Relapsed/Refractory Multiple Myeloma
Conditions
Keywords
Relapsed/Refractory, Multiple Myeloma, BCMA, CAR-T
Brief summary
This study is a single-armed, open-label, multicenter Phase 1/2 study to evaluate the efficacy and safety of Fully Human BCMA Chimeric Antigen Receptor Autologous T Cell Injection (Equecabtagene Autoleucel) in subjects with relapsed and refractory Multiple Myeloma.
Detailed description
This study is divided into two stages: Part 1 and Part 2. Part 1: For exploratory research purposes, no more than 3 subjects will be enrolled at an exploratory dose. Part 2: The purpose of this phase is to explore the efficacy of Equecabtagene Autoleucel (Eque-cel) as a last-line treatment for RRMM and further confirm its safety. In this Study，Leukapheresis procedure will be performed to manufacture Eque-cel modified T cells. Bridging therapy is allowed between PBMC collection and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide is performed for three consecutive days. After 1-day rest, subjects will receive a single dose infusion of Eque-cel at 1.0 x 10\^6 CAR+ T cells/Kg or 0.5 x 10\^6 CAR+ T cells/Kg（if all three subjects in Part 1 experience the Toxicity Requiring Dose Reduction）. Subjects will be followed in the study for a minimum of 2 years after Eque-cel infusion.
Interventions
DRUGFully Human BCMA Chimeric Antigen Receptor Autologous T Cell Injection (Eque-cel)
Eque-cel consists of autologous T lymphocytes transduced with anti-BCMA CAR lentiviral vector that contains a unique CAR structure with a fully human single-chain variable fragment (scFv).
Sponsors
Nanjing IASO Biotechnology Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria * 1\. Aged 18 to 70 years, male or female. * 2\. Patients with a confirmed diagnosis of relapsed/refractory multiple myeloma according to the IMWG diagnostic criteria. * 3\. Patients who have received at least three prior treatment regimens (including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibody-based chemotherapy regimens) and have documented disease progression during or within 12 months of their most recent anti-myeloma treatment. * 4\. Patients with measurable disease at screening, as determined by any of the following criteria: * Serum M-protein level: IgG type M-protein level ≥ 10 g/L, IgA, IgD, IgE, IgM type M-protein level ≥ 5 g/L * Urinary M-protein level ≥ 200 mg/24 hours * 5\. Light-chain multiple myeloma without measurable M protein in serum or urine: involved serum free light chain ≥ 100 mg/L with an abnormal serum κ/λ free light chain ratio. ECOG PS 0 or 1. * 6\. Patients must have adequate organ function and meet all of the following pre-enrollment laboratory test results: Hematological Tests: * Absolute Neutrophil Count (ANC) ≥ 1×109/L (Supportive growth factors are permitted, but supportive treatment must not have been administered within 7 days prior to the laboratory test) * Absolute Lymphocyte Count (ALC) ≥ 0.3×109/L * Platelet Count ≥ 50×109/L (Supportive transfusions must not have been administered within 7 days prior to the laboratory test) * Hemoglobin ≥ 60 g/L (Red blood cell \[RBC\] transfusions must not have been administered within 7 days prior to the laboratory test, but recombinant human erythropoietin is permitted) Liver Function: * ALT and AST ≤ 2.5×upper limit of normal (ULN) * Serum Total Bilirubin ≤ 1.5 x ULN Renal Function: Creatinine clearance (CrCl) calculated using the Cockcroft-Gault formula ≥ 40 mL/min CrCl = (140 - age) × weight (kg) × \[0.85 for women\] / 72 × \[ serum creatinine (mg/dL)\] Coagulation function: * Fibrinogen ≥ 1.0 g/L * Activated partial thromboplastin time (APTT) ≤ 1.5× ULN * Prothrombin time (PT) ≤ 1.5× ULN Corrected serum calcium ≤11 mg/dL Oxygen saturation \> 91% Left ventricular ejection fraction (LVEF) ≥ 50%. * 7\. Female patients of childbearing potential or male patients with partners of childbearing potential agree to use effective contraception (safe-day contraception not included) throughout the study period from screening through one year after Eque-cel infusion. "Effective contraceptive methods" specifically refers to: User-independent methods: 1) Intrauterine devices, intrauterine hormone-releasing systems; 2) Partner has undergone vasectomy. User-dependent methods: 1) Combined hormonal contraception (containing estrogen and progestin) with ovulation suppression: Oral; 2) Progestin-only hormonal contraception with ovulation suppression ( oral). -8. Prior to screening, subjects must manually sign an Institutional Review Board-approved ICF.
