Phase I/II Trial of Allograft Engineered MSC-IFNα Combined With or Without Immunochemotherapy for Locally Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Incidence of treatment related adverse events(TRAE)
研究概览
简要总结
The goal of this first-in-human, single-center, prospective, open-label, phase 1/2 trial is to evaluate the safety and efficacy of the interferon alpha expressing mesenchymal stromal cells (MSC-IFNα) combined with or without immunochemotherapy in patients with locally advanced/metastatic solid tumors. The main questions aimed to answer are 1) to evaluate the safety and feasibility of MSC-IFNα in the treatment of locally advanced/metastatic solid tumors;2) to evaluate the anti-tumor effects of the MSC-IFNα combined with or without immunochemotherapy in the treatment of locally advanced/metastatic solid tumors; 3) to evaluate the pharmacokinetics/pharmacodynamics of MSC-IFNα and related immune effector cells.
详细描述
[Introduction] Mesenchymal Stromal Cells (MSCs) have been shown to home to the sites of injury or damage and secrete immunomodulatory factors. This feature makes MSCs an ideal carrier to deliver drugs or cytokines to the tumor microenvironment (TME) and therefore have a potential therapeutic role in cancer treatment.
Interferon(IFN) has been widely used for cancer treatment for its pleiotropic antitumor effects. IFN receptor signals mediate intrinsic and extrinsic effects on tumor cells and the TME, including tumor-infiltrating lymphocytes as well as tumor-associated stroma. Additionally, IFNs also exert direct intrinsic antitumor effects including inhibition of cell proliferation by inducing cell cycle arrest, cell death via apoptosis and ferroptosis, cell differentiation, and senescence, thus acting as a tumor suppressor. Accumulating evidence suggests that IFNs play critical roles in cancer immunotherapy, however, the variations in responses and the adverse effects have reduced their popularity in clinical applications. New IFN-based strategies should be considered as a high priority.
Our team has developed a protocol to genetically express IFNα in bone marrow-derived MSCs. In vitro and in vivo experiments have shown that the MSC-IFNα cells possess a potent ability to home to TME and to secret IFNα. By changing TME, MSC-IFNα induces strong anti-tumor effects in several cancer types in animal models. In addition, preliminary data also indicated that the combination of IFNα-MSCs with chemotherapy and/or programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)blockade may bring an even stronger anti-tumor immunity.
In this study, by producing MSC-IFNα cells with human umbilical-cord-derived mesenchymal stromal cells (hUC-MSCs, passage 5 to passage 7), the investigators plan to conduct a first-in-human, prospective, open-label, phase 1/2 trial to evaluate the safety and efficacy of MSC-IFNα combined with or without immunochemotherapy in patients with locally advanced/metastatic solid tumors.
[Study design] Phase 1 Arm 1. Safety evaluation of MSC-IFNα monotherapy A total of 3-9 subjects will be enrolled for the safety evaluation of MSC-IFNα monotherapy. All treatment-related adverse events (TRAE) will be recorded for at least 28 days after cell infusion. Subjects with any grade 3-4 TRAE that lasts for 7 days or more within the 28 days after infusion will be determined as treatment intolerance (TI).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age from 18 to 75 years with estimated life expectancy >3 months.
- •Histopathological confirmed locally advanced or metastatic solid tumors including, but not limited to, lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, and sarcomas.
- •Failed to at least first-line and second-line treatments or initially diagnosed locally advanced/metastatic solid tumors that have no National Comprehensive Cancer Network(NCCN) guideline-recommended therapy.
- •Have at least one measurable target lesion.
- •Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study.
- •Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 to 2 at the time of enrollment.
- •Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
- •Previous treatment with anti-PD-1/PD-L1 antibodies is allowed.
- •Ability to understand and sign a written informed consent document.
- •Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and up to 90 days after the last dose of the drug.
排除标准
- •Active, known, or suspected autoimmune diseases.
- •Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms, and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
- •Subjects are being treated with either corticosteroid (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
- •History of psychiatric disorders including depression, suicidality, and mania.
