limiting damage to healthy cells. This study will help determine whether VTRU200 can be given safely and whether it shows early signs of helping people with difficult-to-treat blood cancers.
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