Relapsed/Refractory B-cell Lymphoma
Conditions
Keywords
Relapsed/refractory, B-cell lymphoma
Brief summary
This single-arm, open-label pilot study will assess the safety and efficacy of RN1701, a bispecific CD19/CD20-targeted allogeneic CAR-T-cell product, in patients with relapsed or refractory B-cell lymphoma. Up to 19 participants will be enrolled in a conventional 3 + 3 dose-escalation scheme. The primary objective of the study is to evaluate the safety and feasibility of RN1701 for the treatment of relapsed/refractory B-cell lymphoma. The secondary objective is to evaluate the efficacy of RN1701 for the treatment of relapsed/refractory B-cell lymphoma. The exploratory objective is to evaluate the expansion, persistence, and ability of RN1701 to deplete CD19- and/or CD20-positive cells in patients with relapsed/refractory B-cell lymphoma.
Interventions
BIOLOGICALRN1701 injection
RN1701 injection is a bispecific CD19/CD20-targeted allogeneic CAR-T. A single infusion of CAR-T cells will be administered intravenously
Sponsors
Allorunning Therapeutics
YANRU WANG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary participation; full understanding of the study and provision of written informed consent obtained before any study-related procedure not part of standard care; willingness to comply with follow-up. 2. Age 18-75 years; either sex. 3. ECOG performance status 0-1. 4. Histologically confirmed large B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, or indolent lymphoma transformed to DLBCL; CD19 and/or CD20 positive. 5. At least one measurable lesion per Lugano criteria: nodal lesion longest diameter \>1.5 cm, extranodal lesion \>1.0 cm. 6. Prior treatment response must meet one of the following: • Large B-cell lymphoma, grade 3B follicular lymphoma, transformed indolent lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy, or SD after ≥4 cycles. ii. Relapse ≤12 months after achieving CR with first-line chemo-immunotherapy. iii. Relapse/progression ≤12 months after autologous HSCT. iv. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen. v. Transformed indolent lymphoma: prior chemotherapy for iNHL and ≥1 systemic regimen after transformation, fulfilling the above refractory/relapse criteria. • Grade 1, 2, or 3A follicular lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy. ii. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen. • Mantle-cell lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy, or SD after ≥4 cycles. ii. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen. 7. Estimated life expectancy ≥3 months. 8. Screening laboratory values (may be repeated once): * Hemoglobin ≥8.0 g/dL (no transfusion within 7 days). * Platelets ≥50×10⁹/L (no transfusion within 7 days). * ANC ≥1.0×10⁹/L (growth-factor support allowed if none within 7 days of test). * AST/ALT ≤3×ULN (≤5×ULN if liver involvement). * Serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault). * Total bilirubin ≤2×ULN (≤3×ULN if liver involvement); except congenital bilirubin disorders (e.g., Gilbert's syndrome: direct bilirubin ≤1.5×ULN). * INR, PT, APTT \<1.5×ULN. 9. Toxicities from prior anti-cancer therapy (except alopecia, nausea, and the above lab values) must have stabilized at baseline or resolved to ≤Grade 1. 10. WOCBP must have a negative high-sensitivity serum β-hCG pregnancy test at screening and again before the first dose of cyclophosphamide/fludarabine. 11. Subjects of reproductive potential must use effective contraception for ≥12 months after completing study therapy.
