肿瘤细胞治疗研究
英文原题：A Vaccine (VSV-hIFNβ-NIS) With or Without Cyclophosphamide and Combinations of Ipilimumab, Nivolumab, and Cemiplimab in Treating Relapsed or Refractory Multiple Myeloma, Acute Myeloid Leukemia or Lymphoma
这是一项 I 期注册临床试验，评估人源细胞治疗用于非霍奇金淋巴瘤、肿瘤、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：招募中。计划入组 99 例。试验地点：美国 · 斯科茨代尔、罗切斯特（共 2 个中心）。登记号：NCT03017820。
不限性别 · ≥ 18 Years
纳入标准： * 年龄 >= 18 岁 * 符合以下条件的复发或难治性疾病： * A、B、C 或 D 组：既往接受过免疫调节酰亚胺药物 (IMID)、蛋白酶体抑制剂和烷化剂治疗的多发性骨髓瘤 (MM) * 除 D 组外的所有组：以下组织学类型的复发性外周 T 细胞淋巴瘤 (PTCL)：外周 T 细胞淋巴瘤-非特指型 (PTCL-NOS)；血管免疫母细胞性 T 细胞淋巴瘤 (AITL)、间变性大细胞淋巴瘤 (ALCL) 和蕈样肉芽肿 (MF)。患者必须标准治疗失败，对于 PTCL-NOS、AITL 和 ALCL，必须大剂量治疗联合自体干细胞移植失败或不适合接受该治疗 * 仅 B 组和 C 组：任何分期的 B 细胞淋巴瘤（伯基特淋巴瘤除外），或组织细胞/树突状细胞肿瘤 (HCN) * 仅 E 组：以下组织学类型的复发性外周 T 细胞淋巴瘤 (PTCL)：外周 T 细胞淋巴瘤-非特指型 (PTCL-NOS)；间变性大细胞淋巴瘤 (ALCL) 和蕈样肉芽肿 (MF) * 仅 F 组：低肿瘤负荷 B 细胞淋巴瘤（伯基特淋巴瘤除外）扩展队列 * 仅 G 组：低肿瘤负荷外周 T 细胞淋巴瘤 (PTCL) 扩展队列 * 丙氨酸氨基转移酶 (ALT) 和天冬氨酸氨基转移酶 (AST) =< 2 倍正常值上限 (ULN)（注册前 =< 15 天内获得） * 肌酐 =< 2.0 mg/dL（注册前 =< 15 天内获得） * 直接胆红素 =< 1.5 x ULN（注册前 =< 15 天内获得） * 国际标准化比值 (INR)/凝血酶原时间 (PT) 和活化部分凝血活酶时间 (aPTT) =< 1.5 x ULN（注册前 =< 15 天内获得） * 如有基线肝病，Child Pugh 评分不超过 A 级（注册前 =< 15 天内获得） * 有生育能力者妊娠试验阴性（注册前 =< 15 天内获得） * 仅限多发性骨髓瘤：符合以下至少一项定义的多发性骨髓瘤可测量疾病： * 蛋白电泳检测血清单克隆蛋白 >= 1.0 g/dL * 24 小时尿电泳检测尿单克隆蛋白 >= 200 mg * 血清免疫球蛋白游离轻链 >= 10 mg/dL 且血清免疫球蛋白 kappa 与 lambda 游离轻链比值异常 * 仅限多发性骨髓瘤：中性粒细胞绝对计数 (ANC) >= 1000/uL（注册前 =< 14 天内获得） * 仅限多发性骨髓瘤：血小板 (PLT) >= 100,000/uL（注册前 =< 14 天内获得） * 仅限多发性骨髓瘤：血红蛋白 >= 8.5 g/dl（注册前 =< 14 天内获得） * 仅限 AML：无 ANC 限制（注册前 =< 14 天内获得） * 仅限 AML：PLT >= 10,000/uL（允许通过输血使血小板 >= 10,000）（注册前 =< 14 天内获得） * 仅限 AML：血红蛋白 >= 7.5 g/dl（注册前 =< 14 天内获得） * 仅限AML：无未代偿的弥散性血管内凝血（DIC-按国际血栓与止血学会[ISTH]标准诊断） * 仅限TCL/BCL：ANC >= 1,000/uL（注册前 =< 14天内获得） * 仅限TCL/BCL：PLT >= 100,000/uL（注册前 =< 14天内获得） * 仅限TCL/BCL：血红蛋白 >= 8.5 g/dl（注册前 =< 14天内获得） * 仅限TCL/BCL：通过CT或磁共振成像（MRI）可测量疾病：必须至少有一个单径 > 2 cm的病灶或血液中肿瘤细胞 > 5 x 10^9/L；注：如果皮肤病灶至少一个径 > 2 cm，并用尺子拍照且图像可在病历中获得，则可以使用 * 仅限HCN：ANC >= 1,000/uL，注册前 =< 15天内获得 * 仅限HCN：PLT >= 100,000/uL，注册前 =< 15天内获得 * 仅限HCN：血红蛋白 >= 8.0 g/dl，注册前 =< 15天内获得 * 仅限HCN：通过CT或MRI可测量疾病：必须至少有一个单径 >= 1.5 cm的病灶或血液中肿瘤细胞 >5 x10^9/L。注：如果皮肤病灶至少一个径 >= 1.5 cm，并用尺子拍照且图像可在病历中获得，则可以使用 * 无活动性中枢神经系统（CNS）受累；注：入组前腰椎穿刺不是强制性的 * 能够提供书面知情同意 * 愿意返回Mayo Clinic进行随访 * 预期寿命 >= 12周 * 东部肿瘤协作组（ECOG）体能状态（PS）0、1或2 * 愿意提供强制性生物标本用于研究目的 排除标准： * 存在并可接受治愈性治疗 * 未控制的感染 * 活动性结核或肝炎，或慢性肝炎 * 以下任何既往治疗： * 化疗（IMIDs、烷化剂、蛋白酶体抑制剂）注册前 =< 2周 * 免疫治疗（单克隆抗体）注册前 =< 4周 * 在AML或TCL情况下，实验性药物在末次给药后4个半衰期内 * 纽约心脏协会分级III或IV级，已知有症状的冠状动脉疾病，或系统回顾中有冠状动脉疾病症状，或已知心律失常（心房颤动或室上性心动过速[SVT]） * 活动性CNS疾病或癫痫发作疾病或已知CNS疾病或神经系统症状；在AML情况下，通过腰椎穿刺或神经影像学检测到的活动性CNS受累（仅在临床有指征时进行） * 人类免疫缺陷病毒（HIV）检测阳性结果或其他免疫缺陷或免疫抑制 * 其他同时进行的化疗、免疫治疗、放疗，或任何被认为属于研究性治疗的辅助治疗（用于非美国食品药品监督管理局[FDA]批准的适应症且处于研究调查背景下）； * 注：在AML中，允许在整个治疗方案期间同时使用羟基脲以帮助控制增殖性计数； * 