GSL Synthetase Inhibitor Eliglustat Combined With CD30 Target Immunotherapy for the Treatment of of CD30+ Lymphoma: an Open-Label, Randomized, Phase I/II Study
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
- Number of Subjects with treatment-related adverse events (AEs)
研究概览
简要总结
Targeted therapy against the CD30 molecule has achieved some progress in CD30-positive Hodgkin lymphoma, but its efficacy remains unsatisfactory. Previous studies have demonstrated that N-glycan modifications in the extracellular domain of target proteins can disrupt immune synapse formation with CAR-T cells. Our preliminary research has shown that ablation of N-glycans on CD30 enhances the anti-tumor effect of CD30-targeted therapy.It is hypothesized that Eliglustat, by inhibiting GSL synthesis,may potentiate the anti-tumor effect. Consequently,we designed and initiated a single-center, open-label phase I/II clinical study to evaluate the efficacy and feasibility of Eliglustat combined with CD30 targeted immunotherapy in patients with CD30-positive lymphoma. The primary endpoint of this study is the safety and efficacy of Eliglustat combined with CD30 targeted therapies.
详细描述
CD30-targeted therapies, including Brentuximab Vedotin (BV) and CD30-targeted CAR-T cells, have demonstrated limited efficacy in Hodgkin lymphoma,facing challenges such as the lack of durable responses with BV and low complete response (CR) rates with CD30 CAR-T cells. Existing research indicates that N-glycan modifications in the extracellular domain of target proteins may mediate resistance of tumor cells to CAR-T cell therapy.Our preliminary studies have demonstrated that disrupting the CD30 N-glycans in HL tumor cells enhances the anti-tumor effect of CD30-targeted therapy. Based on this, we hypothesize that the glucosylceramide synthase (GSL synthesis) inhibitor Eliglustat, by inhibiting GSL synthesis, may affect N-glycan structure of target proteins and consequently enhancing anti-tumor efficacy.
To further validate the role of Eliglustat in modulating anti-tumor therapy for CD30-positive lymphoma, we designed and initiated a single-center, open label phase I/II clinical study. This study aims to evaluate the efficacy and feasibility of Eliglustat combined with CD30 immunotherapy in patients with CD30-positive lymphoma.Primary Endpoints:1）safety and of Eliglustat combined with CD30 targeted therapies；2）CR rate (%) in the CAR-T cell plus Eliglustat treatment group; Progression-free survival (PFS) in the BV plus Eliglustat treatment group.Secondary Endpoints: 1)Other efficacy indicators (e.g., Objective Response Rate [ORR]) of Eliglustat combined with CD30- targeted molecular therapy; 2) Efficacy biomarkers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •18 to 75 years of age.
- •ECOG performance of less than
- •Subjects must have histological confirmation CD30+ lymphoma.
- •Patients must have at least one line of antitumor therapy
- •Life expectancy of at least 3 months.
- •Subjects with lymphoma must have at least one measureable lesion >1cm as defined by lymphoma response criteria.
- •Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to ≤ grade 1 toxicity.
- •Subjects with autologous hematopoietic stem-cell transplantation are eligible which must be more than 3 months.
- •Subjects must have adequate marrow, live, renal and heart functions.
排除标准
- •Participants with CD30- lymphoma.
- •CYP2D6 ultra-rapid metabolizers (URMs).
- •The patients is taking a CYP2D6 inhibitor and/or concomitantly with a strong or moderate CYP3A inhibitor.
- •Subjects with a history of severe hypersensitivity reactions to CD30 target immunotherapy.
- •History of allergy or intolerance to study drug components.
- •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.
- •Uncontrolled intercurrent 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.
- •Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
- •Previous or concurrent cancer within 3 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
- •Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
- •Vaccination within 30 days of study enrollment.
- •Active alimentary tract hemorrhage or history of alimentary tract hemorrhage in 1 month.
- •Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented
- •Being participating any other trials or withdraw within 4 weeks.
- •Unable to swallow and retain oral medication, malabsorption syndrome, conditions that significantly impair gastrointestinal function, total gastrectomy or small bowel resection, ulcerative colitis, symptomatic inflammatory bowel disease, partial or complete intestinal obstruction.
- •Researchers believe that other reasons are not suitable for clinical trials.
研究组 & 干预措施
Patients with CD30+ lymphoma
Eliglustat 63mg will be administered twice daily in patients who are CYP2D6 extensive metabolizers (EMs), or intermediate metabolizers (IMs), in the first 14 days and the following every other week until 24 weeks. For patients who still benefit from the trial, eliglustat 63mg will be administered twice daily every other week to 96 weeks.
CD30 target immunotherapy: Brentuximab Vedotin 1.2-1.8mg/kg day 1 Q21d; or CD30-targeting CAR-T Cell Therapy( Application should be in accordance with the specific instructions for each cell preparation).
干预措施: Eliglustat, CD30 target immunotherapy (Drug)
结局指标
主要结局
Number of Subjects with treatment-related adverse events (AEs)
时间窗: Up to 120 days after the last dose of study drugs]
Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0.
CR rate (CRR) in the CAR-T cell plus Eliglustat treatment group
时间窗: 12 months
The Complete Response Rate (CRR), as assessed by the investigator, is the proportion of all evaluable subjects who achieve a complete response.
Progression-free survival (PFS) in the BV plus Eliglustat treatment group.
时间窗: 2 years
Time from the date of first administration of the study drug to disease progression or death from any cause (any earliest date).
次要结局
- Objective Response Rate [ORR](12 months)
- CR rate (CRR) /Progression-free survival (PFS)based on CD30 expression level in tumor tissue.(12 months)
研究者
Han weidong
Director of Biotherapeutic Department
Chinese PLA General Hospital