Phase I, Open-Label Study of Autologous Mutant KRAS and ILT4-Redirected T-cell Receptor Cells (TCR1188-ABC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V6.0
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Signed, written informed consent
排除标准
- •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.
- •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.
- •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.
研究组 & 干预措施
Dose level -1
1.11 x 10^8 TCR1188-ABC cells
干预措施: Tocilizumab (Drug)
Dose level -1
1.11 x 10^8 TCR1188-ABC cells
干预措施: Fludarabine + Cyclophosphamide combination (Drug)
Dose level 3
3 x 10^9 TCR1188-ABC cells
干预措施: Fludarabine + Cyclophosphamide combination (Drug)
Dose level 3
3 x 10^9 TCR1188-ABC cells
干预措施: TCR1188-ABC cells (Biological)
Dose level -1
1.11 x 10^8 TCR1188-ABC cells
干预措施: TCR1188-ABC cells (Biological)
Dose level 1
3.33 x 10^8 TCR1188-ABC cells
干预措施: TCR1188-ABC cells (Biological)
Dose level 2
1 x 10^9 TCR1188-ABC cells
干预措施: TCR1188-ABC cells (Biological)
Dose level 1
3.33 x 10^8 TCR1188-ABC cells
干预措施: Tocilizumab (Drug)
Dose level 3
3 x 10^9 TCR1188-ABC cells
干预措施: Tocilizumab (Drug)
Dose level 2
1 x 10^9 TCR1188-ABC cells
干预措施: Tocilizumab (Drug)
Dose level 2
1 x 10^9 TCR1188-ABC cells
干预措施: Fludarabine + Cyclophosphamide combination (Drug)
Dose level 1
3.33 x 10^8 TCR1188-ABC cells
干预措施: Fludarabine + Cyclophosphamide combination (Drug)
结局指标
主要结局
Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V6.0
时间窗: Up to 15 years following TCR1188-ABC cell administration
Type, frequency, severity, and attribution of adverse events
Occurrence of dose-limiting toxicities (DLTs)
时间窗: Up to 28 days following TCR1188-ABC cell administration
Type, frequency, severity, and attribution of dose limiting adverse events as defined by the protocol
Identification of the maximum tolerated dose (MTD)
时间窗: 28 days post-TCR1188-ABC cell infusion
The highest dose at which 0 or 1 DLT occurs in 6 DLT-evaluable subjects will be declared the MTD.
次要结局
- Occurrence of product release failures(3 months)
- Proportion of TCR1188-ABC cells that fail to meet the protocol-defined dose(3 months)
- Overall Response Rate (ORR)(Up to 12 months following TCR1188-ABC cells administration)
- Duration of Response (DOR)(Up to 15 years following TCR1188-ABC cell administration)
- Progression-Free Survival (PFS)(Up to 15 years following TCR1188-ABC cell administration)
- Overall Survival (OS)(Up to 15 years after last TCR1188-ABC cells administration)