Exclusion criteria
* 1\. Patients with graft-versus-host disease (GVHD) or requiring long-term use of immunosuppressants. * 2\. Patients with a history of BCMA-targeted therapy. * 3\. Patients who have undergone autologous hematopoietic stem cell transplantation (auto-HSCT) within 12 weeks prior to apheresis, two auto-HSCTs, or prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). * 4\. Patients who have received prior anti-myeloma therapy, including: * Monoclonal antibody therapy within 21 days prior to apheresis. * Cytotoxic chemotherapy or proteasome inhibitor therapy within 14 days prior to apheresis. * Immunomodulatory therapy within 7 days prior to apheresis. * Other anti-myeloma therapy within 14 days or within 5 half-lives (whichever is longer) prior to apheresis. * 5\. Use of systemic corticosteroids at a therapeutic dose (defined as \>20 mg/day of prednisone or equivalent) within 7 days prior to apheresis. Physiological replacement steroids, topical steroids, and inhaled steroids are permitted. * 6\. Patients with uncontrolled hypertension despite medical therapy. * 7\. Severe cardiac disease, including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association \[NYHA\] grade ≥ III), and severe arrhythmia. * 8\. Unstable systemic disease as determined by the investigator, including but not limited to severe liver, renal, or metabolic disease requiring treatment. * 9\. Patients with malignancies other than multiple myeloma (MM) within 5 years prior to screening. excluding adequately treated cervical epithelial cell adenocarcinoma, basal cell carcinoma or squamous cell skin cancer, localized prostate cancer after curative surgery, and ductal carcinoma in situ after curative surgery. * 10\. Patients with a history of solid organ transplantation. * 11\. Patients with suspected or confirmed central nervous system infiltration by plasma cell neoplasms. * 12\. Multiple myeloma patients with extramedullary lesions (excluding those with only paraskeletal extramedullary lesions where the single largest transverse diameter is ≤3cm). * 13\. Multiple myeloma patients with concomitant plasma cell leukemia (peripheral blood plasma cell count ≥5%). * 14\. Major surgery within 2 weeks prior to apheresis or planned surgery within 2 weeks after study treatment (subjects scheduled for local anesthesia surgery may participate in this study). * 15\. Received investigational drugs from other interventional clinical trials within 1 month prior to signing the Informed Consent Form (ICF). * 16\. Patients with an uncontrolled active infection (excluding CTCAE Grade 2 urinary tract infection or respiratory infection) within 7 days prior to apheresis. * 17\. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive with detectable hepatitis B virus (HBV) DNA in peripheral blood; Hepatitis C virus (HCV) positive with hepatitis C virus (HCV) RNA positive in peripheral blood; Human Immunodeficiency Virus (HIV) antibody positive; Cytomegalovirus (CMV) DNA test positive; Syphilis test positive. * 18\. Pregnant or lactating women. * 19\. Patients with psychiatric disorders, impaired consciousness, or central nervous system disease. * 20\. Patients whose non-hematologic toxicities from previous antimyeloma therapy have not resolved to baseline or Grade ≤ 1 (NCI-CTCAE v5.0) (excluding alopecia and Grade 2 peripheral neuropathy). * 21\. Other conditions deemed ineligible for enrollment by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety endpoint (Part 1)- Adverse Event（AEs） | up to 2 years from Eque-cel infusion | Incidence and severity of adverse events as assessed by NCI-CTCAE v5.0 (except CRS and ICANS assessed according to the criteria of 2019 ASTCT criteria). |
| Safety endpoint (Part 1)-CRS | up to 2 years from Eque-cel infusion | Incidence and severity of cytokine release syndrome (CRS； based on the 2019 ASTCT criteria） |
