Plasma Cell Myeloma, Relapsed/Refractory Multiple Myeloma (RRMM)
Conditions
Keywords
Relapsed/Refractory Multiple Myeloma, Chimeric Antigen Receptor T-cell Therapy, Multiple Myeloma, CS1 CAR-T, Autologous T Cells, SLAMF7, Anti-SLAMF7 Chimeric Antigen Receptor T Cells, Adoptive Cellular Immunotherapy, Plasma Cell Neoplasm
Brief summary
This investigator-initiated, exploratory clinical trial is designed to evaluate the feasibility, safety, and preliminary antitumor activity of autologous CS1-targeted chimeric antigen receptor T (CAR-T) cells in adults with relapsed or refractory multiple myeloma (MM). Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Despite advances in treatment, patients with relapsed or refractory disease often have limited therapeutic options after multiple lines of therapy. CS1, also known as signaling lymphocytic activation molecule family member 7 (SLAMF7; CD319), is highly expressed on myeloma cells throughout the course of disease and has been investigated as a therapeutic target. The clinical activity of the anti-SLAMF7 monoclonal antibody elotuzumab supports the rationale for targeting this antigen. CS1-targeted CAR-T cell therapy is being investigated as a potential treatment option for patients with relapsed or refractory multiple myeloma. This is an open-label, single-center, non-randomized, Phase I dose-escalation study evaluating autologous CS1-targeted CAR-T cells. The primary objectives are to evaluate the feasibility and safety of autologous CS1-targeted CAR-T cell therapy and to assess its preliminary antitumor activity. Eligible participants are adults with relapsed or refractory multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) criteria who have received multiple prior lines of therapy, have measurable disease, and meet protocol-defined organ function requirements.
Detailed description
This investigator-initiated Phase 1 clinical study is designed to evaluate the feasibility, safety, tolerability, and preliminary antitumor activity of autologous CS1-targeted chimeric antigen receptor T (CAR-T) cells in adults with relapsed or refractory multiple myeloma (MM). Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Although treatment options for multiple myeloma have expanded, patients with relapsed or refractory disease may develop resistance to available therapies and have limited treatment options. Cellular immunotherapies directed against antigens expressed on malignant plasma cells represent a potential therapeutic approach for this patient population. CS1, also known as signaling lymphocytic activation molecule family member 7 (SLAMF7; CD319), is a cell-surface antigen that is highly expressed on plasma cells and multiple myeloma cells. The expression of CS1 on malignant plasma cells provides a rationale for investigating CS1-directed CAR-T cell therapy. Autologous CS1-targeted CAR-T cells are genetically modified T lymphocytes designed to recognize CS1-expressing cells and mediate an immune response against target cells. This is a single-center, single-group, open-label, non-randomized Phase 1 study without a control arm. The study uses a dose-escalation design to evaluate different dose levels of autologous CS1-targeted CAR-T cells. Participants receive the investigational treatment according to the protocol-defined dose-escalation scheme. The investigational treatment consists of a single infusion of autologous CS1-targeted CAR-T cells. Participants undergo collection of autologous T cells for manufacture of the investigational CAR-T cell product. Once the CAR-T-cell product is ready, participants receive a single infusion of CS1-targeted CAR-T cells at the assigned dose level. Participants are subsequently monitored according to the study protocol for treatment-related adverse events, tolerability, and clinical and laboratory findings. The primary purpose of the dose-escalation portion of the study is to characterize the safety and tolerability of CS1-targeted CAR-T cell therapy across the planned dose levels. The study will also provide preliminary information regarding the antitumor activity of the investigational treatment. Disease assessments and safety evaluations will be conducted according to protocol-defined procedures and criteria. The study is intended to generate preliminary clinical evidence regarding the feasibility, safety, tolerability, and potential antitumor activity of autologous CS1-targeted CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. The findings may provide information to support further clinical investigation of CS1-targeted CAR-T cell therapy in this patient population.
Interventions
BIOLOGICALInfusion of CS1 CAR-T cell product
Infusion of CS1 CAR-T cell product
Sponsors
Qi Junyuan
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study. No masking is implemented because both investigators and participants are aware of the treatment administered.
