TCR1188-ABC Cells in KRAS-mutated Cancers

Phase I, Open-Label Study of Autologous Mutant KRAS and ILT4-Redirected T-cell Receptor Cells (TCR1188-ABC)

This is a Phase I, open-label dose finding study to assess the safety, manufacturing feasibility, and preliminary efficacy of TCR1188-ABC cells in patients with KRAS-mutated cancers. Initially, patients with KRAS G12V mutation positive metastatic pancreatic adenocarcinoma, cholangiocarcinoma, colorectal cancer, or non-small cell lung cancer (NSCLC) will be targeted for participation. Up to 4 total dose levels will be evaluated using a 3+3 dose escalation design.

Inclusion Criteria:

1. Patients ≥ 18 years of age

2. Patients with one of the following diagnoses:

   1. Histologically confirmed metastatic pancreatic adenocarcinoma or cholangiocarcinoma
   2. Histologically confirmed metastatic colorectal cancer
   3. Histologically confirmed metastatic non-small cell lung cancer

3. HLA-A*11:01 positive as confirmed by a CLIA certified laboratory.

4. KRAS G12V mutation positive disease as confirmed on tissue, blood, or plasma by next generation sequencing by a CLIA certified laboratory.

5. Received prior treatment for their primary malignancy as follows:

   1. Pancreatic Cancer/Cholangiocarcinoma Patients: At least one prior line of standard of care therapy for advanced stage disease. For pancreatic cancer patients, this must include a gemcitabine or fluorouracil (5 FU)-based regimen.
   2. Colorectal Cancer Patients: At least three prior lines of standard of care therapy for advanced stage disease. Prior treatment must include all of the following unless the patient was ineligible for a specific therapy type: i). a fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimen, ii). an anti-vascular endothelial growth factor (VEGF) agent, and iii). regorafenib, trifluridine-tipiracil, or fruquintinib. Patients with microsatellite instability-high (MSI-H) disease must also have received, or be ineligible for, prior treatment with an immune checkpoint inhibitor.
   3. Non-Small Cell Lung Cancer Patients: At least one prior line of standard of care therapy for advanced stage disease.

6. Evidence of radiographically detectable disease within 8 weeks of physician-investigator confirmation of eligibility.

7. Adequate organ function within 4 weeks of eligibility confirmation by a physician-investigator defined as:

   1. Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50 cc/min per the Cockcroft-Gault Equation; Patient must not be on dialysis.
   2. ALT/AST ≤ 5 x ULN (patients with liver metastases) or ALT/AST ≤ 2.5 x ULN (patients without liver metastases)
   3. Total bilirubin ≤ 1.5 mg/dL x ULN, unless the subject has Gilbert's syndrome (if so, direct bilirubin must be ≤ 2.0 mg/dL x ULN)
   4. Left Ventricle Ejection Fraction (LVEF) ≥ 50% confirmed by ECHO/MUGA
   5. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air

8. Patients must have adequate hematologic reserve within 4 weeks of eligibility confirmation by a physician-investigator and must not be dependent on transfusions to maintain these hematologic parameters. Adequate hematologic reserve is defined as:

   1. Hemoglobin ≥ 8 g/dL
   2. Absolute neutrophil count ≥ 1000/μL
   3. Platelet count ≥ 100,000/μL

9. ECOG Performance Status that is either 0 or 1.

10. Signed, written informed consent

Exclusion Criteria:

1. Active hepatitis B or hepatitis C infection
2. Patients with a severe acquired or inherited immunodeficiency, including HIV positive patients with a CD4 count ≤ 350 cells/μL. In order to qualify, HIV positive patients must also be on an established antiretroviral therapy regimen with a viral load of <400 copies/mL.
3. Any other active, uncontrolled infection.
4. Class III/IV cardiovascular disability according to the New York Heart Association Classification (see Appendix 5).
5. Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in the study.
6. Active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to eligibility confirmation by a physician-investigator. [Note: non-invasive cancers treated with curative intent (e.g., non-melanoma skin cancer) may still be eligible].
7. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
8. Patients requiring chronic treatment with systemic steroids or immunosuppressant medications. Low-dose physiologic replacement therapy with corticosteroids equivalent to prednisone 10 mg/day or lower, topical steroids and inhaled steroids are acceptable. For additional details regarding use of steroid and immunosuppressant medications, please see Section 5.6.
9. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg daily of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
10. Patients with unstable angina, serious uncontrolled cardiac arrhythmia, and/or myocardial infarction within 6 months of physician-investigator confirmation of eligibility.
11. Prior history of myocarditis.
12. Patients with pneumonitis/interstitial lung disease requiring steroid treatment.
13. Patients with active/untreated brain metastases. [Note: History of treated metastases may still be eligible.]
14. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40) or tocilizumab.