Phase I Trial of TmCD19-IL18 CAR T Cells in Patients With Relapsed or Refractory CD19+ Cancers

University of Pennsylvania1 个研究点分布在 1 个国家目标入组 26 人开始时间: 2023年11月13日最近更新: 2026年7月10日

适应症

干预措施

试验速览

阶段: 1 期
状态: 进行中（未招募）
发起方: University of Pennsylvania
入组人数: 26
试验地点: 1
主要终点: Incidence of Adverse Events as assessed by CTCAE v5.0

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a Phase I, open-label dose finding study to assess the safety and feasibility, pharmacokinetics, and preliminary efficacy of TmCD19-IL18 CAR T cells in patients with CD19+ cancers. This study will take place in two parts: a Dose-Finding Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In the Dose-Finding Phase, dose levels will be evaluated using a 3+3 dose escalation design to determine the MTD. Cumulative safety experience and manufacturing feasibility data from the Dose-Finding Phase will then be used to identify the dose level that can be progressed into the Dose Expansion Phase.

详细描述

This study will be initiated with a single disease-specific cohort (Cohort A: Non-Hodgkin Lymphoma). However, the study design allows for additional disease populations to be incorporated into the protocol as new cohorts in the future. Each disease-specific cohort will be evaluated independently for safety and dose-limiting toxicities (DLTs).

In Cohort A, up to 5 total TmCD19-IL18 CAR T cell dose levels will be evaluated as described below:

Dose Level 1 (N = 3 to 6): Subjects will receive a single dose of 7x10⁶ TmCD19-IL18 CAR T cells via IV infusion administration on Day 0, following lymphodepleting chemotherapy. This dose level will be evaluated as follows:
If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level 2 (DL2).
In the event that 2 or more DLTs occur at Dose Level 1, enrollment at this dose level will be stopped and Dose Level -1 (DL-1) will be opened.
Dose Level -1 (N= 3 to 6): Subjects will receive a single de-escalated dose of 2x10⁶ TmCD19-IL18 CAR T cells via IV infusion on Day 0, following lymphodepleting chemotherapy. This dose level will be evaluated as follows:
If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.
If 0 DLT/3 or 1 DLT/3 subjects occurs at DL-1, the study will enroll an additional 3 subjects at this dose level. As of Protocol Amendment V4, if 0 DLT/6 Subjects or 1 DLT/6 Subjects occurs at DL-1, the study will advance to a new intermediate Dose Level 1a (DL1a).

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

•Signed informed consent form
•Documentation of CD19 expression on malignant cells by flow cytometry/IHC from a CLIA certified laboratory.
•a. Cohort A (NHL): Within 6 months of physician-investigator confirmation of eligibility as long as there has been no intervening CD19 directed therapy since expression confirmed. Results outside of this window may be used, if there is no accessible tumor site and the subject did not receive intervening CD19 directed therapy since CD19 expression was confirmed.
•Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:
•Have no active GVHD and require no immunosuppression
•Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
•Adequate organ function defined as:
•Estimated creatinine clearance > 35 mL/min and not on dialysis
•ALT/AST ≤ 3x upper limit of normal range
•Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl)
•Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
•Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO
•Evidence of active disease within 12 weeks of physician-investigator confirmation of eligibility.
•Male or female age ≥ 18 years.
•ECOG Performance Status that is either 0 or
•Disease-specific criteria:
•a. Cohort A (NHL): i. Patients with any of the following diagnoses: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS), germinal center or activated B-cell types; Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e., "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma.
•1. Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria:
•Relapsed/refractory disease after at least 2 prior lines of appropriate therapy; OR
•Relapsed/refractory disease after autologous SCT; OR
•Relapsed/refractory disease after allogeneic SCT.
•ii. Follicular lymphoma
•Patients must have either relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
•Received at least 2 prior lines of appropriate therapy (not including single agent monoclonal antibody therapy) and progressed within 2 years after second or higher line of therapy.
•iii. Mantle cell lymphoma
•Patients must have either failed standard of care CAR T cell therapy (e.g., Tecartus™, etc.) or other investigational CAR T cell product, OR be ineligible for standard of care Tecartus™; and
•Patients must also meet one of the following criteria:
•Relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a BTK inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy; OR
•Relapsed/refractory disease after prior autologous SCT; OR
•Relapsed/refractory disease after prior allogeneic SCT. iv. Marginal Zone Lymphoma
•1. Patients must have received at least 2 prior lines of appropriate therapy which includes a BTK inhibitor (not including single agent monoclonal antibody therapy).

排除标准

•Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
•Class III/IV cardiovascular disability according to the New York Heart Association Classification.
•Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
•Active acute or chronic GVHD requiring systemic therapy.
•Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
•Receipt of prior huCART19-IL18 therapy.
•CNS disease as defined by disease-cohort as follows:
•a. Cohort A: Active CNS disease. Note: Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
•Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
•Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment.
•Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.