Plasma Cell Leukemia (PCL), Relapsed/Refractory Multiple Myeloma (RRMM)
Conditions
Brief summary
This study is a single-center, open-label, dose-exploration trial designed to evaluate the tolerability and safety of different doses of IASO104 in patients with relapsed/refractory plasma cell neoplasms, determine the recommended dose of IASO104, and assess its pharmacokinetic and pharmacodynamic characteristics. Additionally, the study will preliminarily observe the efficacy of the investigational drug in a small sample of subjects with relapsed/refractory multiple myeloma.
Detailed description
This study adopts a "3+3" dose-escalation design, with three predefined dose levels: 0.5×10⁶ CAR-T cells/kg, 1.0×10⁶ CAR-T cells/kg, and 3.0×10⁶ CAR-T cells/kg, administered as a single infusion.For each dose group, the first subject must be observed for at least 2 weeks after infusion before subsequent subjects can be treated. If stable biological activity or clinical benefit is observed at a lower dose level, the study may proceed with 1-2 expanded dose groups at lower levels after discussion between the investigator and sponsor, without requiring MTD determination.During the dose-escalation phase, 2-3 subjects will be enrolled per dose level, with the total number of subjects depending on the escalation progression (estimated 4-6 subjects in this phase). Treatment in the next dose group may only begin after all subjects in the current group have completed DLT assessment post-infusion.
Interventions
BIOLOGICALIASO104
IASO104 is a personalized, BCMA-targeted, genetically modified autologous T-cell immunotherapy product.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
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 18-75 years, any gender. 2. Diagnosis of multiple myeloma (MM) per International Myeloma Working Group (IMWG) diagnostic criteria. 3. Prior therapy requirements: MM patients: ≥3 prior lines of therapy, including: * 1 proteasome inhibitor (PI) * 1 immunomodulatory drug (IMiD) * 1 anti-CD38 monoclonal antibody Exception: No minimum line requirement for subjects refractory to PIs, IMiDs, and anti-CD38 therapy. Primary plasma cell leukemia (pPCL): ≥1 prior line including ≥1 PI and ≥1 IMiD. 4. Documented disease progression during/within 12 months after last anti-myeloma therapy (exemption: No 12-month requirement if last line was CAR-T). 5. Measurable disease at screening (≥1 of the following): Serum M-protein: IgG ≥10 g/L IgA/IgD/IgE/IgM ≥5 g/L Urine M-protein ≥200 mg/24h Serum free light chains (FLC): Involved FLC ≥100 mg/L with abnormal κ/λ ratio Bone marrow plasma cells ≥30% (if no measurable M-protein/FLC). 6. ECOG performance status 0-1. 7. Life expectancy ≥12 weeks. 8. Adequate organ function (all lab values within 7 days prior to enrollment): Hematology: Absolute neutrophil count (ANC) ≥1×10⁹/L (allowed: growth factor support, but none within 7 days) Absolute lymphocyte count (ALC) ≥0.3×10⁹/L Platelets ≥50×10⁹/L (no transfusion within 7 days) Hemoglobin ≥60 g/L (no RBC transfusion within 7 days; erythropoietin allowed) Liver: ALT/AST ≤2.5×ULN Total bilirubin ≤1.5×ULN Renal: Calculated CrCl ≥40 mL/min (Cockcroft-Gault) Coagulation: Fibrinogen ≥1.0 g/L aPTT/PT ≤1.5×ULN Pulmonary: SpO₂ \>91% (room air) Cardiac: LVEF ≥50% (echocardiography). 9. Contraception: Subjects/partners must use effective contraception from consent through 1 year post CAR-T infusion (excluded: calendar method). 10. Signed informed consent approved by the Ethics Committee prior to screening.