Intervention model description
Single-group, open-label study without a control arm. All participants receive a single infusion of autologous CS1-targeted CAR-T cells.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects fully understand the trial purpose, study design, procedures, and potential adverse reactions, voluntarily agree to participate, and sign written informed consent before any study-related procedures are performed. 2. Subjects have no contraindications to leukapheresis. 3. Subjects are aged ≥ 18 years at screening. 4. Subjects have a confirmed diagnosis of relapsed or refractory multiple myeloma (RRMM) consistent with the International Myeloma Working Group (IMWG) diagnostic criteria. 5. Subjects have documented disease progression after receiving at least two lines of prior systemic therapy. Autologous or allogeneic hematopoietic stem cell transplantation (SCT) with corresponding supportive care is defined as one line of therapy. Subjects must have progressed after at least one proteasome inhibitor and one immunomodulatory agent. Subjects must have previously received CD38 monoclonal antibody therapy or be unsuitable for CD38 monoclonal antibody administration. All subjects must be currently ineligible for or decline autologous or allogeneic SCT. 6. Subjects have evaluable disease and meet at least one of the following conditions: 1. Serum M-protein ≥ 10 g/L; for subjects with IgA, IgD, IgE, or IgM multiple myeloma, serum M-protein ≥ 5 g/L. 2. 24-hour urinary M-protein ≥ 200 mg. 3. For light-chain multiple myeloma without measurable serum or urine M-protein: abnormal serum κ/λ free light chain (FLC) ratio and involved FLC ≥ 100 mg/L; 4. Presence of evaluable plasmacytoma on imaging examination, or bone marrow plasma cell proportion ≥ 10%, with reserved bone marrow fluid or tissue for CS1 expression detection. 7. Subjects have adequate organ function within the screening period and within 10 days prior to treatment initiation, as defined below: a. Renal function: i. Serum creatinine ≤ 2.5 × upper limit of normal (ULN); OR ii. 24-hour creatinine clearance ≥ 30 mL/min (calculated via the Cockcroft-Gault formula). b. Hepatic function: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN; ii. Total bilirubin (TBil) ≤ 2.0 × ULN. c. Hematological function: i. Absolute neutrophil count ≥ 0.5 × 109/L; ii. Absolute lymphocyte count ≥ 0.7 × 109/L; iii. Platelet count ≥ 25 × 109/L; iv. Hemoglobin ≥ 60 g/L. d. Biochemical and other baseline indicators: i. Corrected serum calcium ≤ 14 mg/dL (≤ 3.5 mmol/L) or ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L); ii. Prothrombin time (PT) ≤ ULN + 3 seconds; iii. Oxygen saturation ≥ 92% while breathing ambient air. 8. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to treatment initiation. Post-menopausal status (minimum 2 years of amenorrhea), prior total hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or congenital infertility confirms non-childbearing potential. 9. Subjects of childbearing potential, and male subjects with sexually active female partners of childbearing potential, must agree to use highly effective contraceptive methods (failure rate \< 1%) throughout the treatment period and for 12 months after the last study drug administration, including tubal ligation, male sterilization, hormonal implants, combined oral/injectable hormonal contraceptives, and approved intrauterine devices.
Exclusion criteria
1. Female subjects who are pregnant or breastfeeding. 2. Subjects unable to tolerate venous puncture required for leukapheresis and screening laboratory assessments. 3. Subjects with any of the following prior treatment histories: 1. Prior hematopoietic stem cell transplantation within 12 weeks before leukapheresis. 2. Administration of any live vaccine within 4 weeks before leukapheresis or planned live vaccine administration during study participation. 3. Use of immunosuppressive agents for the prophylaxis or treatment of graft-versus-host disease (GVHD) within 4 weeks before leukapheresis, or a confirmed diagnosis of acute or chronic GVHD at screening. 4. Receipt of any investigational product within 4 weeks prior to signing the informed consent form. 5. Concurrent enrollment in any other interventional clinical trial at screening. 4. Subjects presenting with any of the following medical conditions at screening: 1. Confirmed active central nervous system involvement, or clinical manifestations suggestive of multiple myeloma meningeal infiltration. 2. Poorly controlled hypertension despite stable medical therapy, defined as systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg at screening. 3. Left ventricular ejection fraction (LVEF) \<50% measured via screening Doppler echocardiography. 4. Any arrhythmia graded Grade 2 or higher per NCI CTCAE Version 5.0. 5. Prolonged QTc interval corrected by Fridericia formula (QTcF), defined as QTcF \>450 ms in male subjects or QTcF \>470 ms in female subjects. The correction formula is QTcF = QT / RR0.33. Subjects with such QTcF prolongation and concomitant use of QT-prolonging medications (including Class Ia and Class III antiarrhythmic agents) are excluded. 6. Documented personal history of torsades de pointes or congenital long QT syndrome. 