注：在TCL中，患者可使用局部润肤剂或皮质类固醇、醋酸浸泡等以控制瘙痒和预防感染；不允许使用局部化疗（不允许使用局部氮芥） * 以下任何一项，因为本研究涉及一种研究性药物，其对新陈代谢、致突变和致畸效应对发育中的胎儿和新生儿尚不明确： * 孕妇或不愿使用有效避孕措施的育龄妇女 * 哺乳期妇女 * 在与任何女性发生性行为时不愿使用避孕套（即使已接受过输精管切除术）的男性，在服药期间及停止治疗后4周内 * 仅限AML：当前存在弥散性血管内凝血（DIC） * 仅限A组（低肿瘤负荷）的额外排除标准： * 诊断为AML * 仅限多发性骨髓瘤：浆细胞 > 25% 或浆细胞瘤最大直径 > 5cm * 仅限淋巴瘤或HCN：任何肿块 >5cm * 诊断为伯基特淋巴瘤 * 仅限B组（高肿瘤负荷）的额外排除标准： * 诊断为AML * 诊断为伯基特淋巴瘤 * 仅限C组（联合环磷酰胺）的额外排除标准： * 诊断为AML * 诊断为伯基特淋巴瘤 * 仅限E组（联合CEMIPLIMAB）的额外排除标准： * 诊断为AML * 诊断为AITL * 仅限F组（BCL扩增队列）的额外排除标准： * 诊断为伯基特淋巴瘤 * 仅限G组（PTCL扩增队列）的额外排除标准： * 诊断为皮肤TCL
Inclusion Criteria: * Age \>= 18 years * Relapsed or refractory disease as follows: * Groups A, B, C or D: Multiple myeloma (MM) previously treated with an immunomodulatory imide drug (IMID), a proteosome inhibitor, and an alkylating agent * All Groups except D: Relapsed peripheral T-cell lymphoma (PTCL) of the following histologies: peripheral T-cell lymphoma-NOS (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell (ALCL), and mycosis fungoides (MF). Patients should have failed standard therapy and in the case of PTCL-NOS, AITL, and ALCL either have failed or be ineligible for high-dose therapy with autologous stem cell transplant * Group B and C only: B-cell lymphoma (other than Burkitt's lymphoma), or histiocytic/dendritic cell neoplasms (HCN) at any stage * Group E only: Relapsed peripheral T-cell lymphoma (PTCL) of the following histologies: peripheral T-cell lymphoma-NOS (PTCL-NOS); anaplastic large cell (ALCL), and mycosis fungoides (MF) * Group F only: Expansion Cohort for B-cell lymphoma (other than Burkitt's lymphoma) with low tumor burden * Group G only: Expansion Cohort for peripheral T cell lymphoma (PTCL) with low tumor burden * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2 times upper limit of normal (ULN) (obtained =\< 15 days prior to registration) * Creatinine =\< 2.0 mg/dL (obtained =\< 15 days prior to registration) * Direct bilirubin =\< 1.5 x ULN (obtained =\< 15 days prior to registration) * International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (obtained =\< 15 days prior to registration) * If baseline liver disease, Child Pugh score not exceeding class A (obtained =\< 15 days prior to registration) * Negative pregnancy test for persons of child-bearing potential (obtained =\< 15 days prior to registration) * FOR MULTIPLE MYELOMA ONLY: Measurable disease of multiple myeloma as defined by at least ONE of the following: * Serum monoclonal protein \>= 1.0 g/dL by protein electrophoresis * \>= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis * Serum immunoglobulin free light chain \>= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio * FOR MULTIPLE MYELOMA ONLY: Absolute neutrophil count (ANC) \>= 1000/uL (obtained =\< 14 days prior to registration) * FOR