Exclusion criteria
1. Active graft-versus-host disease (GVHD) or requiring long-term immunosuppressive therapy. 2. Prior hematopoietic stem cell transplantation (HSCT): Autologous HSCT (Auto-HSCT) within 12 weeks before apheresis, ≥2 prior Auto-HSCTs, Any prior allogeneic HSCT (Allo-HSCT). 3. Prior cell therapy targeting plasma cells within 3 months before apheresis, or detectable residual cellular therapy products in peripheral blood. 4. Recent anti-myeloma therapies (relative to apheresis): Monoclonal antibody treatment within 21 days, Cytotoxic chemotherapy or proteasome inhibitors within 14 days, Immunomodulatory drugs within 7 days, Other anti-tumor therapies within 14 days or 5 half-lives (whichever is shorter). 5. Chronic corticosteroid use (\>20 mg/day prednisone or equivalent), except for physiologic replacement, topical, or inhaled use. 6. Uncontrolled hypertension despite medication. 7. Severe cardiac disease, including: Unstable angina, Myocardial infarction (within 6 months before screening), Congestive heart failure (NYHA Class ≥III), Severe arrhythmias. 8. Unstable systemic illnesses per investigator's judgment (e.g., severe hepatic, renal, or metabolic disorders requiring medication). 9. Other malignancies within 5 years, excluding: Carcinoma in situ of the cervix, Basal/squamous cell skin cancer, Localized prostate cancer post-radical resection, Ductal breast carcinoma in situ post-resection. 10. History of solid organ transplantation. 11. Suspected or confirmed CNS involvement by plasma cell neoplasms. 12. Major surgery within 2 weeks before apheresis or planned within 2 weeks post-treatment (allowed: minor procedures under local anesthesia). 13. Investigational drugs within 1 month before apheresis. 14. Uncontrolled active infections: Persistent symptoms despite appropriate therapy, Requiring IV antimicrobials at screening. 15. Viral infections: HBV: HBsAg(+) or HBcAb(+) with detectable HBV DNA, HCV: HCV Ab(+) with detectable HCV RNA, HIV Ab(+), CMV DNA(+), Syphilis: TRUST(+) and TPPA(+). 16. Pregnancy or lactation. 17. Psychiatric disorders, cognitive impairment, or active CNS diseases. 18. Other conditions deemed ineligible by the investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| incidence and severity of adverse events (AEs) | Minimum 2 years after IASO104 infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Minimum 2 years after IASO104 infusion | The proportion of subjects achieving stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) after treatment with IASO104 injection |
| Progression-Free Survival (PFS) | Minimum 2 years after IASO104 infusion | Progression-free survival (PFS) was defined as the time from initiation of IASO104 injection treatment to disease progression or death from any cause, whichever occurred first. |
| Overall Survival (OS) | Minimum 2 years after IASO104 infusion | Overall survival (OS) was defined as the time from initiation of IASO104 injection treatment to death from any cause. |
| Time to Response (TTR) | Minimum 2 years after IASO104 infusion | Time to response (TTR) was defined as the interval from initiation of IASO104 injection treatment to first achievement of disease response (≥ partial response \[PR\]). |
| Time to Complete Response (TTCR) | Minimum 2 years after IASO104 infusion | Time to complete response (TTCR) was defined as the interval from initiation of IASO104 injection treatment to first achievement of complete response (CR) or better (including stringent complete response \[sCR\]) |
| Minimal Residual Disease (MRD)-negative rate | Minimum 2 years after IASO104 infusion | Proportion of subjects achieving bone marrow minimal residual disease (MRD)-negativity by next-generation flow cytometry (NGF) following study treatment |
| Duration of MRD Negativity | Minimum 2 years after IASO104 infusion | Duration of MRD negativity was defined as the time from first achievement of MRD-negative status to first MRD recurrence (conversion to positive) |
| Pharmacokinetic (PK) Endpoints | Minimum 2 years after IASO104 infusion | Peak concentration (C\<sub\>max\</sub\>) of CAR-T cells Area under the curve (AUC) over: 0-28 days post-infusion (AUC\<sub\>0-28d\</sub\>) 0-90 days post-infusion (AUC\<sub\>0-90d\</sub\>) 0-180 days post-infusion (AUC\<sub\>0-180d\</sub\>) Infusion to last measurable timepoint (AUC\<sub\>0-last\</sub\>) |
| Duration of Response (DOR) | Minimum 2 years after IASO104 infusion | Duration of response (DOR) was defined as the time from the first documented achievement of response (≥ partial response \[PR\]) to disease progression or death from any cause (whichever occurred first) in subjects treated with IASO104 injection. |
| Pharmacodynamic (PD) Endpoints | Minimum 2 years after IASO104 infusion | Levels of soluble BCMA (sBCMA) in peripheral blood at each timepoint |
Outcome results
None listed