PHASE 1, OPEN-LABEL, FIRST-IN-HUMAN TRIAL OF INTRAPERITONEA L Lm-LLO-TT AND GEMCITABINE IN PARTICIPANTS WITH UNRESECTABLE PANCREATIC DUCTAL ADENOCARCINOMA
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Safety and tolerability
研究概览
简要总结
ClinicalTrials.gov Brief Summary
This Phase 1, open-label, first-in-human study is designed to evaluate the safety, tolerability, and recommended dose of intraperitoneal (IP) administration of Lm-LLO-TT in combination with low-dose gemcitabine in adults with previously treated, unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC). Up to 18 participants will be enrolled.
Lm-LLO-TT is a live attenuated Listeria monocytogenes-based immunotherapy engineered to express a tetanus toxoid antigen. The study will assess the safety of administering Lm-LLO-TT directly into the peritoneal cavity and characterize its use in combination with low-dose gemcitabine.
Eligible participants will receive a tetanus toxoid booster vaccination during screening and undergo placement of an intraperitoneal access port before treatment. Participants will receive a single loading dose of Lm-LLO-TT followed by five cycles of low-dose gemcitabine and low-dose Lm-LLO-TT administered over approximately 17 days. Participants will be monitored for adverse events, laboratory abnormalities, dose-limiting toxicities, and disease outcomes throughout the study.
The primary objective is to assess safety and tolerability and to determine the maximum tolerated dose and recommended dose for future clinical studies. Secondary objectives include evaluation of anti-tumor activity. Exploratory objectives include assessment of immune biomarkers, changes in pancreatic cancer-related symptoms, and changes in pain medication use.
Participants will undergo tumor imaging assessments following treatment and during follow-up. A post-treatment tumor biopsy will be required for the first 10 enrolled participants and optional for subsequent participants. Participants will be followed for safety, disease status, and survival for up to 6 months after treatment initiation.
详细描述
This is a Phase 1, open-label, first-in-human, dose-escalation study designed to evaluate the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of intraperitoneal (IP) administration of Lm-LLO-TT in combination with low-dose gemcitabine in participants with previously treated unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC). Up to 18 participants will be enrolled. The study will use a Bayesian Optimal Interval (BOIN) dose-escalation design to identify the MTD and RP2D of Lm-LLO-TT for future clinical development.
PDAC is associated with poor clinical outcomes and limited treatment options in the advanced disease setting. Lm-LLO-TT is a live attenuated Listeria monocytogenes-based immunotherapy engineered to express a tetanus toxoid (TT) antigen linked to listeriolysin O (LLO). This study will evaluate the safety and biologic activity of administering Lm-LLO-TT directly into the peritoneal cavity in combination with low-dose gemcitabine.
Eligible participants are adults with histologically confirmed PDAC and measurable disease according to RECIST version 1.1 who have received at least one prior systemic treatment regimen for unresectable or metastatic disease or have a contraindication to standard therapies. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, adequate organ function, and a life expectancy greater than 3 months.
During screening, participants will undergo tetanus toxoid immunity testing. All participants will receive a tetanus toxoid booster vaccination before treatment initiation. Tetanus antibody titers will be evaluated before and after the booster vaccination, and evidence of an immune response to tetanus toxoid is required for enrollment. Participants will also undergo placement of an intraperitoneal access port before the first administration of study treatment.
Treatment begins with a single escalating loading dose of Lm-LLO-TT administered intraperitoneally on Day 1. Beginning on Day 2, participants will receive low-dose intraperitoneal gemcitabine followed the next day by low-dose intraperitoneal Lm-LLO-TT. This alternating schedule will be repeated for a total of five gemcitabine/Lm-LLO-TT treatment cycles over approximately 17 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Able and willing to provide written informed consent. Adults aged 18 years or older. Histologically confirmed pancreatic ductal adenocarcinoma (PDAC) with measurable disease per RECIST v1.
- •Previously treated with at least one line of chemotherapy for metastatic or unresectable disease, including a fluoropyrimidine-based or gemcitabine-based regimen, or have a contraindication to these therapies.
- •No radiation therapy, targeted therapy, or chemotherapy within 14 days prior to first study treatment; no immunotherapy or biologic therapy within 28 days prior to first study treatment.
- •Recovery to ≤ Grade 2 from clinically significant toxicities of prior therapy. ECOG Performance Status 0-
- •Estimated life expectancy greater than 3 months. Adequate organ function, including adequate hematologic, hepatic, and renal function.
- •Participants with treated brain metastases may be enrolled if clinically stable for at least 1 month.
- •Willing to comply with study procedures and contraceptive requirements. Participants with HIV may be enrolled if receiving antiretroviral therapy and CD4 count is >400 cells/µL.
- •Participants with hepatitis B may be enrolled if viral load is undetectable and appropriately treated; participants with hepatitis C may be enrolled following curative treatment.
- •Demonstrated tetanus toxoid (TT) immune responsiveness, either at baseline or following administration of a tetanus toxoid booster during screening.
排除标准
- •History of chronic comorbidities that would significantly limit participation in the study, including severe heart failure (NYHA Class III-IV), end-stage renal disease, substance dependence, or inadequate venous access, as determined by the investigator.
- •Candidate for curative-intent surgical resection.
- •Surgery within 2 weeks prior to first study treatment.
- •Evidence of hepatic cirrhosis or clinically/radiographically significant ascites.
- •Blood transfusion within 14 days prior to study treatment or requirement for frequent blood transfusions (>2 per month).
- •Treatment with systemically active corticosteroids within 28 days before study treatment (except low-dose dexamethasone ≤2 mg/day or prednisone ≤10 mg/day).
- •Systemic antibiotic therapy within 14 days prior to first dose of Lm-LLO-TT.
- •Receipt of another investigational product or vaccine within 28 days prior to first study treatment.
- •Receipt of any vaccine other than the protocol-required tetanus toxoid booster within 4 weeks before study treatment or during the initial DLT evaluation period.
- •Major surgery, significant traumatic injury, unhealed surgical wounds, or planned surgery requiring general anesthesia within 28 days before study treatment.
- •Active, uncontrolled HIV, hepatitis B, hepatitis C, or HTLV-1 infection, or CD4 count <400 cells/µL.
- •Presence of implanted prosthetic devices, including orthopedic prostheses, pacemakers, or prosthetic heart valves.
- •Chronic immunosuppressive therapy for autoimmune or rheumatologic conditions.
- •Pregnant or breastfeeding individuals.
- •Active uncontrolled bacterial infection requiring intravenous antibiotics, fever >38.1°C, or unexplained fever within 7 days before Day
- •History of Guillain-Barré syndrome within 6 weeks of a previous tetanus toxoid vaccination or prior Arthus-type hypersensitivity reaction to tetanus vaccine.
研究组 & 干预措施
Low dose
Low dose
干预措施: Lm-LLO-TT (Biological)
High dose
干预措施: Lm-LLO-TT (Biological)
Middle dose
Middle dose
干预措施: Lm-LLO-TT (Biological)
结局指标
主要结局
Safety and tolerability
时间窗: Day 1 to Day 45
Incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of intraperitoneal Lm-LLO-TT in combination with low-dose gemcitabine
次要结局
- Objective Response Rate(Up to 6 months)
- Disease Control Rate (DCR)(Day 1 to 6 months)
- Progression-Free Survival (PFS)(Day 1 to 6 months)