RN1701 Injection in the Treatment of Relapsed/Refractory B-Cell Lymphomas

An Exploratory Clinical Study of the Safety and Efficacy of RN1701 Injection in the Treatment of Relapsed/Refractory B-Cell Lymphomas

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.

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.