Phase I/II Study of Autologous T Cells Engineered Using the Sleeping Beauty System to Express T-Cell Receptors (TCRs) Reactive Against Cancer-specific Mutations in Subjects With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events
研究概览
简要总结
A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors
详细描述
A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors.
An HLA Typing and Tumor Neoantigen Mutation Testing Protocol (Protocol # TCR001-002) has been used to identify patients for potential enrollment into this Study Protocol. Subjects who have completed the HLA Typing and Tumor Neoantigen Mutation Testing Protocol, i.e., subjects for whom a TCR matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' TCR library will be eligible for enrollment on this study.
The Phase I part of this study is a prospective, open-label, dose-escalation study of TCR-T cell drug product in patients with progressive or recurrent solid tumors who have failed standard therapy. The Phase II part is a prospective, open-label, single dose portion of the study. The Phase II part will begin once the MTD/RP2D in the Phase I part has been determined.
Subjects with one of the following histologically confirmed solid tumors will be included:
- Cohort 1: Gynecologic cancer (e.g., ovarian, endometrial)
- Cohort 2: Colorectal cancer
- Cohort 3: Pancreatic cancer
- Cohort 4: Non-small cell lung cancer (NSCLC); NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas
- Cohort 5: Cholangiocarcinoma
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 who have completed the HLA Typing and Tumor Neoantigen Identification Protocol (TCR001-002) and for whom a TCR(s) matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' Clinical TCR library
- •Patients who have previously received at least one line of standard systemic therapy for their advanced/metastatic cancer and have either progressed, recurred, or were intolerant to the previous treatment. Specifically:
- •Gynecologic cancers (i.e., ovarian or endometrial):
- •Ovarian cancer
- •Endometrial cancer
- •Colorectal cancer
- •Pancreatic cancer
- •Non-small cell lung cancer (NSCLC)
- •Cholangiocarcinoma
- •Patients must have evaluable or measurable disease per RECIST 1.1 with at least one lesion that can be measured that is not the biopsied lesion.
- •Patients must be able to provide written informed consent.
- •Patients must be age ≥ 18 years.
- •Clinical Performance Status of ECOG 0 or
- •Approval from the Alaunos Medical Monitor is required for ECOG of
- •Patient must be willing and able to provide written informed consent for the long-term follow-up protocol (TCR001-202) for up to 15 years post TCR-T Cell drug product infusion per FDA requirements.
- •Adequate bone marrow reserves as assessed by the following hematology laboratory criteria:
- •Adequate major organ system function
- •A washout period must have elapsed since completion of any prior systemic therapy, and apheresis with guidelines as follows (windows other than what is listed below should be allowed only after consultation with the Medical Monitor); subjects' non-hematologic toxicities from any prior systemic therapy must have recovered to ≤ Grade 1 (with the exception of neuropathy and alopecia) or baseline prior to starting the protocol's therapy.
- •Patients may have undergone minor surgical procedures or limited-field radiotherapy provided any major organ toxicities have recovered to ≤ Grade
- •Female patients must not be pregnant or breastfeeding.
排除标准
- •Patients with known active CNS metastases
- •Concurrent systemic steroid therapy
- •Any form of primary immunodeficiency
- •Patients who have decreased immune competence
- •History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, aldesleukin or bendamustine
- •Severe chronic respiratory condition
- •History of a bleeding disorder or unexplained major bleeding diathesis
- •Arm B Criteria only: Clinically significant patient history which in the judgment of the principal investigator (PI) would compromise the subject's ability to tolerate high-dose aldesleukin;
- •Any major bronchial occlusion or bleeding not amenable to palliation.
- •Patients with psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements.
- •Participants with known active, uncontrolled bacterial, fungal, or viral infection
- •Patients with a prior history or concurrent malignancy
- •Active unstable or clinically significant medical condition
- •History of any major cardiovascular conditions within the past 6 months
研究组 & 干预措施
TCR-T Cell Drug Product
Phase I: Dose-escalation of TCR-T Cell Drug Product
Phase II: Single dose of TCR-T Cell Drug Product after MTD/RP2D determine in Phase I portion of the study
干预措施: Neoantigen specific TCR-T cell drug product (Biological)
TCR-T Cell Drug Product with Aldesleukin (IL-2)
Phase I: Dose-escalation of TCR-T Cell Drug Product with Aldesleukin (IL-2)
Phase II: Single dose of TCR-T Cell Drug Product with Aldesleukin (IL-2) after MTD/RP2D determine in Phase I portion of the study
干预措施: Neoantigen specific TCR-T cell drug product (Biological)
TCR-T Cell Drug Product with Aldesleukin (IL-2)
Phase I: Dose-escalation of TCR-T Cell Drug Product with Aldesleukin (IL-2)
Phase II: Single dose of TCR-T Cell Drug Product with Aldesleukin (IL-2) after MTD/RP2D determine in Phase I portion of the study
干预措施: Aldesleukin (IL-2) (Biological)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events
时间窗: From initiation of lymphodepletion through Day 28 after TCR-T cell infusion, and through long-term follow-up for up to 1 year.
Treatment-emergent adverse events (TEAEs) were defined as any adverse event that began or worsened after initiation of lymphodepletion and up to 28 days following TCR-T cell infusion. TEAEs were coded using MedDRA and summarized by system organ class and preferred term, severity, and relationship to study treatment. Participants were followed for delayed or ongoing toxicities for up to 1 year.
Frequency of Dose Limiting Toxicities
时间窗: From Day 0 to Day 28 post TCR-T cell drug product infusion.
Number of participants experiencing DLTs, defined as specific adverse events attributable to the TCR-T cell drug product occurring within the first 28 days of infusion. DLTs include, but are not limited to, Grade 4 neutropenia lasting ≥ 14 days, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with significant bleeding, and ≥ Grade 3 febrile neutropenia with hemodynamic compromise. Non-hematologic DLTs include Grade 3 or 4 Cytokine Release Syndrome (CRS) that does not improve to Grade ≤ 2 within 72 hours, and Grade 3 Immune-effector cell-associated neurotoxicity syndrome (ICANS) that does not resolve to Grade ≤ 2 within 7 days, among others. The severity of adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Determination of Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D)
时间窗: From Day 0 to Day 28 post TCR-T cell drug product infusion.
The MTD and/or RP2D was to be determined based on dose-limiting toxicities observed during the dose-escalation phase. The planned definition required ≥2 patients at a given dose level to experience a DLT to declare that dose not tolerated.
次要结局
- Feasibility of TCR-T Cell Drug Product Manufacturing(From apheresis collection to the release of the final TCR-T cell drug product for infusion, estimated to be approximately 5 weeks)
- TCR-T Cell Persistence(Baseline through Month 18 post-infusion.)
- Percent Change in TCR-T Cell Count From Post Dose to Day 28(Post-dose through Day 28)