MULTIPLE MYELOMA ONLY: Platelet (PLT) \>= 100,000/uL (obtained =\< 14 days prior to registration) * FOR MULTIPLE MYELOMA ONLY: Hemoglobin \>= 8.5 g/dl (obtained =\< 14 days prior to registration) * FOR AML ONLY: No ANC restriction (obtained =\< 14 days prior to registration) * FOR AML ONLY: PLT \>= 10,000/uL (transfusion to get platelets \>= 10,000 is allowed) (obtained =\< 14 days prior to registration) * FOR AML ONLY: Hemoglobin \>= 7.5 g/dl (obtained =\< 14 days prior to registration) * FOR AML ONLY: Absence of uncompensated disseminated intravascular coagulation (DIC- as diagnosed by standard International Society on Thrombosis and Hemostasis \[ISTH\] criteria) * FOR TCL/BCL ONLY: ANC \>= 1,000/uL (obtained =\< 14 days prior to registration) * FOR TCL/BCL ONLY: PLT \>= 100,000/uL (obtained =\< 14 days prior to registration) * FOR TCL/BCL ONLY: Hemoglobin \>= 8.5 g/dl (obtained =\< 14 days prior to registration) * FOR TCL/BCL ONLY: Measurable disease by CT or magnetic resonance imaging (MRI): must have at least one lesion that has a single diameter of \> 2 cm or tumor cells in the blood \> 5 x 10\^9/L; NOTE: skin lesions can be used if the area is \> 2 cm in at least one diameter and photographed with a ruler and the images are available in the medical record * FOR HCN ONLY: ANC \>= 1,000/uL obtained =\< 15 days prior to registration * FOR HCN ONLY: PLT \>= 100,000/uL obtained =\< 15 days prior to registration * FOR HCN ONLY: Hemoglobin \>= 8.0 g/dl obtained =\< 15 days prior to registration * FOR HCN ONLY: Measurable disease by CT or MRI: Must have at least one lesion that has a single diameter of \>= 1.5 cm or tumor cells in the blood \>5 x10\^9/L. NOTE: Skin lesions can be used if the area is \>= 1.5 cm in at least one diameter and photographed with a ruler and the images are available in the medical record * Absence of active central nervous system (CNS) involvement; NOTE: pre-enrollment lumbar puncture not mandatory * Ability to provide written informed consent * Willingness to return to Mayo Clinic for follow-up * Life expectancy \>= 12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 * Willing to provide mandatory biological specimens for research purposes Exclusion Criteria: * Availability of and patient acceptance of curative therapy * Uncontrolled infection * Active tuberculosis or hepatitis, or chronic hepatitis * Any of the following prior therapies: * Chemotherapy (IMIDs, alkylating agents, proteosome inhibitors) =\< 2 weeks prior to registration * Immunotherapy (monoclonal antibodies) =\< 4 weeks prior to registration * Experimental agent in case of AML or TCL within 4 half-lives of the last dose of the agent * New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia \[SVT\]) * Active