A Phase 1/2 Study of T-cell Expressing an Anti-CD22 Chimeric-Antigen Receptor (SHB-04-CD22) in Patients With CD22-expressing B-cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Efficacy Evaluation
研究概览
简要总结
This is a phase I/II trial of T-cell expressing an anti-CD22 Chimeric-Antigen-Receptor (CAR) in patients with CD22 expressing B-cell malignancies. This trial is an open label, single-arm, for pediatric and adult patients with relapsed/refractory B-cell malignancies.
详细描述
B-cell precursor Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and an adult malignancy with poor prognosis. B-cell non-Hodgkin lymphoma (NHL) and common lymphocytic leukemia (CLL) arise from mature B-cells, and are more commonly seen in the adult and elderly population. In the recent decade, advances in immunotherapy targeting cell surface markers, using antibodies, antibody-drug conjugates, bispecific antibodies or CAR-T cells, have improved the outcome of patients with relapsed and refractory B-cell malignancies. CAR-T cell products targeting CD19, a common B-cell antigen, are approved for B-cell malignancies. Treatment with CD19 CAR-T cells was FDA approved for pediatric ALL, adult ALL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma (MCL) and primary mediastinal B-cell lymphoma (PMBCL). Still, most patients with B-cell malignancies treated nowadays with commercial CD19 CAR T-cells relapse. To address this, alternative immunotherapy targets have been proposed. CD22 is an additional co-receptor on B-cells, commonly expressed in B-cell malignancies such as ALL, and has been most studied in this context. Autologous T cells will be harvested from patients with B-cell malignancies and then activated and transduced with a retrovirus containing a chimeric-antigen receptor (CAR), manufactured by the Advanced Biotherapy Center (ABC) at the Sheba Medical Center. Patients will undergo a one-time cell collection via apheresis, after which the cells will be sent to the laboratory for activation and introduction of a gene that recognizes the CD22 antigen. Patients will receive lymphodepleting chemotherapy followed by a single dose of CD22 CAR-T cells (SHB-04-CD22), after which they will be monitored and undergo various research assessments (including blood tests, genetic tests, and assessments of the disease status). Patients will be closely monitored for approximately 3 months after treatment to assess response and safety of the treatment. Long-term survival monitoring will take place once a year for 15 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 80 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient must have a CD22-expressing hematologic malignancy, relapsed or refractory after receiving at least 2 lines of standard therapy including CD19-directed therapy (For CD19 positive disease):
- •Relapse following standard relapse protocol (2nd relapse), including CD19 CART.
- •Primary refractory, i.e. failed to achieve morphologic remission after 2 lines of induction chemotherapy.
- •Age 1-80 years
- •CD22 expression shown by flow cytometry on at least 70% of leukemic blasts / lymphoma cells
- •Adequate CD3 count (above 120 CD3+ cells per microliter blood)
- •Clinical performance status: Patients > 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
- •Females of child-bearing potential must have a negative pregnancy test
- •Cardiac function: LV ejection fraction >45% or shortening fraction >28%
- •At least 60 days after autologous or allogeneic BMT
- •At least 30 days after prior CAR therapy in absence of response
排除标准
- •Hyperleukocytosis (WBC>50,000) or rapidly progressive disease that in the judgment of the PI can compromise the ability of the patient to complete the study
- •Pregnant or breast-feeding females
- •Hepatic dysfunction, defined as bilirubin > x2 upper normal limit (except when explained by hemolysis or Gilbert) or SGOT > x2.5 upper normal limit.
- •Evidence of active Hepatitis B, Hepatitis C or HIV infection.
- •Prior therapy:
- •Patients should be off steroids for at least 2 weeks prior to apheresis
- •Patients should be off systemic anti-neoplastic treatment for 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy. Patients who received prior clofarabine and fludarabine should have a wash out period of 3 months prior to apheresis.
- •Patients should have recovered from all toxicities attributed to prior therapy. Cytopenias that are considered disease related rather than therapy related are exempt from this exclusion.
- •Radiation therapy should be completed at least 3 weeks prior to apheresis.
研究组 & 干预措施
Single arm, open label, dose escalation: Anti CD22 CAR-T (SHB-04-CD22)
Phase 1 of this study includes a dose escalation plan of anti CD22 CAR-T (SHB-04-CD22). Treatment will start at dose level 1. According to safety assessments, dose will increase to next dose level.
Dose level 1: 3x10^5 CAR+ T cells per kilogram Dose level 2: 1x10^6 CAR+ T cells per kilogram Dose level 3: 3x10^6 CAR+ T cells per kilogram
Phase 2 of this study will be a dose expansion phase of the dose recommended based on safety and expected efficacy.
干预措施: CD22 CAR-T cells (Other)
结局指标
主要结局
Efficacy Evaluation
时间窗: 1 month to 1 year post treatment.
An evaluation of the feasibility and efficacy of administering anti-CD22-CAR T cells (SHB-04-CD22) in patients with B-cell malignancies at the Sheba Medical Center. Efficacy will be determined by an evaluation of disease response in participants post treatment. Disease response will be assessed by blasts percentage in bone marrow for ALL patients and by PET-CT scan based on the Lugano classification for NHL patients.
Safety Evaluation: Treatment Related Toxicities
时间窗: From enrollment to 3 months post treatment.
An evaluation of safety of the use of autologous anti-CD22 CAR T cells (SHB-04-CD22) manufactured at the Sheba Medical Center, in patients with relapsed/refractory B-cell malignancies. Safety will be determined by evaluation of participants with treatment-related adverse events, as assessed by CTCAE 5.0.
Minimal toxic dose evaluation
时间窗: From first dose to end 3 months post treatment.
An evaluation of the minimal toxic dose of CD22 CAR-T cells (SHB-04-CD22). This will be determined by evaluation of participants with treatment-related adverse events, as assessed by CTCAE 5.0, and according to different dose levels administered.
次要结局
未报告次要终点
研究者
Elad Jacoby, MD
Principal Investigator, Pediatric Hematology and Oncology
Sheba Medical Center