CAR T Cell Immunotherapy for Pancreatic Cancer
Status and phase
Conditions
Treatments
Details and patient eligibility
About
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
Full 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 1-3x10^7/m^2 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 3.
- 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 1-3x10^6 cells/m^2 (Cohort -1).
- 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 1-3x10^6 cells/m^2. This de-escalated cohort will be designated Cohort -1.
• Cohort -1 (N=3-6): will receive a single dose of 1-3x10^6 cells/m^2 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 will advance to allow for additional cohorts to be explored.
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Cohorts 2 and 3. Enrollment into these additional cohorts may occur in parallel, however infusions will be staggered as follows to allow for monitoring/assessment of toxicities:
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Cohorts 2 and 3: As of Protocol Amendment V7, Infusion #1/Day 0 for the next 6 subjects in Cohorts 2 and 3 must be staggered by at least 28 days; This includes a minimum of 3 evaluable subjects in Cohort 2 and 3 evaluable subjects in Cohort 3. A DLT assessment will be performed after the 3rd evaluable subject in each cohort reaches the Day 21 safety follow-up visit. If no DLTs are identified in the 1st three evaluable subjects in both Cohorts 2 + 3, subsequent infusions of new subjects within either cohort may occur in parallel; however, no more than two new subjects may be infused within a 14-day period, irrespective of cohort assignment. If both cohorts have not yet infused 3 evaluable subjects without a DLT, all infusions will continue to be staggered by 28 days until this provision is met.
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Cohort 4: Infusion #1/Day 0 for the first 3 subjects in Cohort 4 must be staggered by at least 28 days. A DLT assessment will be performed after the 3rd evaluable subject in this cohort reaches the Day 21 safety follow-up visit. If no DLTs are identified in the 1st three evaluable subjects, subsequent infusions of new subjects may occur in parallel, however no more than two new subjects may be infused within a 14-day period. If 1 DLT is identified in the 1st three evaluable subjects, Infusion #1 for all subsequent subjects will continue to be staggered by at least 28 days and DLT assessments will be performed after each evaluable subject reaches the Day 21 safety follow-up visit.
- Cohort 2 Participants (N = Up to 6): will receive a single dose of 1-3x10^7/m^2 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.
**Cohort 2 is prematurely closed. This closure is the result of feasibility concerns specific to the clinical/disease status of these patients at this stage of their treatment.**
• Cohort 3 Participants (N = Up to 6): will receive a single dose of 1-3x10^7/m^2 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.
**Cohort 3 is prematurely closed. This closure is the result of feasibility concerns specific to the clinical/disease status of these patients at this stage of their treatment.**
• Cohort 4 Participants (N = Up to 6): will allow for the administration of lentiviral transduced huCART-meso cells during 1st line standard of care chemotherapy. A single dose of 1-3x10^7/m^2 huCART-meso cells will be administered on day 0 via intrahepatic delivery (Hepatic Arterial Infusion), following a 1 week washout after standard of care chemotherapy. This 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 all eligibility to receive additional infusions. Additional doses of standard of care chemotherapy may also be administered between huCART-meso infusions at the physician-investigator's discretion, as long as the required washout windows are appropriately adhered to. huCART-meso infusions may also be discontinued at any time in favor of resuming standard of care chemotherapy at the physician-investigator's discretion.
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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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Inclusion Criteria
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Patients with the following diagnoses:
- Cohorts 1 and -1: Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma
- Cohort 2: Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma; and either cytologically-proven ascites or known peritoneal disease on radiologic imaging.
- Cohort 3 - 4: 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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Prior treatment requirements:
- Cohorts 1 - 3: Failure of at least one prior standard of care chemotherapy for advanced stage disease.
- Cohort 4: At lease stable disease on the first-line standard of care chemotherapy for advanced stage disease.
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Cohorts 1-3 and -1: 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:
i. Absolute neutrophil count ≥ 1,000/μl ii. Platelets ≥75,000/μl iii. Hemoglobin ≥ 8 g/dL iv. Direct bilirubin ≤ 2.0 mg/dl unless the subject has Gilbert's disease syndrome (≤ 3.0 mg.dl) 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
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Exclusion Criteria:
- EXCLUSION CRITERIA HAS BEEN RETIRED
- 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.
- HIV infection
- Active hepatitis B or hepatitis C infection
- 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.
- Patients with ongoing or active infection.
- Dependence on systemic steroids or immunosuppressant medications.
- Patients requiring supplemental oxygen therapy.
- Prior therapy with lentiviral gene modified cells.
- History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
- 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.
- 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.
- Pregnant or breastfeeding women.
- EXCLUSION CRITERIA HAS BEEN RETIRED
- EXCLUSION CRITERIA HAS BEEN RETIRED
- 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. Note: "Greater than lobar" = "in more than 1 lobe".
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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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Patients with radiographic evidence of significant pleural effusion that is not readily amenable to minimally invasive drainage.
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Cohort 3 and 4 Subjects Only: Patients with a contraindication to IV contrast.
Trial design
Primary purpose
Allocation
Interventional model
Masking
18 participants in 5 patient groups
Trial contacts and locations
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Central trial contact
Abramson Cancer Center Clinical Trials Service
Data sourced from clinicaltrials.gov
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