CNS disorder or seizure disorder or known CNS disease or neurologic symptomatology; in case of AML active CNS involvement as detected by lumbar puncture or neuro-imaging (only to be done if clinically indicated) * Human immunodeficiency virus (HIV) positive test result or other immunodeficiency or immunosuppression * Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (used for a non-Food and Drug Administration \[FDA\] approved indication and in the context of a research investigation); * NOTE: in AML, the concurrent use of hydroxyurea to help control proliferative counts is allowed throughout the treatment protocol; * NOTE: in TCL, patients may use topical emollients or corticosteroids, acetic acid soaks, etc. to control pruritus and prevent infection; no topical chemotherapy is allowed (no topical nitrogen mustard) * Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: * Pregnant women or women of reproductive ability who are unwilling to use effective contraception * Nursing women * Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment * AML ONLY: Current disseminated intravascular coagulopathy (DIC) * ADDITIONAL EXCLUSION CRITERIA FOR GROUP A (LOW TUMOR BURDEN) ONLY: * Diagnosis of AML * Multiple myeloma only: \> 25% plasma cells or plasmacytoma \> 5cm in largest diameter * Lymphoma or HCN only: Any mass \>5cm * Diagnosis of Burkitt's lymphoma * ADDITIONAL EXCLUSION CRITERIA FOR GROUP B (HIGH TUMOR BURDEN) ONLY: * Diagnosis of AML * Diagnosis of Burkitt's lymphoma * ADDITIONAL EXCLUSION CRITERIA FOR GROUP C (COMBINATION WITH CYCLOPHOSPHAMIDE) ONLY: * Diagnosis of AML * Diagnosis of Burkitt's lymphoma * ADDITIONAL EXCLUSION CRITERIA FOR GROUP E (COMBINATION WITH CEMIPLIMAB) ONLY: * Diagnosis of AML * Diagnosis of AITL * ADDITIONAL EXCLUSION CRITERIA FOR GROUP F (BCL EXPANSION COHORT) ONLY: * Diagnosis of Burkitt's lymphoma * ADDITIONAL EXCLUSION CRITERIA FOR GROUP G (PTCL EXPANSION COHORT) ONLY: * Diagnosis of cutaneous TCL
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：Incidence of adverse events of grade 3 or higher · Assessed by the Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by cohort and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence. · Up to 2 years
次要终点：Clinical response；Progression-free survival；Overall survival
** A组不再入组 ** 随修正案10于2025年9月18日关闭。
** B组不再入组 ** 随修正案11于2026年5月21日关闭
** C组不再入组 ** 随修正案10于2025年9月18日关闭。
** D组不再入组 ** 随修正案10于2025年9月18日关闭。
PTCL患者在第-3天接受cemiplimab IV输注30分钟，并在第1天接受VSV-hIFNβ-NIS IV输注30-60分钟，前提是无疾病进展或不可接受的毒性。患者可在第2-6天口服ruxolitinib以进行症状管理。患者还在基线时以及之后根据临床指征接受PET/CT、活检，并在整个研究期间采集血液、颊细胞和尿液样本。患者在筛选期间接受超声心动图或MUGA扫描，并在研究期间对影像阳性区域进行可选活检。
BCL患者在第1天接受VSV-IFNbeta-NIS IV输注30分钟，并在第2-6天口服ruxolitinib，前提是无疾病进展或不可接受的毒性。患者还在筛选期间以及之后根据临床指征接受PET/CT、骨髓穿刺和活检、肿瘤或淋巴结活检，并在整个研究期间采集血液、颊细胞和尿液。患者在筛选期间接受超声心动图或MUGA扫描，并在研究期间对影像阳性区域进行可选活检。
