Phase 1 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of CS1 CAR-T (WS-CART-CS1) in Subjects With Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Part A: Frequency and severity of treatment-emergent adverse events
研究概览
简要总结
Despite recent therapeutic advances, multiple myeloma (MM) remains an incurable disease. Although survival has improved, there are nevertheless diminishing durations of response to each subsequent line of therapy. This highlights the need for further therapeutic innovation. BCMA-targeting CAR-T cells show impressive response rates; however, their median duration of response is disappointing. The investigators propose that CS1(SLAMF7)-targeting CAR-T cells will fill a gap in the MM armamentarium.
CS1 is an attractive target in MM because it is expressed in most patients. Elotuzumab (Empliciti®), an approved anti-CS1 antibody, has proven the clinical efficacy of this target. CAR-T cells are an ideal modality to target CS1, given that two approved treatments, ide-cel (idecabtagene vicleucel, AbecmaTM) and cilta-cel (ciltacabtagene autoleucel, Carvykti™), have proven the potential for cellular immunotherapy in MM.
The investigators are testing the safety and preliminary anti-myeloma efficacy of WS-CART-CS1, a CAR-T cell therapy targeting CS1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory multiple myeloma after 3 or more prior lines of therapy, including proteasome inhibitor (e.g. bortezomib or carfilzomib), anti-CD38 therapy (e.g. daratumumab), and anti-BCMA therapies (e.g. BCMA bispecific antibodies or BCMA CAR-T)
- •Measurable disease, defined as meeting at least one of the following criteria:
- •Serum M-protein ≥ 0.5 g/dL
- •Urine M-protein ≥ 200 mg/24 h
- •In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase) must be >10 mg/dL for consideration of defining progression before enrollment
- •A biopsy-proven plasmacytoma
- •Bone marrow plasma cells > 30% of total bone marrow cells
- •At least 18 years of age.
- •ECOG performance status ≤ 1
- •Adequate renal, hepatic, respiratory, and cardiovascular function, as defined below:
- •Renal function:
- •calculated creatinine clearance ≥ 50 mL/min/1.73 m2 OR
- •radioisotope glomerular filtration rate ≥ 50 mL/min/1.73 m2 OR
- •normal serum creatinine based on age/gender per institutional normal range
- •Hepatic function:
- •ALT (SGPT) ≤ 5 x ULN for age
- •Total bilirubin ≤ 2.0 x IULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin)
- •Respiratory function:
- •Minimum level of pulmonary reserve defined as oxygen saturation > 91% measured by pulse oximetry on room air
- •Cardiovascular function:
- •LVEF ≥ 45% confirmed by echocardiogram or MUGA within 28 days of screening
- •The effects of CS1 CAR-T on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (at least 2 forms of contraception, including one barrier method) prior to study entry and for 12 months after CS1 CAR-T infusion. If a female subject or female partner of a male subject becomes pregnant during therapy or within 12 months following WS-CART-CS1 infusion, the investigator must be notified in order to facilitate outcome follow-up.
- •Ability to understand and willingness to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).
排除标准
- •Any prior systemic therapy for multiple myeloma within 14 days before planned day of leukapheresis.
- •A history of other malignancy with the exception of treated non-melanomatous skin cancers and malignancies for which all treatment was completed at least 2 years before registration and the subject has no evidence of disease.
- •Currently receiving any other investigational agents.
- •Receipt of any cellular therapy within 8 weeks prior to the planned start of conditioning.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CS1 CAR-T or other agents used in the study.
- •History of Grade 3 CRS or ICANS with other CAR-Ts (including BCMA CAR).
- •Active hepatitis B, active hepatitis C, any uncontrolled infection, or HIV infection.
- •Ongoing or active infection or other serious underlying medical condition that would impair the ability to receive protocol treatment.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
研究组 & 干预措施
Part A Dose Escalation: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part A is the dose escalation portion of the study.
干预措施: Lymphodepleting chemotherapy (Drug)
Part B Dose Expansion: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part B is the dose expansion portion of the study. The dose of WS-CART-CS1 will be determined in Part A of the study.
干预措施: Lymphodepleting chemotherapy (Drug)
Part A Dose Escalation: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part A is the dose escalation portion of the study.
干预措施: WS-CART-CS1 (Biological)
Part B Dose Expansion: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part B is the dose expansion portion of the study. The dose of WS-CART-CS1 will be determined in Part A of the study.
干预措施: WS-CART-CS1 (Biological)
结局指标
主要结局
Part A: Frequency and severity of treatment-emergent adverse events
时间窗: From leukapheresis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)
* Graded by CTCAE v 5.0. * Adverse events will be tracked at the time of leukapheresis through 28 days post leukapheresis, to capture any AEs related to leukapheresis only. * Adverse events will then be collected beginning with lymphodepletion chemotherapy and continue through Day 100 post WS-CART-CS1 infusion or until initiation of another anticancer therapy, whichever occurs first. * After Day 100, only targeted AEs will be reported through 24 months after WS-CART-CS1 infusion or until disease progression or relapse, whichever occurs first. Targeted AEs include and are limited to secondary malignancies, CRS, ICANS, prolonged cytopenia (defined as Grade 3 neutropenia or thrombocytopenia lasting more than 28 days after WS-CART-CS1 infusion), and SAEs or SUSARs that are not attributable to progressive disease or extraneous causes.
Part A: Frequency of dose-limiting toxicities (DLTs)
时间窗: From WS-CART-CS1 infusion through 28 days
DLTs are defined in the protocol.
Part B: Frequency and severity of treatment-emergent adverse events
时间窗: From leukaphereis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)
* Graded by CTCAE v 5.0. * Adverse events will be tracked at the time of leukapheresis through 28 days post leukapheresis, to capture any AEs related to leukapheresis only. * Adverse events will then be collected beginning with lymphodepletion chemotherapy and continue through Day 100 post WS-CART-CS1 infusion or until initiation of another anticancer therapy, whichever occurs first. * After Day 100, only targeted AEs will be reported through 24 months after WS-CART-CS1 infusion or until disease progression or relapse, whichever occurs first. Targeted AEs include and are limited to secondary malignancies, CRS, ICANS, prolonged cytopenia (defined as Grade 3 neutropenia or thrombocytopenia lasting more than 28 days after WS-CART-CS1 infusion), and SAEs or SUSARs that are not attributable to progressive disease or extraneous causes.
次要结局
- Part A MTD and Part B: Disease-specific objective response rate (ORR)(Within 3 months of WS-CART-CS1 infusion)
- Part A MTD and Part B: Minimal residual disease (MRD) negativity in the marrow(Week 12)
- Part A MTD and Part B: Duration of response (DoR)(-From response 24 months after WS-CART-CS1 infusion (estimated to be 24 months))
- Part A MTD and Part B: Progression-free survival (PFS)(From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years))
- Part A MTD and Part B: Overall survival (OS)(From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years))