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 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 1-3x106 cells/m2 (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 1-3x106 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 willmay advance to allow for additional cohorts to be exploredCohorts 2 and 3. Enrollment into these additional cohortsCohort 2 and Cohort 3 may occur in parallel, however infusions will be staggered as follows to allow for monitoring/assessment of toxicities:.~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.~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 1-3x107/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 (see Section 6.7.2). Cohort 2 will be prematurely closed with Protocol Amendment V8. 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 1-3x107/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 (see Section 6.7.2). Cohort 3 will be prematurely closed with Protocol Amendment V8. 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 1-3x107/m2 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 (see Section 6.7.2). 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 described in Section 5.6 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.
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