Study of Anti-CEA CAR-T + Chemotherapy VS Chemotherapy Alone in Patients With CEA+Pancreatic Cancer & Liver Metastases

A Randomized Open-Label Phase 2b Study of Hepatic Infusions of Anti-CEA CAR-T Cells Alternating With Systemic Chemotherapy Versus Chemotherapy Alone In Patients With Liver Metastases Due To CEA-Expressing Pancreatic Adenocarcinoma

This study is a randomized open-label phase 2b study of the efficacy and safety of regional infusion therapy with Anti-CEA CAR-T cells using the hepatic immunotherapy for metastases (HITM) method and the Trisalus pressure enabling drug delivery (PEDD) device alternating with systemic chemotherapy versus chemotherapy alone in patients with CEA-expressing pancreatic adenocarcinoma with liver metastases.

The study consists of 5 periods: Screening/Leukapheresis Period, Bridging Therapy Period, Randomization Period, Treatment Period, and Observation Period (which will be the long-term follow-up period to monitor for overall survival and long-term safety).

Patients in this trial with CEA-expressing pancreatic adenocarcinoma with liver metastases must have developed disease progression after first-line treatment with FOLFIRINOX (irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin) or gemcitabine-based chemotherapy. Patients will be randomized to either the "anti-CEA CAR-T Cells + systemic chemotherapy treatment arms", or the "chemotherapy alone treatment arms."

If the patients achieve at least stable disease during the Bridging Therapy Period, they will be in the Second-Line Group of Treatment Arms. Patients who develop disease progression during the Bridging Period will be in the Third-Line Group of Treatment Arms.

Patients in the Second-Line or Third-Line treatment arms who are randomized to the treatment arms of "Anti-CEA CAR-T cells plus systemic chemotherapy" will receive hepatic infusions of Anti-CEA CAR-T cells in Cycles 1 and 3 (ie, each 42-day cycle is 3 weekly doses of Anti-CEA CAR-T cells administered as hepatic arterial infusions using a PEDD device with low dose systemic IL-2 support), alternating with the systemic chemotherapy regimen they received during the Bridging Therapy Period in Cycle 2 and Cycles >= 4. Systemic chemotherapy will be administered in 28-day cycles until the development of disease progression.

Patients in the Second-Line or Third-Line treatment arms who are randomized to the treatment arms "chemotherapy alone" arms will continue to receive the same systemic chemotherapy that they received during the Bridging Therapy Period. Systemic chemotherapy will be administered in 28-day or 21-day cycles (depending on the type of systemic chemotherapy regimen the patient will receive) until the development of disease progression.

Inclusion Criteria:

• Patients must have documented CEA-expressing pancreatic adenocarcinoma with unresectable liver metastases. Documentation of CEA-expressing adenocarcinoma may be demonstrated by an elevated serum CEA level (≥ 10 ng/mL) or by the detection of CEA on the cell surface of adenocarcino3.
• Documentation of disease progression of pancreatic adenocarcinoma following the initiation of first-line treatment with FOLFIRINOX or gemcitabine-based therapy.ma cells by immunohistochemistry (IHC).
• The primary pancreatic tumor may be intact and limited lung metastases (≤ 3 lesions, none > 1 cm in longest diameter) and lymphoid metastases (≤ 3 lesions, none > 1 cm in longest diameter) are permitted.
• There must be at least one measurable metastatic liver lesion ( ≥ 10 mm in longest diameter).
• ECOG performance status of 0 or 1.
• Be willing and able to comply with the study schedule and all other protocol requirements.
• Females of childbearing potential must have 2 negative pregnancy tests prior to the start of study treatment, and must agree to pregnancy tests during the study; sexually active female and male patients must be willing to use an effective birth control to avoid pregnancy.

Exclusion Criteria:

• Received anti-cancer chemotherapy or investigational systemic anti-cancer treatments other than first line FOLFIRINOX or gemcitabine-based chemotherapy for advanced pancreatic adenocarcinoma.
• Received FOLFIRINOX or gemcitabine-based therapy within 14 days before receiving the first dose of study treatment.
• Have any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable chronic toxicities (≤ Grade 2) that are not expected to resolve.
• Have a history of histologically confirmed metastases outside the liver, lungs, or lymph nodes.
• More than 50% replacement of one or both hepatic lobes with tumor.
• Tumor causing biliary obstruction not amenable to stenting.
• Received prior anti-CEA agents, CAR-T, CAR-T cell line, CAR-NK, CAR-pNK, or CAR-NK cell line therapies.
• Have any clinically significant low baseline lab results for hemoglobin, platelet counts, or neutrophil counts at screening.
• Has any untreated or ongoing intra-abdominal infection or bowel obstruction.
• Has any clinically significant elevated baseline lab results for serum creatinine, aspartate aminotransferase (AST), and total bilirubin (except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome), and alkaline phosphatase at screening.
• Known HIV or acquired immunodeficiency syndrome-related illness, acute or history of chronic hepatitis B or C.
• Female patients who are pregnant or breastfeeding.
• Has active bacterial, viral or fungal infections.
• Has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study.
• Has any condition, including the presence of laboratory abnormalities that places the patient at an unacceptable risk if the patient was to participate in the study.
• Are receiving medications that are strong inducers CYP3A4 or CYP2C8 within 2 weeks of initiating treatment in the Bridging Therapy Period (rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine, rifabutin, rifapentine, St. John's wort).
• Are receiving medications that inhibit CYP3A4 or CYP2C8 within 1 week of initiating treatment in the Bridging Therapy Period (ketoconazole and other imidazole antifungals, erythromycin, clarithromycin, itraconazole, voriconazole, fluoxetine, gemfibrozil, cimetidine, lopinavir, nefazodone, telaprevir, ritonavir, saquinavir, indinavir, or nelfinavir).
• Are receiving medications that inhibit UGT1A1 within 1 week of initiating nanoliposomal irinotecan therapy (atazanavir, gemfibrozil, indinavir).
• Left ventricular ejection fraction (LVEF) < 40%