CAR T Cell Immunotherapy for Pancreatic Cancer
Study Details
Study Description
Brief Summary
Phase I study to establish the safety and feasibility of both intravenous administration and local delivery of lentiviral transduced huCART-meso cells in patients with histologically confirmed unresectable or metastatic pancreatic adenocarcinoma
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a Phase I study evaluating the safety and feasibility of lentiviral transduced huCART-meso cells in up to 4 cohorts. Lymphodepleting chemotherapy will not be utilized as part of the planned dosing strategy.
• Cohort 1 (N=3-6): will receive a single dose of 1-3x107/m2 lentiviral transduced huCART-meso cells on day 0 via intravenous infusion.
- Enrollment into Cohort 1 will be paused after the 3rd subject is infused to allow for a formal DLT assessment (performed by the Clinical PI and Medical Director) and DSMB review. If 1 DLT/3 subjects occurs in Cohort 1, the Sponsor (with guidance from the DSMB), will determine whether the study will enroll an additional 3 subjects at this dose level to further establish safety via intravenous infusion, or advance to Cohorts 2 and 3 to explore local delivery of huCART-meso cells at the same dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs at any time, the study may advance to Cohorts 2 and
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If 2 DLTs occur at this dose level at any time, enrollment in Cohort 1 will be stopped and the dose will be de-escalated by 10-fold to 1-3x106 cells/m2 (Cohort -1).
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The infusions in Cohort 1 will be staggered by at least 28 days to allow for the assessment of DLTs for cohort progression, expansion, or dose de-escalation.
In the event that 2 DLTs occur among subjects enrolled in Cohort 1, then enrollment in Cohort 1 will be stopped and the dose will be de-escalated by 10-fold to 1-3x106 cells/m2. This de-escalated cohort will be designated Cohort -1.
• Cohort -1 (N=3-6): will receive a single dose of 1-3x106 cells/m2 lentiviral transduced huCART-meso cells on day 0. Up to 6 subjects will be infused in Cohort -1 if ≤ 1 DLT occurs.
If 0 DLT/3 subjects or 1 DLT/6 subjects occurs in Cohort 1, the study may advance to Cohorts 2 and 3. Enrollment into Cohort 2 and Cohort 3 may occur in parallel.
- Cohort 2 (N= up to 6): will receive a single dose of 1-3x107/m2 lentiviral transduced huCART-meso cells on day 0 via intraperitoneal (i.p.) administration. The initial i.p. infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. The subject must meet eligibility to receive additional infusions.
o Infusion #1 for the first three subjects in Cohort 2 will be staggered by at least 21 days to allow for the assessment of DLTs. A DLT assessment will be performed after the 2nd subject reaches the Day 21 safety follow-up visit. If no DLTs are identified in the 1st two subjects, subsequent infusions may occur consecutively, however no more than two new subjects may be infused concurrently.
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Cohort 3 (N= up to 6): will receive a single dose of 1-3x107/m2 lentiviral transduced huCART-meso cells on day 0 via intrahepatic delivery (Hepatic Arterial Infusion). The initial intrahepatic infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. The subject must meet eligibility to receive additional infusions.
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Infusion #1 for the first three subjects in Cohort 3 will be staggered by at least 21 days to allow for the assessment of DLTs. A DLT assessment will be performed after the 2nd subject reaches the Day 21 safety follow-up visit. If no DLTs are identified in the 1st two subjects, subsequent infusions may occur consecutively, however no more than two new subjects may be infused concurrently.
Adverse events will be collected and evaluated during the protocol specified adverse event reporting period. Subjects will be continually evaluated for dose-limiting toxicities (DLT). In the event of 2 DLTs in a specific cohort, additional enrollment and treatment activity will be paused to allow for further investigation.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1: huCART-meso cells via intravenous infusion (IV). Subjects will receive a single dose of 1-3x10^7/m^2 lentiviral transduced huCART-meso cells on day 0 via intravenous infusion. |
Biological: huCART-meso cells
Intravenous administration or local delivery of lentiviral transduced huCART-meso cells.
