Lymphoma, B-Cell Refractory
Conditions
Brief summary
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.
Detailed description
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.
Interventions
In Vivo Circular RNA Chimeric Antigen Receptor (CAR) T Cell Therapy
Sponsors
Ruijin Hospital
RiboX Therapeutics Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years, any gender. 2. Able to provide written informed consent. 3. 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) 4. 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. 5. 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). 6. Measurable disease per Lugano 2014 or iwCLL 2018 criteria. 7. LVEF ≥ 40% by echocardiogram. 8. For patients with prior CD19-targeted therapy, confirmed CD19 positivity at screening. 9. 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. 10. 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.
Exclusion criteria
1. Prior anticancer therapy-related toxicities unresolved to baseline or ≤ Grade 1 (alopecia and peripheral neuropathy excepted). 2. Central nervous system (CNS) involvement by lymphoma. 3. Need for urgent treatment due to tumor mass effect or spinal cord compression. 4. Known hypersensitivity to any component of IP, including mRNA/LNP-based products. 5. History of another primary malignancy within the past 3 years, except adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ. 6. Active hepatitis B (HBsAg-positive with detectable HBV DNA) or hepatitis C (HCV RNA-positive) infection. 7. Active or prior HIV infection. 8. Uncontrolled active systemic infection requiring IV therapy within 1 week before dosing. 9. Active or history of acute/chronic GVHD. 10. 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). 11. Hepatic impairment (ALT/AST \>2×ULN, or \>3×ULN with hepatic involvement; bilirubin \>2×ULN, unless Gilbert syndrome). 12. Renal impairment (CrCl \<50 mL/min by Cockcroft-Gault). 13. Uncontrolled ischemic heart disease, NYHA Class III-IV heart failure, or baseline QTcF ≥450 ms (male) / ≥470 ms (female). 14. Severe psychiatric disorder history. 15. Pregnancy or breastfeeding. 16. 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. 17. Participation in another clinical study with investigational therapy within 3 months before dosing, or prior participation in cell/gene therapy trials. 18. Planned radiotherapy within 6 weeks after screening (unless only non-irradiated PET-positive lesions remain eligible). 19. Planned allogeneic HSCT within 90 days after screening. 20. Significant comorbidities or unstable medical conditions deemed by the investigator to compromise safety or study compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 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. |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response (TTR) | Up to Week 24 (EOS) | Evaluate the time interval from the first IP infusion to the first documented CR or PR. |
| Duration of Response (DOR) | Up to Week 48 survival follow-up | Evaluate the time interval from the first documented CR or PR to the first documented progressive disease (PD) or all-cause death, whichever occurs first. |
| Event-Free Survival (EFS) | Up to Week 48 survival follow-up | Evaluate the time interval from the first IP infusion to the first documented PD, relapse, initiation of new anti-lymphoma therapy, or all-cause death, whichever occurs first. |
| Progression-Free Survival (PFS) | Up to Week 48 survival follow-up | Evaluate the time interval from the first IP infusion to the first documented PD or all-cause death, whichever occurs first. |
| Absolute count and percentage of CAR-expressing positive immune cells | From pre-dose baseline through Week 24 (EOS) | Detect and analyze the absolute count and percentage of CAR-expressing positive immune cells in peripheral blood at each time point, and assess dynamic changes from baseline. |
| CD7 expression kinetics on immune cells | From pre-dose baseline through Week 24 (EOS) | Dynamically detect CD7 expression levels on peripheral blood immune cells at each time point and analyze kinetic changes from baseline. |
| Overall Survival (OS) | Up to Week 48 survival follow-up | Evaluate the time interval from the first IP infusion to all-cause death. |
| PK parameters of IP components | From pre-dose baseline through Week 24 (EOS) | Determine the PK parameters of the circRNA component and cationic lipid component of the IP respectively. |
| Incidence of immunogenicity to IP | From pre-dose baseline through Week 24 (EOS) | Count the number and percentage of participants with pre-existing antibodies (anti-PEG, anti-CAR, anti-CD7 VHH) and treatment-induced antibodies (anti-PEG, anti-CAR, anti-CD7 VHH) against IP. |
| Correlation between cytokine levels and treatment response adverse events(TRAE) | From pre-dose baseline through Week 24 (EOS) | Detect serum cytokine levels and conduct exploratory correlation analysis between cytokine concentrations and clinical outcomes. |
| Overall Response Rate (ORR) | From Week 4 through Week 24 (EOS) | Calculate the proportion of participants achieving Complete Response (CR) or Partial Response (PR). Tumor response is assessed per Lugano 2014 criteria, iWCLL 2018 criteria, and the 11th International WM Workshop criteria. |
Countries
China
Contacts
CONTACTLi WANG
Outcome results
None listed