A Phase 1, Open-Label, Single-Arm, Dose-Escalation, Investigator-Initiated Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of an In Vivo Circular RNA Chimeric Antigen Receptor (CAR) T Cell Therapy in Adult Participants With Relapsed or Refractory B-Cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Incidence and severity of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
This is an investigator-initiated, open-label, single-arm, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (PD), and preliminary efficacy of an in vivo circular RNA chimeric antigen receptor T cell in adult participants with R/R B-cell malignancies.
详细描述
This is an investigator-initiated, open-label, single-arm, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (PD), and preliminary efficacy of an in vivo circular RNA chimeric antigen receptor T cell in adult participants with R/R B-cell malignancies.
Investigational product (IP)will be explored across four dose levels (as described in the table below) in adult participants with R/R B-cell malignancies, including diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], Waldenström macroglobulinemia [WM], and marginal zone lymphoma (MZL).
The study consists of three periods: screening period, treatment period, and post-treatment follow-up period.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years, any gender.
- •Able to provide written informed consent.
- •Confirmed diagnosis of relapsed/refractory (R/R) CD19-positive B-cell malignancy, including:
- •Diffuse large B-cell lymphoma (DLBCL)
- •Follicular lymphoma (FL)
- •Mantle cell lymphoma (MCL)
- •Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL)
- •Waldenström macroglobulinemia (WM)
- •Marginal zone lymphoma (MZL)
- •ECOG performance status 0 or 1.and have archival tumor biopsy tissue and pathology report from the most recent relapse, or at least one palpable superficial tumor lesion at screening, and agree to biopsy/resection before the first dose of IP for disease confirmation.
- •Disease refractory to or relapsed after ≥ 2 prior lines of standard therapy, including required agents per disease subtype (e.g., anti-CD20, BTK inhibitors, chemotherapy, or ASCT if applicable).
- •Measurable disease per Lugano 2014 or iwCLL 2018 criteria.
- •LVEF ≥ 40% by echocardiogram.
- •For patients with prior CD19-targeted therapy, confirmed CD19 positivity at screening.
- •Women of childbearing potential (WOCBP) must have a negative serum pregnancy test and agree to use effective contraception during the study and for 6 months after last treatment.
- •Male patients with female partners must agree to use condoms, and partners must use effective contraception, during the study and for 6 months after last treatment.
排除标准
- •Prior anticancer therapy-related toxicities unresolved to baseline or ≤ Grade 1 (alopecia and peripheral neuropathy excepted).
- •Central nervous system (CNS) involvement by lymphoma.
- •Need for urgent treatment due to tumor mass effect or spinal cord compression.
- •Known hypersensitivity to any component of IP, including mRNA/LNP-based products.
- •History of another primary malignancy within the past 3 years, except adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ.
- •Active hepatitis B (HBsAg-positive with detectable HBV DNA) or hepatitis C (HCV RNA-positive) infection.
- •Active or prior HIV infection.
- •Uncontrolled active systemic infection requiring IV therapy within 1 week before dosing.
- •Active or history of acute/chronic GVHD.
- •Inadequate hematologic function (ANC <1.0×10⁹/L, Hb <70 g/L, PLT <50×10⁹/L, lymphocytes ≤0.5×10⁹/L) or coagulation abnormalities (INR/APTT ≥1.5×ULN).
- •Hepatic impairment (ALT/AST >2×ULN, or >3×ULN with hepatic involvement; bilirubin >2×ULN, unless Gilbert syndrome).
- •Renal impairment (CrCl <50 mL/min by Cockcroft-Gault).
- •Uncontrolled ischemic heart disease, NYHA Class III-IV heart failure, or baseline QTcF ≥450 ms (male) / ≥470 ms (female).
- •Severe psychiatric disorder history.
- •Pregnancy or breastfeeding.
- •Received prohibited treatments within 4 weeks before dosing, including high-dose corticosteroids (>20 mg prednisone equivalent daily), chemotherapy, immunosuppressive therapy, prior CAR-T or other gene/cell therapy, or T-cell engagers.
- •Participation in another clinical study with investigational therapy within 3 months before dosing, or prior participation in cell/gene therapy trials.
- •Planned radiotherapy within 6 weeks after screening (unless only non-irradiated PET-positive lesions remain eligible).
- •Planned allogeneic HSCT within 90 days after screening.
- •Significant comorbidities or unstable medical conditions deemed by the investigator to compromise safety or study compliance.
结局指标
主要结局
Incidence and severity of treatment-emergent adverse events (TEAEs)
时间窗: From first dose of investigational product (IP) up to the end of study (Week 24 / EOS)
Count the number and percentage of participants with treatment-emergent adverse events (TEAEs). The severity of all TEAEs is graded according to CTCAE Version 5.0.
Incidence of dose-limiting toxicities (DLTs)
时间窗: 28 days after the first dose of IP
Count the number and percentage of participants who experience at least one dose-limiting toxicity (DLT) as defined by the study protocol.
次要结局
- Overall Response Rate (ORR)(From Week 4 through Week 24 (EOS))
- Time to Response (TTR)(Up to Week 24 (EOS))
- Duration of Response (DOR)(Up to Week 48 survival follow-up)
- Event-Free Survival (EFS)(Up to Week 48 survival follow-up)
- Progression-Free Survival (PFS)(Up to Week 48 survival follow-up)
- Absolute count and percentage of CAR-expressing positive immune cells(From pre-dose baseline through Week 24 (EOS))
- CD7 expression kinetics on immune cells(From pre-dose baseline through Week 24 (EOS))
- Overall Survival (OS)(Up to Week 48 survival follow-up)
- PK parameters of IP components(From pre-dose baseline through Week 24 (EOS))
- Incidence of immunogenicity to IP(From pre-dose baseline through Week 24 (EOS))
- Correlation between cytokine levels and treatment response adverse events(TRAE)(From pre-dose baseline through Week 24 (EOS))