Exclusion criteria
* Subjects with any of the following conditions are ineligible for this trial: 1. Any malignancy other than B-cell non-Hodgkin lymphoma ever diagnosed or treated, except: * Malignancy that received curative therapy and has shown no evidence of active disease for ≥2 years before enrolment; or * Adequately treated non-melanoma skin cancer with no current evidence of disease. 2. Prior anti-cancer therapy within the stated windows (before lymphodepletion): * CNS prophylaxis (e.g., intrathecal methotrexate and/or cytarabine) within 7 days; * Cytotoxic chemotherapy or radiotherapy within 14 days; * Small-molecule targeted or epigenetic therapy within 14 days or 5 half-lives, whichever is longer; * Monoclonal antibody, bispecific antibody, or antibody-drug conjugate within 21 days or 5 half-lives, whichever is shorter; * Investigational drug or invasive investigational device within 28 days (if the therapy is also investigational, the 28-day wash-out applies); * Autologous haematopoietic stem-cell transplant or CD19-directed autologous CAR-T therapy within 100 days. 3. Any autologous cellular or gene therapy other than CD19-directed autologous CAR-T. 4. Any allogeneic cellular (including CAR-T) or gene therapy. 5. Prior allogeneic haematopoietic stem-cell transplantation. 6. Positive donor-specific antibody (DSA). 7. At least one of the following high-risk features: * Sum of the product of perpendicular diameters (SPD) of all measurable lesions ≥100 cm²; * Bulky disease: single mass ≥7.5 cm; mediastinal mass with maximum diameter \>1/3 of thoracic diameter; * Obstructive/compressive emergency (e.g., bowel obstruction, vascular compression) requiring urgent intervention at screening. 8. Active CNS involvement (symptomatic or positive CSF/imaging); subjects with prior CNS disease now in remission (asymptomatic with negative CSF and imaging) are eligible. 9. Significant bleeding diathesis: gastrointestinal bleeding, haemorrhagic cystitis, coagulopathy, hypersplenism (splenomegaly on exam/US, cytopenias, hyperplastic marrow) or ongoing anticoagulation. 10. Chronic concomitant systemic corticosteroids or other immunosuppressants, except: topical, ocular, intra-articular, nasal or inhaled corticosteroids; short-course steroids for prophylaxis (e.g., contrast allergy). 11. Severe underlying medical conditions: * Active serious viral, bacterial or uncontrolled systemic fungal infection; * Active systemic autoimmune disease requiring therapy. 12. Significant cardiac disease: * NYHA class III or IV congestive heart failure; * Myocardial infarction or CABG within 6 months before enrolment; * Clinically relevant ventricular arrhythmia or unexplained syncope not vasovagal or dehydration-related; * Severe non-ischaemic cardiomyopathy; * Left ventricular ejection fraction (LVEF) \<45% by echo or MUGA within 4 weeks before lymphodepletion. 13. Resting oxygen saturation \<92%. 14. Clinically relevant prior or current CNS disorder: epilepsy, seizure-like episodes, paralysis, aphasia, stroke, severe head trauma, dementia, Parkinson's disease, cerebellar disorder, organic brain syndrome or major psychiatric illness. 15. Live-attenuated vaccine within 4 weeks before screening. 16. Major surgery within 2 weeks before screening or planned within 2 weeks after study treatment (local anaesthesia allowed). 17. Positive screen for HBsAg, HBeAg, HBV DNA, HCV antibody, HCV RNA, or HIV antibody. 18. Life-threatening allergy, hypersensitivity or intolerance to study-drug excipients including, but not limited to, DMSO. 19. Lactating women. 20. Any condition that, in the investigator's opinion, renders the subject unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity and adverse-event grading after RN1701 treatment | up to 12 months after infusion | all toxicities and AEs will be assessed according to the National Cancer Institute CTCAE v5.0 |
| CRS grading after RN1701 treatment | up to 12 months after infusion | Cytokine Release Syndrome (CRS) will be graded using the Lee DW et al. CRS grading scale. Grade 1: Fever, mild symptoms, manageable with supportive care Grade 2: Moderate symptoms (eg, hypotension, hypoxia), requires intervention (eg, intravenous fluids, antipyretics) Grade 3: Severe symptoms (eg, multiorgan involvement), requires corticosteroids and tocilizumab Grade 4: Life-threatening, requires intensive care unit (ICU) care and urgent interventions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR = CR + PR) of patients receive RN1701 treatment | 1, 3, 6, and 12 months after infusion | according to the Lugano criteria and CSCO guidelines |
| Disease control rate (DCR = CR + PR + SD) of patients receive RN1701 treatment | 1, 3, 6, and 12 months after infusion | according to the Lugano criteria and CSCO guidelines |
| Assessment includes contrast-enhanced CT of head/neck, chest, abdomen, and pelvis, plus whole-body PET-CT | 1, 3, 6, and 12 months after infusion | Tumor measurements and evaluations must be performed with the same technique used at baseline |
| CAR copies and cell count of CAR-T in blood after RN1701 treatment | Days 0, 1, 3, 5, 7, 9, 11, 14, 21, 28 and month 2, 3, 6, 9, 12 after infusion | — |
Countries
China
Contacts
Primary ContactXiaoming Fei, PhD
Outcome results
None listed