Multiple Myeloma in Relapse, Multiple Myeloma, Refractory
Conditions
Brief summary
The goal of this study is to evaluate the safety of a new type of CAR T-cell, UF-KURE-BCMA, for the treatment of patients with advanced multiple myeloma that has not responded to other therapies. The main question is whether the use of these new CAR T-cells is safe for patients with this condition. Secondarily, the study will also look at the response of myeloma to this therapy.
Detailed description
This is a Phase I, single-arm, open-label, dose-escalation study using a 3+3 design that evaluates the safety of UF (ultrafast)- KURE-BCMA for patients with relapsed/refractory multiple myeloma. Eligible patients are adults (≥18 years) with relapsed or refractory multiple myeloma after ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. The study will accrue a total of 12 patients. The primary objectives of this study are: * To determine the recommended Phase 2 dose (RP2D) of UF-KURE-BCMA * To establish the safety profile and identify dose-limiting toxicities (DLTs) The secondary objectives: * Manufacturing feasibility * Overall response rate (ORR) per IMWG criteria * Duration of response (DOR) * Progression-free survival (PFS) * Overall survival (OS) The exploratory objectives include: * CAR-T cell persistence and expansion * Replication-competent lentivirus (RCL) testing * Cytokine profiling * CAR-T cell phenotype characterization * Anti-BCMA CAR antibody development * Spatial multi-omics analysis of the bone marrow microenvironment The study endpoints include: Primary Endpoint Incidence of dose-limiting toxicities occurring within 28 days of CAR-T cell infusion Secondary Endpoints * Manufacturing success rate (≥75%) * Treatment-emergent adverse events * ORR, DOR, PFS, and OS per IMWG criteria The Investigational Product is UF-KURE-BCMA, an autologous CAR-T cells manufactured using an ultra-fast process (approximately 17-20 hours), that targets specifically BCMA, a marker expressed on the surface of the myeloma cell. The study will evaluate 3 different dose levels: * Level -1: 3 × 10⁶ cells (≥50 kg) / 2 × 10⁶ cells (\<50 kg) * Level 1 (Starting Dose): 10 × 10⁶ cells (≥50 kg) / 7 × 10⁶ cells (\<50 kg) * Level 2: 15 × 10⁶ cells (≥50 kg) / 10 × 10⁶ cells (\<50 kg) Prior to the cell infusion, the patients will receive a chemotherapy regimen (lymphodepleting regimen) that includes: Cyclophosphamide 300 mg/m² IV plus fludarabine 30 mg/m² IV, administered daily for 3 days (Days -4 to -2) The study will last 28 days, which is Dose-limiting toxicity (DLT) observation period. The follow-up period is 24 months with a long-term safety follow-up of 15 years. The study endpoints: Primary Endpoint Incidence of dose-limiting toxicities occurring within 28 days of CAR-T cell infusion Secondary Endpoints * Manufacturing success rate (≥75%) * Treatment-emergent adverse events * ORR, DOR, PFS, and OS per IMWG criteria Statistical Methods A standard 3+3 dose-escalation design will be used. Safety and efficacy will be summarized using descriptive statistics. Time-to-event endpoints will be analyzed using the Kaplan-Meier method.
Interventions
BIOLOGICALAdministration of CAR T-cells at 3 different dose levels
The patients will receive one of 3 dose levels as outlined above.