7. Occurrence of any of the following cardiovascular adverse events within 6 months prior to signing informed consent: i. Myocardial infarction; ii. Severe or unstable angina pectoris; iii. Coronary artery bypass graft or peripheral arterial bypass surgery; iv. Congestive heart failure. h. Medical history of severe craniocerebral trauma, altered mental status, epilepsy, severe cerebral ischemia, or intracerebral hemorrhage. i. Any congenital or acquired neurological, vascular, or systemic disorder that may interfere with study safety monitoring or efficacy evaluation (examples include Parkinson's disease, cerebral palsy, diabetic neuropathy). j. Uncontrolled active infectious disease identified by investigator assessment during screening. k. Confirmed human immunodeficiency virus (HIV) infection. l. Positive hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody with active hepatitis B viremia (HBV DNA level exceeding the upper limit of normal). m. Positive anti-hepatitis C virus antibody (Anti-HCV) with detectable active HCV viremia, defined as HCV RNA ≥ 1.00×102 copies/mL. n. Well-documented severe hypersensitivity or anaphylactic reaction to human, humanized, or murine monoclonal antibodies. o. Prior history of solid organ transplantation. p. History of alcohol or illicit drug abuse within 52 weeks before screening visit, or ongoing alcohol abuse judged by the investigator. q. Unremitted psychotropic substance abuse history or clinically significant psychiatric disorders. r. Severe, inadequately controlled concomitant diseases (including but not limited to neurological, renal, hepatic, endocrine, and gastrointestinal disorders) that would prevent safe study participation per investigator judgment. s. Any clinically significant abnormal findings across nervous, cardiovascular, hematologic/lymphatic, immune, renal, hepatic, gastrointestinal, respiratory, metabolic, or skeletal systems that warrant exclusion from study enrollment. 5. Any other clinical condition determined by the investigator to render the subject unsuitable for participation in this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) Within 28 Days After Autologous CS1 CAR-T Cell Infusion | From the first CS1 CAR-T cell infusion through Day 28 after the first infusion | DLT is defined as a treatment-related adverse event or laboratory abnormality occurring after CS1 CAR-T cell infusion that meets protocol-defined criteria and is not attributable to the underlying disease, disease progression, concomitant disease, or concomitant medication. Hematologic DLT is non-disease-related Grade 4 toxicity lasting more than 30 days, excluding lymphopenia. Non-hematologic DLT is treatment-related Grade ≥3 toxicity that does not decrease to Grade ≤1 or baseline within 14 days despite appropriate management. Protocol-specified exceptions apply. The number and percentage of participants with DLTs will be summarized by CS1 CAR-T cell dose level. |
| Number of Participants With Treatment-Related Adverse Events Within 28 Days After Autologous CS1 CAR-T Cell Infusion | From the first CS1 CAR-T cell infusion through Day 28 after infusion | Treatment-related adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE). The number and percentage of participants experiencing treatment-related adverse events will be summarized by severity grade and relationship to CS1 CAR-T cell infusion during the protocol-defined 28-day DLT assessment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) According to the International Myeloma Working Group (IMWG) 2016 Criteria | From Day 28 after first infusion through Month 24 after infusion | ORR is defined as the percentage of participants achieving a best overall response of partial response (PR), minimal response (MR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), according to the IMWG 2016 response criteria. ORR will be summarized descriptively with the corresponding 95% confidence interval. |
| Complete Response Rate (sCR + CR) According to the International Myeloma Working Group (IMWG) 2016 Criteria | From Day 28 after first infusion through Month 24 after infusion | Complete response rate is defined as the percentage of participants achieving a best overall response of stringent complete response (sCR) or complete response (CR), according to the IMWG 2016 response criteria. CR requires negative serum and urine immunofixation, disappearance of soft-tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR additionally requires a normal serum free light-chain ratio and absence of clonal plasma cells in bone marrow. |
| Time to Response (TTR) According to the International Myeloma Working Group (IMWG) 2016 Criteria | From first infusion through Month 24 after infusion | TTR is defined as the time from the first CS1 CAR-T cell infusion to the first documented response of PR or better according to the IMWG 2016 criteria. TTR will be summarized descriptively among participants who achieve a response. |
| Duration of Response (DOR) According to the International Myeloma Working Group (IMWG) 2016 Criteria | From first documented response through Month 24 after infusion | DOR is defined as the time from the first documented response of PR or better according to the IMWG 2016 criteria to the first documented disease progression or death from any cause, whichever occurs first. Participants without progression or death will be censored at the date of the last disease assessment. |
| Progression-Free Survival (PFS) After CS1 CAR-T Cell Infusion | From first infusion through Month 24 after infusion | PFS is defined as the time from the first CS1 CAR-T cell infusion to the first documented disease progression according to the IMWG 2016 criteria or death from any cause, whichever occurs first. Participants without documented progression or death will be censored at the date of the last adequate disease assessment. PFS will be estimated using the Kaplan-Meier method. |
| Overall Survival (OS) After CS1 CAR-T Cell Infusion | From first infusion through Month 24 after infusion | OS is defined as the time from the first CS1 CAR-T cell infusion to death from any cause. Participants who are alive at the last known follow-up will be censored on the date they were last known to be alive. OS will be estimated using the Kaplan-Meier method. |
| Disease Control Rate (DCR) According to the International Myeloma Working Group (IMWG) 2016 Criteria | From Day 28 after first infusion through Month 24 after infusion | DCR is defined as the percentage of participants achieving a best overall response of minimal response (MR), partial response (PR), very good partial response (VGPR), complete response (CR), stringent complete response (sCR), or stable disease (SD), according to the IMWG 2016 criteria. DCR will be summarized descriptively with the corresponding 95% confidence interval. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORJunyuan Qi, MD
Tianjin Institute of Hematology & Hospital, Chinese Academy of Medical Sciences
Outcome results
None listed