CAR T Cells in Mesothelin-Expressing Breast Cancer
Study Details
Study Description
Brief Summary
Phase 1 - Safety and Proof of Concept
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a phase I study to establish the safety and feasibility of lentiviral transduced CAR T cell products in patients with mesothelin expressing breast cancer. This study will be initiated as a single cohort (described below), however the adaptive design will allow for additional disease indications and other investigational CAR T cell products to be explored as separate cohorts under this protocol in the future.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose Level 1 3.00 x 10^7 CAR T cells administered intratumoral |
Drug: huCART-meso cells
Autologous T cells lentivirally transduced with chimeric anti-mesothelin immunoreceptor M5 scFv fused to the 4-1BB and CD3ζ signaling domains
Device: Mesothelin Expression Testing
Laboratory Developed Test
|
| Experimental: Dose Level -1 3.00 x 10^6 CAR T cells administered intratumoral |
Drug: huCART-meso cells
Autologous T cells lentivirally transduced with chimeric anti-mesothelin immunoreceptor M5 scFv fused to the 4-1BB and CD3ζ signaling domains
Device: Mesothelin Expression Testing
Laboratory Developed Test
|
Outcome Measures
Primary Outcome Measures
- Occurrence of treatment-limiting toxicities (TLTs) [90 days]
- Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. [15 years]
Secondary Outcome Measures
- Proportion of manufacturing product that do not meet the release criteria. [60 days]
manufacturing failures
- Proportion of the products that meet the target dose. [60 days]
- Proportion of enrolled subjects that receive study treatment. [60 days]
- Proportion of eligible subjects that receive study treatment [60 days]
- Proportion of subjects for which standard of care treatment is not impacted due to CAR T cell related toxicity. [90 days]
- Kinetics of expansion and persistence of infused cells by flow cytometry. [90 days]
- Kinetics of expansion and persistence of infused cells by quantitative PCR. [90 days]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with locally advanced unresectable or metastatic triple-negative breast cancer as confirmed by all of the following:
-
ER-negative or low-ER positive (≤ 10% by IHC)
-
PR-negative or low-PR positive (≤ 10% by IHC)
-
HER2 negative by IHC/FISH
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Patients with an accessible lesion that can be targeted for both intratumoral injection and surgical excision/biopsy by either a surgeon or interventional radiology.
-
Confirmed tumor mesothelin expression by ≥ 10% of malignant cells by IHC.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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Adequate organ and bone marrow function defined as:
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Bilirubin ≤ 2.0 x ULN
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Serum Creatinine ≤ 1.5 x ULN
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ALT/AST ≤ 3 x ULN
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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) ≥ 45% confirmed by echocardiogram
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Male and female patients ≥ 18 years of age.
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Provides written informed consent.
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Subjects of reproductive potential must agree to use acceptable birth control methods
Exclusion Criteria:
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Active invasive cancer other than the study-targeted malignancy.
-
Evidence of active hepatitis B or hepatitis C. The following would not qualify as an active infection, thus would not exclude the subject from participating:
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Positive HBV serology with undetectable viral load and ongoing antiviral prophylaxis for potential HBV reactivation.
-
Positive HCV serology with quantitative PCR for plasma HCV RNA below the lower limit of detection, with or without concurrent antiviral HCV treatment.
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Patients with ongoing or active infection.
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Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg/day of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
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Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (≤ 10mg daily equivalent of prednisone). Use of inhaled or topical steroids is allowable.
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History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
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Pregnant or breastfeeding women.
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Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heart Association Classification or other cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study. This determination will be made by a cardiologist if cardiac issues are suspected.
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Patients with significant lung disease as follows:
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Patients with radiographic evidence of greater than lobar lymphangitic pulmonary involvement, greater than lobar bronchial wall thickening suggestive of peribronchial lymphatic disease extension, and/or evidence of extensive bilateral parenchymal metastatic burden.
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Patients with radiographic and/or clinical evidence of active radiation pneumonitis.
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Patients with radiographic evidence of underlying interstitial lung disease, including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy, targeted agents, amiodarone, nitrofurantoin, etc).
-
Patients with active central nervous system (CNS) involvement. Screening for this (e.g. lumbar puncture, brain MRI, etc) is not required unless the patient is symptomatic and/or radiographic findings are present.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
Sponsors and Collaborators
- University of Pennsylvania
Investigators
- Principal Investigator: Julia Tchou, MD, PhD, University of Pennsylvania
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UPCC# 15122, IRB # 852205