Sponsors
Kure Cells, INC
CellServe LLC
Roya Clinical
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A standard 3+3 dose-escalation design will be used to evaluate 3 dose levels. Safety and efficacy will be summarized using descriptive statistics. Time-to-event endpoints will be analyzed using the Kaplan-Meier method.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must meet ALL of the following criteria to be eligible for study enrollment: 1. Age: ≥18 years at time of signing informed consent 2. Diagnosis: Documented multiple myeloma meeting one of the following: * Relapsed disease: Progression after achieving at least minimal response (MR) to prior therapy * Refractory disease: Non-responsive or progressive disease while on therapy or within 60 days of last treatment (in subjects who achieved ≥MR on prior therapy) 3. Prior Therapy: * Received ≥3 prior lines of anti-myeloma therapy * Prior therapy must include: At least one proteasome inhibitor At least one immunomodulatory drug (e.g., lenalidomide, pomalidomide, thalidomide) At least one anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab) o Prior anti-BCMA CAR-T therapy is permitted if subject achieved PFS ≥6 months post-infusion 4. Measurable Disease: At least one of the following at screening (for response assessment eligibility): * Serum M-protein ≥0.5 g/dL by protein electrophoresis (SPEP) * Urine M-protein ≥200 mg/24 hours by protein electrophoresis (UPEP) * Serum free light chain (FLC) difference ≥10 mg/dL with abnormal FLC ratio Note: Subjects with non-measurable disease may enroll for safety assessment 5. Performance Status: ECOG Performance Status 0-2 (see Appendix A) 6. Organ Function: Adequate organ function as defined by: Hepatic: o Total bilirubin ≤2× institutional upper limit of normal (ULN), except subjects with Gilbert's syndrome * AST and ALT ≤2.5× institutional ULN Renal: o Calculated creatinine clearance ≥30 mL/min (Cockcroft-Gault formula) Cardiac: o Left ventricular ejection fraction (LVEF) ≥45% by echocardiogram or MUGA Pulmonary: o ≤Grade 1 dyspnea o Oxygen saturation ≥92% on room air o If PFTs performed: FEV₁ ≥50% predicted and DLCO ≥40% predicted (corrected for hemoglobin) 7. Prior Therapy Washout: o ≥2 weeks since last radiation or systemic anti-myeloma therapy (standard agents) o ≥4 weeks since last investigational therapy o ≥6 weeks since autologous stem cell transplant 8. Informed Consent: Ability to understand and willingness to provide written informed consent 9. Contraception Requirements (for subjects of reproductive potential): Female subjects: o Women of childbearing potential must: Have negative serum pregnancy test at screening Agree to use highly effective contraception (failure rate \<1% per year) from enrollment through 6 months post-CAR-T infusion * Acceptable methods: bilateral tubal ligation, male partner sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing IUD, copper IUD * Sexual abstinence is acceptable if consistent with subject's preferred lifestyle Male subjects: * Must agree to use condom plus effective contraception if partner is of childbearing potential * Must refrain from sperm donation from enrollment through 6 months post-CAR-T infusion
Exclusion criteria
Subjects meeting ANY of the following criteria will be excluded: 1. Disease-Specific Exclusions: * Active CNS involvement by multiple myeloma * Plasma cell leukemia * History of allogeneic hematopoietic stem cell transplantation 2. Malignancy Exclusions: o Second active malignancy, except: Non-melanoma skin cancer Carcinoma in situ (cervix, bladder, breast) Stage 1 uterine cancer Localized prostate cancer 3. Cardiovascular Exclusions: * New York Heart Association (NYHA) Class IV congestive heart failure * Unstable angina pectoris * Clinically significant cardiac arrhythmias * Myocardial infarction, stroke, or TIA within 6 months of enrollment 4. Infectious Disease Exclusions: * Known HIV infection or AIDS-related illness * Active hepatitis B or C infection: Positive HBsAg, or Positive anti-HBc or anti-HCV with detectable viral nucleic acid by PCR * Active infection requiring systemic therapy 5. Neurological Exclusions: * History of clinically relevant CNS pathology including: Epilepsy or seizure disorders Paresis, aphasia Uncontrolled cerebrovascular disease Severe brain injury Dementia Parkinson's disease 6. Autoimmune Disease: * Active autoimmune disease requiring systemic immunosuppression \>15 mg/day prednisone equivalent within past 6 months * Examples: rheumatoid arthritis, lupus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLT occurring within 28 days of CAR-T cell infusion) | Within 28 days of CAR-T cell infusion | DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Manufacturing success rate | 28 days post infusion | Manufacturing success rate is defined as manufacturing process leading to an adequate product per protocol standards. We expect this outcome to occur in ≥75% of the products manufactured. |
| Treatment-emergent adverse events | At 24 months | Treatment adverse events related to the administration of CART-cells |
| ORR per IMWG criteria | At 24 months | Overall response rate |
| DOR | At day 24 months | Duration of Response |
| PFS | At 24 months | Progression-Free Survival |
| OS | At 24 months | Overall Survival |
Contacts
CONTACTDANIEL Couriel, MD, MS, MBA
CONTACTOla Soliman, MD
Outcome results
None listed