TmCD19-IL18 in CD19+ Cancers
- Registration Number
- NCT05989204
- Lead Sponsor
- University of Pennsylvania
- Brief Summary
This is a Phase I, open-label dose finding study to assess the safety, tolerability, manufacturing 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 (as defined below). 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.
- Detailed Description
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).
* Dose Level 1a (N= 3 to 6): Subjects will receive a single dose of 5x10⁶ TmCD19-IL18 CAR T cells via IV infusion on Day 0, following lymphodepleting chemotherapy. This dose level will be evaluated as follows:
* If 0 DLT/3 Subjects or 1 DLT/3 Subjects occurs at DL1a, the study will enroll an additional 3 subjects at this dose level.
* If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.
* Dose Level 2 (N = 3 to 6): Subjects will receive a single fixed dose of 2x107 TmCD19-IL18 CAR T cells via IV infusion 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 3 (DL3).
* If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less than 6 subjects were treated at the previous dose level (DL1), additional subjects will be enrolled at that dose level to reach a minimum of 6 DLT-evaluable subjects for MTD determination.
* Dose Level 3 (N = 3 to 6): Subjects will receive a single fixed dose of 6x107 TmCD19-IL18 CAR T cells via IV infusion 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 occurs, the study will enroll an additional 3 subjects at this dose level.
* If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less than 6 subjects were treated at the previous dose level (DL2), additional subjects will be enrolled at that dose level to reach a minimum of 6 DLT-evaluable subjects for MTD determination.
The DLT observation period is 28 days post-TmCD19-IL18 CAR T cell infusion (Day 0). Formal DLT evaluations will be performed after the 3rd DLT-evaluable subject at each dose level completes this 28-dayDLT monitoring window. These assessments will be performed by the Clinical PI and Sponsor Medical Director in accordance with the definition in Section 8.1.7. This formal evaluation will trigger a decision regarding dose level advancement, expansion, or dose de-escalation.
To allow for appropriate monitoring/assessment of toxicities, the TmCD19-IL18 CAR T cell infusions will be staggered as follows within each disease-specific cohort:
* Dose Level 1 (DL1): The TmCD19-IL18 CAR T cell infusions for the first three subjects treated at DL1 must be staggered by a minimum of 28 days.
* Subsequent Dose Levels:
* If no DLTs were observed at the preceding dose level: The TmCD19-IL18 CAR T cell infusions for the first two subjects treated at this dose level must be staggered by a minimum of 28 days. The TmCD19-IL18 CAR T cell infusions for the 2nd and 3rd subjects treated at this dose level must be staggered by a minimum of 14 days.
* If DLTs were observed at the preceding dose level: The TmCD19-IL18 CAR T cell infusions for the first three subjects treated at a dose level must be staggered by at least 28 days.
* In the event DLT is identified at a dose level (e.g., 1 DLT/3 DLT-evaluable subjects), formal DLT evaluations must be completed after each additional TmCD19-IL18 CAR T cell infusion to evaluate potential dose de-escalation rules. As such, subsequent TmCD19-IL18 CAR T cell infusions within that same dose level must be staggered by a minimum of 28 days.
* If emergent safety concerns are identified, an ad hoc DLT evaluation may be triggered at the request of the Clinical PI and/or Sponsor Medical Director.
Subjects must receive the dose of TmCD19-IL18 CAR T cells as per their dose level assignment in order to be considered DLT-evaluable for dose escalation decisions and MTD determination. Subjects who do not receive the dose of TmCD19-IL18 CAR T cells as per their dose level assignment will not be considered DLT-evaluable for this purpose and will be replaced. However, these subjects will still be followed per protocol, and included in study analyses as described in analyses of secondary and exploratory endpoints..
The highest dose at which 0 or 1 DLT occurs in 6 evaluable subjects will be declared the MTD. The MTD will established for each disease-specific cohort.
Once the MTD of a disease-specific cohort is officially confirmed, the manufacturing feasibility at this dose level will also be formally evaluated. 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 each Cohort-Specific Dose Expansion Phase. Specifically, the dose level selected must be at or below the MTD and feasible from a manufacturing perspective. The sample size for the Expansion Phase will be determined based on the total sample size planned for that disease-specific cohort and the number of DLT-evaluable subjects previously treated in the Dose-Finding Phase prior to opening the Dose Expansion Phase. Please refer to Section 3.3 for complete information.
Retreatment Infusions:
The Retreatment Phase will remain closed until sufficient safety and persistence data is available in initial subjects, and DSMB and FDA approval to open Retreatment has been received.
Subjects who have demonstrated clinical benefit after their initial TmCD19-IL18 CAR T cell infusion (e.g., minimum disease response of stable disease, etc.) may also be eligible to receive retreatment with TmCD19-IL18 CAR T cells at the physician-investigator's discretion. The TmCD19-IL18 retreatment dose administered must either be a) the CAR T cell dose that the subject previously received without DLTs, or b) a CAR T cell that is less than or equal to a dose level that has been evaluated for safety in ≥ 3 other subjects within the same disease-specific cohort with an acceptable rate of DLTs (either 0 DLT/3 Subjects or 1 DLT/6 Subjects). As retreatment infusions will not be used for formal DLT assessments/MTD determination, there are no protocol-defined staggering requirements. Please refer to Section 6.12 for complete details.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 24
Not provided
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Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
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Class III/IV cardiovascular disability according to the New York Heart Association Classification.
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Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
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Active acute or chronic GVHD requiring systemic therapy.
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Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
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Receipt of prior huCART19-IL18 therapy.
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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.
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Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
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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.
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Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description NHL Dose Level 1 TmCD19-IL18 7x10\^6 TmCD19-IL18 cells administered as a single intravenous (IV) infusion NHL Dose Level -1 TmCD19-IL18 2x10\^6 TmCD19-IL18 cells administered as a single intravenous (IV) infusion NHL Dose Level 2 TmCD19-IL18 2x10\^7 TmCD19-IL18 cells administered as a single intravenous (IV) infusion NHL Dose Level 3 TmCD19-IL18 6x10\^7 TmCD19-IL18 cells administered as a single intravenous (IV) infusion NHL Dose Level 1a TmCD19-IL18 5x10\^6 TmCD19-IL18 CAR T cells
- Primary Outcome Measures
Name Time Method Incidence of Adverse Events as assessed by CTCAE v5.0 Up to 15 years Number of subjects with dose limiting toxicities (DLTs) 28 days after TmCD19-IL18 CART T cell infusion Determination of maximum tolerated dose (MTD) 28 days after TmCD19-IL18 CART T cell infusion
- Secondary Outcome Measures
Name Time Method Percentage of manufacturing products that meet release criteria 1 month Overall response rate (ORR) 4 months Progression Free Survival (PFS) 15 years Overall Survival (OS) 15 years Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells 15 years Presence or absence of malignant B cells by Next-Generation Immunoglobulin Heavy Chain Sequencing (NGIS)
Best overall response (BOR) 12 months Duration of response (DOR) 15 years
Trial Locations
- Locations (1)
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States