|
| Experimental: Cohort -1: low dose huCART-meso cells via intravenous infusion In the event that 2 DLTs occur among subjects enrolled in Cohort 1, then enrollment in Cohort 1 will be stopped and the dose will be de-escalated by 10-fold to 1-3x10^6 cells/m2. Subjects will receive a single dose of 1-3x10^6 cells/m^2 lentiviral transduced huCART-meso cells on day 0. |
Biological: huCART-meso cells
Intravenous administration or local delivery of lentiviral transduced huCART-meso cells.
|
| Experimental: Cohort 2 - huCART meso cells via intraperitoneal infusion (IP) Eligible subjects will receive a single dose of 1-3x107/m2 lentiviral transduced huCART-meso cells on day 0 via intraperitoneal (i.p.) administration. The initial i.p. infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. |
Biological: huCART-meso cells
Intravenous administration or local delivery of lentiviral transduced huCART-meso cells.
|
| Experimental: Cohort 3 - huCART meso cells via intrahepatic infusion (hepatic arterial infusion) Eligible subjects will receive a single dose of 1-3x107/m2 lentiviral transduced huCART-meso cells on day 0 via intrahepatic delivery (Hepatic Arterial Infusion). The initial intrahepatic infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. |
Biological: huCART-meso cells
Intravenous administration or local delivery of lentiviral transduced huCART-meso cells.
|
Outcome Measures
Primary Outcome Measures
- Number of study subjects with treatment-related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [2 years]
Secondary Outcome Measures
- Tumor response rates measured according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria [Day 28, Month 3, Month 6]
- Progression-free survival (PFS) [2 years]
- Overall survival (OS) [2 years]
Eligibility Criteria
Criteria
- Inclusion Criteria
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Patients with the following diagnoses:
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Cohorts 1 and -1: Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma
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Cohort 2: Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma; and either cytologically-proven ascites or known peritoneal disease on radiologic imaging.
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Cohort 3: Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma with liver metastases as confirmed by pathology or radiographic imaging.
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INCLUSION CRITERIA HAS BEEN RETIRED
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Failure of at least one prior standard of care chemotherapy for advanced stage disease.
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Subjects must have measurable disease as defined by RECIST 1.1 criteria.
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Patients ≥ 18 years of age.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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Satisfactory organ and bone marrow function as defined by the following:
- Absolute neutrophil count ≥ 1,000/μl ii. Platelets ≥75,000/μl iii. Hemoglobin ≥ 8 g/dL iv. Bilirubin ≤ 2.0x the institutional normal upper limit v. Creatinine ≤ 1.5x the institutional normal upper limit vi. Albumin ≥ 2 vii. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤5x the institutional normal upper limit viii. Cardiac ejection fraction of ≥40% as measured by resting echocardiogram, with no clinically significant pericardial effusion.
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Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT ≤ 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for history of cancer-related thrombosis and has stable coagulation parameters.
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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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EXCLUSION CRITERIA HAS BEEN RETIRED
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Active invasive cancer other than pancreatic adenocarcinoma. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder cancer, or prostate cancer with PSA level < 1.0) are not excluded.
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HIV infection
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Active hepatitis B or hepatitis C infection
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Active autoimmune disease (including but not limited to: systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy within 4 weeks prior to eligibility confirmation by physician-investigator, with the exception of thyroid replacement.
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Patients with ongoing or active infection.
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Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic respiratory conditions or adrenal insufficiency.
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Patients requiring supplemental oxygen therapy.
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Prior therapy with lentiviral gene modified cells.
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History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
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Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heart Association Classification (see Appendix 3) 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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Any clinically significant pleural or peritoneal effusion that cannot be drained with standard approaches. An indwelling drainage device placed prior to eligibility confirmation by physician-investigator is acceptable.
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Pregnant or breastfeeding women.
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EXCLUSION CRITERIA HAS BEEN RETIRED
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Treatment with a PD-1 or PD-L1 inhibitor, including but not limited to nivolumab, pembrolizumab, atezolizumab, and/or durvalumab, within 2 months prior to eligibility confirmation by investigator.
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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)
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Cohort 3 Subjects Only: Patients with a contraindication to IV contrast.
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: Mark O'Hara, MD, Assistant Professor of Medicine, Penn Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 827644 (UPCC 14217)