TCR1188-ABC Cells in KRAS-mutated Cancers

Официальное название

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

Обзор

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.

Вмешательства

• Биопрепарат TCR1188-ABC cells
  TCR1188 modified, base-edited autologous CD4+ and CD8+ T cells expressing TCR1188 and a scFv fragment specific to ILT4 (LILRB2) as a Single infusion on Day 0
• Препарат Fludarabine + Cyclophosphamide combination
  Fludarabine: 30 mg/m2/day x 4 days (Day -7 to -4) Cyclophosphamide: 600mg/m2/day x 3 days (Day -7 to -5)
• Препарат Tocilizumab
  Single administration of 8mg/kg on Day 2 (+3d)

Первичные конечные точки

• Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V6.0 [Срок оценки: Up to 15 years following TCR1188-ABC cell administration]
• Occurrence of dose-limiting toxicities (DLTs) [Срок оценки: Up to 28 days following TCR1188-ABC cell administration]
• Identification of the maximum tolerated dose (MTD) [Срок оценки: 28 days post-TCR1188-ABC cell infusion]

Вторичные конечные точки (6)

• Occurrence of product release failures [Срок оценки: 3 months]
• Proportion of TCR1188-ABC cells that fail to meet the protocol-defined dose [Срок оценки: 3 months]
• Overall Response Rate (ORR) [Срок оценки: Up to 12 months following TCR1188-ABC cells administration]
• Duration of Response (DOR) [Срок оценки: Up to 15 years following TCR1188-ABC cell administration]
• Progression-Free Survival (PFS) [Срок оценки: Up to 15 years following TCR1188-ABC cell administration]
• Overall Survival (OS) [Срок оценки: Up to 15 years after last TCR1188-ABC cells administration]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Pennsylvania — Philadelphia

Идентификаторы

NCT: NCT07594067 · 27225 · 1UG3CA283652-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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