NCT04815356招募中1 期
Phase I Study of Anti-CD22 Chimeric Receptor T Cells in Patients With Relapsed/Refractory Hairy Cell Leukemia and Variant
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 27
- 试验地点
- 2
- 主要终点
- antitumor effect
研究概览
简要总结
Background:
CAR (Chimeric Antigen Receptor) T cell therapy is a type of cancer treatment in which a person s T cells (a type of immune cell) are changed in a laboratory to recognize and attack cancer cells. Researchers want to see if this treatment can help people with hairy cell leukemia (HCL).
Objective:
To test whether it is safe to give anti-CD22 CAR T cells to people with HCL.
Eligibility:
Adults ages 18 and older with HCL (classic or variant type) who have already had, are unable to receive, or have refused other standard treatments for their cancer.
Design:
Participants will be screened with the following:
Medical history
Physical exam
Blood and urine tests
Biopsy sample
Electrocardiogram
Echocardiogram
Lung function tests
Imaging scans
Some screening tests will be repeated during the study.
Participants may need to have a catheter placed in a large vein.
Participants will have magnetic resonance imaging of the brain.
Participants will have a neurologic evaluation and fill out questionnaires.
Participants will have leukapheresis. Blood will be removed from the participant. A machine will divide whole blood into red cells, plasma, and lymphocytes. The lymphocytes will be collected. The remaining blood will be returned to the participant.
Participants will get infusions of chemotherapy drugs.
Participants will get an infusion of the anti-CD22 CAR T cells. They will stay at the hospital for 14 days. Then they will have visits twice a week for 1 month.
After treatment, participants will be followed closely for 6 months, and then less frequently for at least 5 years. Then they will have long-term follow-up for 15 years.
详细描述
Background
- Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias. Most cases of HCL respond well to purine analog chemotherapy and harbor BRAF V600E mutation that can be considered for targeted treatment at the time of relapse. However, there are patients with high-risk HCL such as patients with BRAF wild type IGHV4-34 unmutated HCL who respond poorly to chemotherapy and have poor survival.
- HCL variant (HCLv), also brightly CD22+, resembles HCL morphologically but is more aggressive and responds poorly to standard purine analog chemotherapy. Patients have fewer options of targeted treatment partly due to wild type BRAF. We showed that the overall survival in patients progressed after cladribine-rituximab is less than three years.
- Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin which in 2018 was FDA-approved for adult patients with relapsed/refractory HCL. However, there are patients with HCL and HCLv who progress after treatments with standard purine analog chemotherapy and moxetumomab pasudotox-tdfk, and in the case of classic HCL, even after BRAF +/- MEK inhibition. There is still an unmet need for new treatment options for those with relapsed/refractory disease.
- Adoptive cellular therapy with T-cells genetically modified using viral-based vectors to express chimeric antigen receptors (CAR) targeting the CD22 molecule have demonstrated dramatic clinical responses in patients with CD22+ acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL).
- Moxetumomab pasudotox-tdfk proved that CD22 is a potent target for HCL due to its ubiquitous expression in HCL and HCLv, and cellular therapy represents a promising target for those patients that have progressed after other treatments options with chemotherapy, immunotherapy and targeted therapy. This will be the first trial of anti-CD22 CAR T-cell therapy in the treatment of relapsed/refractory HCL and HCLv.
Objectives
- To assess the safety and feasibility of administering escalating doses of autologous anti-CD22-CAR (M971BBz) engineered T-cells in participants with HCL/HCLv following a cyclophosphamide/fludarabine lymphodepletion regimen.
- Explore whether the administration of anti-CD22-CAR engineered T-cells can mediate antitumor effects in HCL/HCLv.
Eligibility
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
- •INCLUSION CRITERIA
- •Histologically confirmed diagnosis of HCL or HCLv according to morphological and immunophenotypic criteria of WHO classification [WHO, 2008 revised 2016] of lymphoid neoplasm.
