TmCD19-IL18 in CD19+ Cancers
Study Details
Study Description
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, up to 4 total dose levels will be evaluated using a 3+3 dose escalation design in order to determine the MTD (as defined below). Both safety and manufacturing feasibility will then be used to identify the dose level that can be progressed into the Dose Expansion Phase.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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) as follows Dose escalation will begin with Dose Level 1 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 levelwill be evaluated as follows:
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If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level 2 (DL2).
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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. In DL-1, subjects will receive a de-escalated dose of 3x10⁶ TmCD19-IL18 CAR T cells.
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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.
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If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.
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Dose Level 2 (N = 3 to 6): Subjects will receive a single fixed dose of 3x10⁷ TmCD19-IL18 CAR T cells via IV infusion on Day 0, following lymphodepleting chemotherapy. This dose level will be evaluated as follows:
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If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level 3 (DL3).
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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 evaluable subjects for MTD determination.
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Dose Level 3 (N = 3 to 6): Subjects will receive a single fixed dose of 7x107 TmCD19-IL18 CAR T cells via IV infusion Day 0, following lymphodepleting chemotherapy.
This dose level will be evaluated as follows:
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If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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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 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 evaluable subject at each dose level completes this 28-day DLT monitoring window. These assessments will be performed by the Clinical PI and Sponsor Medical Director in accordance with the definition in Section 8.1.6 of the protocol. This formal evaluation will trigger a decision regarding dose level advancement, expansion, or dose de-escalation.
In order to allow for appropriate monitoring/assessment of toxicities, the TmCD19-IL18 CAR T cell infusions will be staggered as follows:
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The TmCD19-IL18 CAR T cell infusions for the first two subjects treated on this study must be staggered by at least 28 days.
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The 3rd subject at each dose level may not receive TmCD19-IL18 CAR T cells until the 1st subject at that dose level has completed the 28-day DLT monitoring window.
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In the event 1 DLT is identified at a dose level (e.g., 1 DLT/3 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.
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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 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 evaluable for this purpose and will be replaced. However, these subjects will still be included in the overall safety analysis, as well as the 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. Both safety and manufacturing feasibility will 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/below the MTD and feasible from a manufacturing perspective. The sample size for the Expansion Phase will be calculated based on the total sample size for that disease-specific cohort and the number of evaluable subjects previously treated in the Dose-Finding Phase prior to opening the Dose Expansion Phase. Please refer to Section 3.3 of the protocol for complete information.
• Cohort-Specific Dose Expansion Phase: Subjects will receive a single fixed dose of TmCD19-IL18 CAR T cells at the selected dose level via IV infusion Day 0, following lymphodepleting chemotherapy. Subjects treated under the expansion phase will be evaluated for overall safety and will not be factored into DLT evaluations/analysis. As such, there are no protocol-defined staggering requirements under this expansion phase.
Re-treatment Infusions:
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 re-treatment with TmCD19-IL18 CAR T cells at the physician-investigator's discretion. The TmCD19-IL18 re-treatment 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 ≥ 1 other subject within the same disease-specific cohort without evidence of DLTs. As re-treatment infusions will not be used for formal DLT assessments/MTD determination, there are no protocol-defined staggering requirements.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: NHL Dose Level 1 7x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion |
Biological: TMhuCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
|
| Experimental: NHL Dose Level -1 3x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion |
Biological: TMhuCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
|
| Experimental: NHL Dose Level 2 3x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion |
Biological: TMhuCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
|
| Experimental: NHL Dose Level 3 7x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion |
Biological: TMhuCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
|
Outcome Measures
Primary Outcome Measures
- 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]
- Incidence of Adverse Events as assessed by CTCAE v5.0 [Up to 15 years]
Secondary Outcome Measures
- Percentage of manufacturing products that meet release criteria [Up to 3 years]
- Overall response rate (ORR) [Up to 3 months]
- Best overall response (BOR) [up to one year]
- Duration of response (DOR) [Up to one year]
- Overall Survival (OS) [Up to one year]
- Progression Free Survival (PFS) [Up to one year]
- Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells [Up to one year]
Polychromatic flow cytometry-based assessment of lymphoma and B cells
- Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells [Up to one year]
Presence or absence of malignant B cells by Next-Generation Immunoglobulin Heavy Chain Sequencing (NGIS)
Eligibility Criteria
Criteria
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Signed informed consent form
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Documentation of CD19 expression on malignant cells by flow cytometry/IHC at the Hospital ofthe University of Pennsylvania.
- Cohort A (NHL): Within 6 months of physician-investigator confirmation of eligibility aslong 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 immuno-suppressionb. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
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Adequate organ function defined as:
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Estimated creatinine clearance > 35 mL/min and not on dialysis
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ALT/AST ≤ 3x upper limit of normal range
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Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl)
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Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
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Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO
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Evidence of active disease within 12 weeks of physician-investigator confirmation of eligibility.
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Male or female age ≥ 18 years.
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ECOG Performance Status that is either 0 or 1.
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Disease-specific criteria:
- 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.
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Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria:
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Relapsed/refractory disease after at least 2 prior lines of appropriate therapy; OR
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Relapsed/refractory disease after autologous SCT; OR
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Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma
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Patients must have either relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
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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.
- 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™; and2. Patients must also meet one of the following criteria:
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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
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Relapsed/refractory disease after prior autologous SCT; OR
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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).
Exclusion Criteria:
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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 (see Appendix 5 of the protocol).
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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 immuno-suppressant medications. For additional details regarding use of steroid and immuno-suppressant medications, please see Section 5.5 of the protocol.
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Receipt of prior huCART19-IL18 therapy.
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CNS disease as defined by disease-cohort as follows:
- 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, as described in protocol Section 4.3 of the protocol.
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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 immuno-suppressive treatment equivalent to ≥10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will beexcluded.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University of Pennsylvania
- Kite, A Gilead Company
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UPCC 12423