| Safety endpoint (Part 1)-ICANS | up to 2 years from Eque-cel infusion | Incidence and severity of immune effector cell-associated neurotoxicity syndrome (ICANS).( based on the 2019 ASTCT criteria) |
| Efficacy endpoint (Part 2): Independent Review Committee (IRC)-assessed ORR | up to 2 years from Eque-cel infusion | Rate of best response (PR, very good PR, CR, sCR) after Eque-cel infusion in all subjects at the time the last subject completed the 6-month follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety endpoint (Part 2)- Adverse Event（AEs） | up to 2 years from Eque-cel infusion | Incidence and severity of adverse events as assessed by NCI-CTCAE v5.0 (except CRS and ICANS assessed according to 2019 ASTCT criteria). |
| Efficacy endpoint -Investigator-assessed overall response rate (ORR) | up to 2 years from Eque-cel infusion | Rate of best response (PR, very good PR, CR, sCR) after Eque-cel infusion for all subjects at the time the last subject completed the 6-month follow-up. |
| Efficacy endpoint -IRC- and investigator-assessed ORR | up to 2 years from Eque-cel infusion | Rate of best response (PR, VGPR, CR, sCR) within 1 month, 3 months, and 6 months after Eque-cel infusion. |
| Efficacy endpoint -IRC and investigator-assessed duration of response (DOR) | up to 2 years from Eque-cel infusion | The period from the first response (PR, VGPR, CR, sCR) to the date of the first documented evidence of disease progression or death from any cause, as defined by the IMWG criteria after treatment. |
| IRC and investigator-assessed time to response (TTR) | up to 2 years from Eque-cel infusion | The period from Eque-cel infusion to the date of the first documented response (PR or better). |
| IRC and investigator-assessed time to complete response (TTCR) | up to 2 years from Eque-cel infusion | The period from Eque-cel infusion to the date of complete response (CR) or stringent complete response (sCR). |
| Minimal residual disease (MRD) assessment by flow cytometry | up to 2 years from Eque-cel infusion | The proportion of subjects achieving MRD negativity and the duration of MRD negativity. |
| IRC and investigator-assessed progression-free survival (PFS) | up to 2 years from Eque-cel infusion | The period from Eque-cel infusion to the date of first disease progression or death from any cause. |
| Overall survival (OS) | up to 2 years from Eque-cel infusion | The period from Eque-cel infusion to death from any cause. |
| Pharmacokinetic Endpoint-Cmax | up to 2 years from Eque-cel infusion | The maximum concentration (Cmax) of BCMA CAR-T cells in peripheral blood after Eque-cel infusion. |
| Pharmacokinetic Endpoint-Tmax | up to 2 years from Eque-cel infusion | The time for BCMA CAR-T cells to reach the maximum concentration (Tmax) after Eque-cel infusion. |
| Pharmacokinetic Endpoint-AUC | up to 2 years from Eque-cel infusion | Area under the curve of 28, 90 days and the last time point of PK measurement (AUC0-28d, AUC0-90d, AUC0-last) for BCMA CAR-T cells. |
| - Pharmacokinetic Endpoint-AUC | up to 2 years from Eque-cel infusion | Area under the curve of 28, 90 days and the last time point of PK measurement (AUC0-28d, AUC0-90d, AUC0-last) for lentiviral vector copy number (VCN). |
| Pharmacodynamic Endpoint-sBCMA | up to 2 years from Eque-cel infusion | The concentration of soluble BCMA in peripheral blood . |
| Pharmacodynamic Endpoint-C-reactive protein (CRP) | up to 2 years from Eque-cel infusion | Changes in the levels of CRP. |
| Pharmacodynamic Endpoint -Ferritin | up to 2 years from Eque-cel infusion | Changes in the levels of Ferritin. |
| Pharmacodynamic Endpoint -Interleukin-6 (IL-6) | up to 2 years from Eque-cel infusion | Changes in the levels of IL-6. |
Countries
Japan
Outcome results
None listed