A Phase I Study Evaluating Safety and Feasibility of Redirected Autologous T Cells Expressing a High Affinity TCR Specific for NY-ESO-1 (LauT-1) in Patients With Advanced Melanoma and Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 9
- 试验地点
- 4
- 主要终点
- Safety as measured by the incidence of treatment emergent adverse events
研究概览
简要总结
A single center, dose escalaion, Phase I clinical trial to demonstrate safety and efficacy of LauT-1, autologous "New York Esophageal Squamous Cell Carcinoma-1 T-Cell Receptor (NY-ESO-1 TCR)-directed T cells in combination with non-myeloablative (NMA) lymphodepleting chemotherapy and low dose irradiation (LDI) in patients with NY-ESO-1 positive sarcoma and melanoma.
详细描述
In this study, the investigators target the cancer testis antigen NY-ESO-1, which is highly expressed in a subset of sarcoma and melanoma but is largely absent in normal tissues. The affinity enhanced, Human Leukocyte Antigen - A2 (HLA-A2) restricted I53F T-cell receptor (TCR) used in this study is derived from a TCR originally isolated from a melanoma patient and recognizes the 157-165 epitope of the NY-ESO-1 protein with high affinity. The patients' own T-cells will be isolated, then genetically modified to express the I53F NY-ESO-1 TCR and expanded to generate the product "LauT-1", which is reinfused into the patients following lymphodepleting chemotherapy (LDCT) and low dose tumor irradiation (LDTI). LDCT allows maximal expansion of the infused T cells, and LDTI has been shown to inflame the tumor microenvironment in preliminary clinical data from recent studies, which may be useful to enhance T-cell infiltration and provide co-stimulatory signals within the tumor microenvironment, thereby maximising the chance to detect and potentially eliminate NY-ESO-1 expressing tumor cells.
In the current phase I study, the investigators assess the safety, maximum tolerated dose (MTD) and feasibility of adoptive transfer of LauT-1 after LDCT and LDTI in HLA-A*0201 and/or HLA-A*0205 positive patients with advanced melanoma or sarcoma expressing NY-ESO-1. The experimental products are given initially to a group of 3 patients (safety cohort; cohort 1). If safe, the next 6 patients will be enrolled using a rule-based 3-patient cohort dose-escalation design using split-dosing to determine the MTD of LauT-1 (cohorts 2 and 3).
Procedures:
After confirming the expression of the NY-ESO-1 protein in at least 50% of the tumor cells and the presence of a permissive HLA allele during the pre-screeening procedure, patients eligible for the study will be undergo medical screening and registration to the study, followed by leukapheresis for the collection of autologous white blood cells (T lymphocytes) for the production of the gene-modified LauT-1 product. After successful leukapheresis, patients are allowed to receive a bridging therapy at the discretion of the PI/treating physician.
If all conditions are met and LauT-1 production is completed, the patient will start intravenous (IV) non-myeloablative lymphodepleting chemotherapy (LDCT) composed of fludarabine and cyclophosphamide. Both treatments will be started on the same day. Fludarabine will be given for four days, and cyclophosphamide for 2 days. LDTI will be administered as a single dose on Day 0 to all irradiable lesions using tomotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •at pre-screening
- •1) Patients with histologically confirmed advanced or metastatic cutaneous melanoma or any type of sarcoma.
- •Inclusion criteria at screening
- •Patients with sarcoma, who have received at least one line of standard therapy (if available) and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
- •Patients with metastatic melanoma:
- •Without proto-oncogene B-Raf (BRAF) mutation who have received at least one line of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
- •With BRAF mutation who have received at least two lines of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
- •Patient must have immunohistochemically documented NY-ESO-1 expression, defined as ≥ 1+ expression on either archival or fresh tumor tissue by immunohistochemistry, in ≥50% of the sampled tumor tissue AND HLA-A*0201 and/or HLA-A*0205 positive, as identified by high-resolution genomic deoxyribonucleic acid (DNA) typing of the HLA-A locus.
- •Age ≥ 18 years
- •Able to undergo apheresis
- •At least one lesion accessible to biopsy for translational research (TR) at D30, without putting the patient at unusual risk.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Life expectancy of greater than 12 weeks.
- •Radiologically measurable disease (as per RECIST v1.1).
- •Adequate organ function
排除标准
- •Patients with an active second malignancy
- •Patients with symptomatic and/or untreated brain metastases, as well as leptomeningeal carcinomatosis. Patients with definitively treated brain metastases will be considered for enrolment after agreement with the Principal Investigator, as long as lesions are stable, there are no new brain lesions, and the patient does not require chronic corticosteroid treatment.
- •History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin). History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
- •History of recent myocardial infarction, or unstable angina, within six months prior to enrolment
- •Patients with prior allogeneic stem cell transplantation or organ transplantation
- •Active severe systemic infections within 2 weeks prior to apheresis
- •Patient requiring regular systemic immunosuppressive therapy. All immunosuppressive medications including but not limited to steroids, mycophenolate mofetil, azathioprine, methotrexate, thalidomide, and anti-Tumor Necrosis Factor-alpha (TNF-alpha) agents must have been discontinued at least 2 weeks before apheresis .
- •History of severe immediate hypersensitivity reaction to any of the agents/ excipients of the study products.
- •Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
- •Subjects, for whom there are concerns that they will not reliably comply with the requirements for contraception, should not be enrolled into the study.
- •Any serious underlying medical condition that could interfere with study medication and potential adverse events.
研究组 & 干预措施
Single arm study
干预措施: Low-dose irradiation (Radiation)
Single arm study
干预措施: NY-ESO-1 TCR redirected autologous T cell product (Biological)
Single arm study
干预措施: Non-myeloablative lymphodepleting chemotherapy (Drug)
结局指标
主要结局
Safety as measured by the incidence of treatment emergent adverse events
时间窗: 90 days
Safety of LauT-1 plus LDI after lymphodepleting chemotherapy will be established by classifying the observed toxicities by the MedDRA system and grading them using the National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE Version 5.0) or American Society for Transplantation and Cellular Therapy (ASTCT) Cytokine Release Syndrom (CRS) consensus grading, as applicable.
Feasibility as measured by the rates of production failure and drop-outs before infusion
时间窗: From start of LauT-1 production to treatment at 3 weeks
Feasibility of LauT-1 production and administration will be evaluated as the number of cases for whom production of LauT-1 was successful (product was released based on specification criteria), and number of patients who receive LauT-1 at the intended dose according to the assigned dose-level, among all registered patients
次要结局
- Overall survival (OS)(24 months)
- 2. Objective response rate (ORR)(90 days for each patient)
- Long term safety as measured by the incidence of TEAE(24 months)
- Disease control rate (DCR)(2 years)
- Progression-free survival (PFS)(24 months)
研究者
Bernhard Gentner
Professor of Immuno-Oncology
Centre Hospitalier Universitaire Vaudois