MSK-TCR5 for the Treatment of Advanced, Unresectable or Metastatic Solid Tumors

Inclusion Criteria

• PART A ( PRIOR TO CELL COLLECTION): Age ≥ 18 years
• PART A ( PRIOR TO CELL COLLECTION): Histologically confirmed advanced or metastatic, unresectable solid tumor
• PART A ( PRIOR TO CELL COLLECTION): Positive for RAS G12D mutation and HLA-A*11:01 allele
• PART A ( PRIOR TO CELL COLLECTION): Subject has advanced solid cancer, defined as unresectable, advanced, and/or metastatic disease after at least 1 line of systemic standard of care (SOC) treatment regimen and for which there are no available curative treatment options. Subjects with stable disease (SD), or that present lack of clinical benefit from previous therapy (including treatment suspension due to toxicity) may be considered eligible for enrollment: * For colorectal carcinoma (CRC): Patients harboring genomic aberrations such as BRAFV600E mutations, HER2 amplifications, or VEGF expression for which Food and Drug Administration (FDA)-approved targeted therapies are available must have received prior treatment with applicable FDA-approved targeted therapies, including multi-kinase inhibitors. Patients whose tumors have deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) must have received an immune checkpoint inhibitor prior to enrolling in this study. * For non-small cell lung cancer (NSCLC): Patients harboring genomic aberrations such as non-resistant EGFR mutations, ALK rearrangement, ROS rearrangement, and BRAF V600E mutation for which FDA-approved targeted therapies are available must have received prior treatment with the applicable FDA-approved targeted therapies. Patients with the appropriate PD-L1 expression score must have received treatment with an FDA-approved checkpoint inhibitor with or without chemotherapy consistent with the FDA-approved label. * Any other solid tumors, including pancreatic ductal adenocarcinoma (PDAC): Patients harboring genomic aberrations for which FDA-approved targeted therapies are available must have received prior treatment with the applicable FDA-approved targeted therapies. Patients whose tumors have dMMR/MSI-H must have received an immune checkpoint inhibitor prior to enrolling in this study
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. * Note: a previously irradiated or locoregionally treated lesion can be considered a target lesion if it progressed post-treatment
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Absolute neutrophil count (ANC) ≥ 1000/mm^3 without granulocyte colony-stimulating factor support (filgrastim within 7 days or peg-filgrastim within 14 days of screening)
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Platelets ≥ 75,000/mm^3 without transfusion within the preceding 7 days of screening
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Hemoglobin ≥ 8.0 g/dL (≥ 80 g/L); blood transfusion permitted within 7 days of screening
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN), or ≤ 5 x ULN if liver or bone metastases present
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN in the presence of documented Gilbert's Syndrome
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Creatinine clearance (CrCl) ≥ 50 mL/min by Cockcroft-Gualt equation

Exclusion Criteria

• PART A ( PRIOR TO CELL COLLECTION): Previous allogeneic stem cell transplantation or prior organ transplantation
• PART A ( PRIOR TO CELL COLLECTION): History of primary immunodeficiency, autoimmune, or inflammatory disease including inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, or Grave’s disease that in the past year has required systemic treatment with corticosteroids > 10mg/day of prednisone or equivalent doses of other corticosteroids or immunosuppressive drugs. * Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal/pituitary insufficiency is not considered a form of systemic treatment and allowed)
• PART A ( PRIOR TO CELL COLLECTION): Primary brain tumor
• PART A ( PRIOR TO CELL COLLECTION): Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression. Patients previously treated for CNS metastases that are radiographically and neurologically stable and off steroids for at least 2 weeks prior to enrollment are eligible
• PART A ( PRIOR TO CELL COLLECTION): Surgery or catheter-based interventions such as transarterial chemoembolization or percutaneous coronary intervention within 2 weeks
• PART A ( PRIOR TO CELL COLLECTION): Uncontrolled significant intercurrent or recent illness including, but not limited to the following conditions: * Significant cardiovascular abnormalities as defined by any one of the following: uncontrolled congestive heart failure or hypertension, clinically significant hypotension, symptomatic coronary artery disease, or a documented ejection fraction (EF) of < 50% as assessed by echocardiogram or multigated acquisition scan (MUGA)
• PART A ( PRIOR TO CELL COLLECTION): Uncontrolled active bacterial, viral, fungal, or mycobacterial infection not responding to antibiotics, antimycotics, or antifungal agents, as well as long term oral treatment with any of these agents
• PART A ( PRIOR TO CELL COLLECTION): Subject has had radiotherapy or systemic anti-cancer therapy within at least 2 weeks or 3 half-lives, whichever is shorter
• PART A ( PRIOR TO CELL COLLECTION): Pregnant or lactating women; women of childbearing age, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception while receiving study treatment and for at least 12 months after all treatment is finished. Sexually active males, unless they are willing to use a condom during intercourse while receiving study treatment and for at least 12 months after all treatment is finished
• PART A ( PRIOR TO CELL COLLECTION): Previously identified allergy, hypersensitivity, or known contraindication to cyclophosphamide, fludarabine, or any other agent associated with lymphodepleting chemotherapy (LDC) or MSK-TCR5
• PART A ( PRIOR TO CELL COLLECTION): Positive serologic test results for HIV
• PART A ( PRIOR TO CELL COLLECTION): Acute or chronic hepatitis B virus (HBV) infection as assessed by serologic (hepatitis B virus surface antigen [HBVsAg]) or polymerase chain reaction (PCR) results, defined as HBVsAg positive (+), hepatitis B virus core antibody (HBVcAb) +, HBV PCR +
• PART A ( PRIOR TO CELL COLLECTION): Acute or chronic hepatitis C virus (HCV) infection as assessed by serologic (HCV ab) or PCR results, defined as HCV antibody (Ab) + with reflex to positive HCV PCR
• PART A ( PRIOR TO CELL COLLECTION): Patient/parent/legally authorized representative (LAR) unable to give informed consent
• PART B (PRIOR TO TREATMENT WITH MSK-TCR5): Any exclusion criterion listed in Part A