- •History of allergy or intolerance to study drug components.
- •Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
- •Uncontrolled concurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia), or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
- •History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
- •Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before enrollment, and a negative result must be documented.
- •Previous or concurrent cancer within 3 years prior to treatment start.
研究组 & 干预措施
MSC-IFNα monotherapy
Subjects will be enrolled for safety evaluation of MSC-IFNα monotherapy. Subjects will receive MSC-IFNα infusion from a dose of 2×10^6 cells/kg 1-4 times every 4-6 weeks. All treatment-related adverse events(TRAE) will be recorded for at least 28 days after the cell infusion.
干预措施: MSC-IFNα (Biological)
MSC-IFNα combined with immunochemotherapy
Subjects will be enrolled and received MSC-IFNα combined with immunochemotherapy, namely nab-paclitaxel (125 mg/m2, 5 days before infusion), cyclophosphamide (200 mg/m2,4 days before infusion) and anti-PD-1 antibody (200mg, 7 days after infusion) for 4 cycles.
From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1 antibody every 4-6 weeks for another 4 cycles for efficacy consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody alone every 3 weeks for another 4 cycles for efficacy maintenance.
干预措施: MSC-IFNα (Biological)
MSC-IFNα combined with immunochemotherapy
Subjects will be enrolled and received MSC-IFNα combined with immunochemotherapy, namely nab-paclitaxel (125 mg/m2, 5 days before infusion), cyclophosphamide (200 mg/m2,4 days before infusion) and anti-PD-1 antibody (200mg, 7 days after infusion) for 4 cycles.
From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1 antibody every 4-6 weeks for another 4 cycles for efficacy consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody alone every 3 weeks for another 4 cycles for efficacy maintenance.
干预措施: Nab paclitaxel (Drug)
MSC-IFNα combined with immunochemotherapy
Subjects will be enrolled and received MSC-IFNα combined with immunochemotherapy, namely nab-paclitaxel (125 mg/m2, 5 days before infusion), cyclophosphamide (200 mg/m2,4 days before infusion) and anti-PD-1 antibody (200mg, 7 days after infusion) for 4 cycles.
From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1 antibody every 4-6 weeks for another 4 cycles for efficacy consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody alone every 3 weeks for another 4 cycles for efficacy maintenance.
干预措施: Cyclophosphamide (Drug)
MSC-IFNα combined with immunochemotherapy
Subjects will be enrolled and received MSC-IFNα combined with immunochemotherapy, namely nab-paclitaxel (125 mg/m2, 5 days before infusion), cyclophosphamide (200 mg/m2,4 days before infusion) and anti-PD-1 antibody (200mg, 7 days after infusion) for 4 cycles.
From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1 antibody every 4-6 weeks for another 4 cycles for efficacy consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody alone every 3 weeks for another 4 cycles for efficacy maintenance.
干预措施: Anti-PD-1 monoclonal antibody (Drug)
结局指标
主要结局
Incidence of treatment related adverse events(TRAE)
时间窗: Up to 12 months since the initiation of MSC-IFNα therapy
Treatment related adverse events (TRAE) are defined as any medical events since the initiation of MSC-IFNα therapy. All TRAEs will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE V5.0)
次要结局
- Objective response rate (ORR) of MSC-IFNα combined with or without immunochemotherapy(Up to 12 months since the initiation of MSC-IFNα therapy)
- Progression free survival (PFS) of MSC-IFNα combined with or without immunochemotherapy(Up to 12 months since the initiation of MSC-IFNα therapy)
- Duration of response(DOR) of MSC-IFNα combined with or without immunochemotherapy(Up to 12 months since the initiation of MSC-IFNα therapy)
- Overall survival (OS) of MSC-IFNα combined with or without immunochemotherapy(Up to 12 months since the initiation of MSC-IFNα therapy)
研究者
Han weidong
Director of Biotherapeutic Department
Chinese PLA General Hospital