UPCC 27225 Phase I, Open-Label Study of Autologous Mutant KRAS and ILT4-Redirected T-cell Receptor Cells (TCR1188-ABC)
Study of Investigational T-cell Therapy for KRAS-Mutated Cancers
Brief description of study
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.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Cholangiocarcinoma, Colorectal Cancer, Non-Small Cell Lung Cancer, Pancreatic Adenocarcinoma
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Age: 18 years or above
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Gender: All
Inclusion Criteria:
- Patients ≥ 18 years of age
- Patients with one of the following diagnoses:
- Histologically confirmed metastatic pancreatic adenocarcinoma or cholangiocarcinoma
- Histologically confirmed metastatic colorectal cancer
- Histologically confirmed metastatic non-small cell lung cancer
- HLA-A*11:01 positive as confirmed by a CLIA certified laboratory.
- KRAS G12V mutation positive disease as confirmed on tissue, blood, or plasma by next generation sequencing by a CLIA certified laboratory.
- Received prior treatment for their primary malignancy as follows:
- 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.
- 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.
- Non-Small Cell Lung Cancer Patients: At least one prior line of standard of care therapy for advanced stage disease.
- Evidence of radiographically detectable disease within 8 weeks of
physician-investigator confirmation of eligibility.
- Adequate organ function within 4 weeks of eligibility confirmation by a
physician-investigator defined as:
- Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50 cc/min per the Cockcroft-Gault Equation; Patient must not be on dialysis.
- ALT/AST ≤ 5 x ULN (patients with liver metastases) or ALT/AST ≤ 2.5 x ULN (patients without liver metastases)
- 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)
- Left Ventricle Ejection Fraction (LVEF) ≥ 50% confirmed by ECHO/MUGA
- Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
- 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- Hemoglobin ≥ 8 g/dL
- Absolute neutrophil count ≥ 1000/μL
- Platelet count ≥ 100,000/μL
- ECOG Performance Status that is either 0 or 1.
- Signed, written informed consent
Exclusion Criteria:
- Active hepatitis B or hepatitis C infection
- 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.
- Any other active, uncontrolled infection.
- Class III/IV cardiovascular disability according to the New York Heart Association Classification (see Appendix 5).
- Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in the study.
- 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].
- Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
- 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.
- Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg daily of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
- Patients with unstable angina, serious uncontrolled cardiac arrhythmia, and/or myocardial infarction within 6 months of physician-investigator confirmation of eligibility.
- Prior history of myocarditis.
- Patients with pneumonitis/interstitial lung disease requiring steroid treatment.
- Patients with active/untreated brain metastases. [Note: History of treated metastases may still be eligible.]
- History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40) or tocilizumab.
This study investigates the treatment of KRAS-mutated cancers. The purpose of this study is to evaluate the safety and preliminary effectiveness of a new investigational treatment in patients with specific types of cancer that have a KRAS mutation.
The study focuses on assessing the safety and how well the investigational treatment works. It will gather information on the treatment's effects in patients with KRAS-mutated cancers.
- Who can participate: Adults 18 years and older with KRAS G12V mutation positive metastatic pancreatic adenocarcinoma, cholangiocarcinoma, colorectal cancer, or non-small cell lung cancer can participate. Participants should have received prior treatment and have adequate organ function.
- Study details: Participants will receive the investigational T-cell therapy.
Study is selecting its participants from a population, or group of people, decided on by the researchers in advance.
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