PTCL患者在第1天接受VSV-IFNbeta-NIS IV输注30分钟，并在第2-6天口服ruxolitinib，前提是无疾病进展或不可接受的毒性。患者还在筛选期间以及之后根据临床指征接受PET/CT、骨髓穿刺和活检、肿瘤或淋巴结活检，并在整个研究期间采集血液、颊细胞和尿液。患者在筛选期间接受超声心动图或MUGA扫描，并在研究期间对影像阳性区域进行可选活检。
这项I期试验研究VSV-hIFNβ-NIS疫苗联合或不联合环磷酰胺，以及联合伊匹木单抗、纳武利尤单抗和西米普利单抗组合，在治疗经过一段时间改善后复发（relapsed）或对治疗无反应（refractory）的多发性骨髓瘤、急性髓系白血病或淋巴瘤患者中的最佳剂量和副作用。VSV-IFNβ-NIS是水疱性口炎病毒（也称为VSV）的一种改造版本。这种病毒可以引起感染，当它引起感染时，通常感染猪、牛或马，但不感染人类。本研究中使用的VSV已经过改造，添加了两个额外的基因（DNA片段）。第一个基因产生一种称为NIS的蛋白质，该蛋白质被插入VSV中。NIS通常存在于甲状腺（颈部的一个小腺体）中，帮助身体浓缩碘。拥有这个额外的基因将使得追踪病毒在体内（哪些器官）的去向成为可能。第二个添加的是人干扰素β（β）或hIFNβ的基因。干扰素是一种天然抗病毒蛋白，旨在保护正常健康细胞免受病毒感染。VSV对干扰素的作用非常敏感。许多肿瘤细胞已经丧失了产生或响应干扰素的能力。因此，被VSV-IFNβ-NIS感染的肿瘤细胞产生干扰素将保护正常细胞，但不保护肿瘤细胞。带有这两个额外片段的VSV被称为VSV-IFNβ-NIS。环磷酰胺属于一类称为烷化剂的药物。它通过损伤细胞DNA起作用，并可能杀死癌细胞。它也可能降低身体的免疫反应。使用单克隆抗体（如伊匹木单抗、纳武利尤单抗和西米普利单抗）的免疫治疗可能帮助身体的免疫系统攻击癌症，并可能干扰肿瘤细胞生长和扩散的能力。给予VSV-IFNβ-NIS联合或不联合环磷酰胺以及伊匹木单抗、纳武利尤单抗和西米普利单抗的组合，可能在治疗复发性外周T细胞淋巴瘤患者中安全有效。
This phase I trial studies the best dose and side effects of the VSV-hIFNβ-NIS vaccine with or without cyclophosphamide and combinations of ipilimumab, nivolumab, and cemiplimab in treating patients with multiple myeloma, acute myeloid leukemia or lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). VSV-IFNβ-NIS is a modified version of the vesicular stomatitis virus (also called VSV). This virus can cause infection and when it does it typically infects pigs, cattle, or horses but not humans. The VSV used in this study has been altered by having two extra genes (pieces of DNA) added. The first gene makes a protein called NIS that is inserted into the VSV. NIS is normally found in the thyroid gland (a small gland in the neck) and helps the body concentrate iodine. Having this additional gene will make it possible to track where the virus goes in the body (which organs). The second addition is a gene for human interferon beta (β) or hIFNβ. Interferon is a natural anti-viral protein, intended to protect normal healthy cells from becoming infected with the virus. VSV is very sensitive to the effect of interferon. Many tumor cells have lost the capacity to either produce or respond to interferon. Thus, interferon production by tumor cells infected with VSV-IFNβ-NIS will protect normal cells but not the tumor cells. The VSV with these two extra pieces is referred to as VSV-IFNβ-NIS. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Immunotherapy with monoclonal antibodies, such as ipilimumab, nivolumab, and cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving VSV-IFNβ-NIS with or without cyclophosphamide and combinations of ipilimumab, nivolumab, and cemiplimab may be safe and effective in treating patients with recurrent peripheral T-cell lymphoma.
MEMBER ACCOUNT
登录成功会直接打开下一页。