- •Participants should have any of the following indications for therapy:
- •ANC <1/nL,
- •Hemoglobin <10g/dL,
- •Platelets<100/nL,
- •Symptomatic splenomegaly,
- •HCL mass with short axis > 2 cm outside or >0.5 cm inside the CNS,
- •HCL/HCLv count >5/nL in blood or >25/mm^3 in CSF,
- •HCL/HCLv count doubling time <6 months and increasing lytic or blastic bone lesions
- •Participants who have eligible blood counts within 4 weeks from the initiation of study will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.
- •HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1)rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab pasudotox-tdft, and 3) BRAF-inhibition.
- •CD22 expression must be detected on greater than 80% of malignant cells by flow cytometry.
- •Participants must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease (MRD) detected by flow cytometry or immunohistochemistry.
- •Age >=18 years
- •ECOG performance <=2 (Karnofsky >=60%, see Appendix A), participants are exempt from this criterion if poor performance status is related to HCL.
- •Participants must have adequate organ function as defined below: Participants must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. If participants exhibit minor lab abnormalities that are determined to be related to HCL (not therapy-related), then those participants will be allowed to participate
- •Total bilirubin <= 3 ULN, unless consistent with Gilbert s (ratio between total and direct bilirubin > 5)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x upper limit of normal (ULN)
- •Alkaline phosphatase < 2.5 ULN
- •Serum creatinine <= 1.5 mg/dL or creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal calculated using eGFR or measured
- •Serum albumin > 2 g/dL
- •Prothrombin time (PT)/International Normalized Ratio (INR) < 2.5x ULN (if on warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, PT < 2.5x ULN
- •Fibrinogen >= 0.5x lower limit of normal
- •Participants with CNS disease are eligible, with exceptions
- •Participants with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active graft-versus-host disease (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to initiation of study intervention.
- •Women of childbearing potential (WOCBP) must agree to use effective contraception (barrier, hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy or 4 months after cells infusion, whichever is later.
- •Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drug.
- •Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 4 months after the last dose of study drug.
- •Ability of participant to understand and the willingness to sign a written informed consent document.
排除标准
- •Pregnancy
- •Systemic chemotherapy, immunotherapy, or radiation therapy <= 2 weeks prior to apheresis with the following exception:
- •Participants receiving steroids may be enrolled, provided there has been no increase in dose for at least 1 week prior to starting apheresis;
- •For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment (including CNS radiation), with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the participant has measurable/evaluable disease outside the radiation port.
- •Other anti-neoplastic investigational agents, or antibody-based therapies currently or within 2 weeks prior to apheresis
- •Participants taking warfarin
- •Prior CAR therapy within 30 days prior to apheresis or prior CAR therapy at any time with evidence for persistence of CAR T cells in blood samples (circulating levels of genetically modified cells of >= 5% by flow cytometry)
- •Seropositive for human immunodeficiency virus (HIV) antibody. (Participants with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy in the future should study results indicate effectiveness.)
- •Seropositive for hepatitis C virus (HCV) or positive for hepatitis B surface antigen (HbsAG). Participants who convert to negative will not be excluded for history of positive test.
- •Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, asthma, chronic obstructive pulmonary disease, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject
- •History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e., gentamicin)
研究组 & 干预措施
Experimental therapy: Dose Escalation
Experimental
Escalating doses of autologous anti-CD22-CAR T-cells in subjects to determine the MTD
干预措施: CD22CART cell infusion (Biological)
Experimental therapy: Dose Expansion
Experimental
Autologous anti-CD22-CAR T-cells at the MTD
干预措施: CD22CART cell infusion (Biological)
结局指标
主要结局
antitumor effect
时间窗: every year for 15 years
The fraction of participants who experience a CR among the 10 evaluable participants treated at the MTD or highest safe dose
safety and feasibility
时间窗: end of treatment
Fraction of participants at each dose level who experience a toxicity along with the grades and types of toxicity and which can successfully manufacture the targeted dose number
次要结局
- expansion and persistence(every year for 5 years)
- event free survival(every year for 15 years)
- MRD negative CR(every year for 15 years)
- duration of response(every year for 15 years)
- progression free-survival(every year for 15 years)
- overall survival(every year for for 15 years or until death)
- time to next treatment(every year for 15 years)
- expansion and persistence(every year for 5 years)
- event free survival(every year for 15 years)
- time to next treatment(every year for 15 years)
研究者
研究点 (2)
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