Fecal Microbiota Transfer in Liver Cancer to Overcome Resistance to Atezolizumab/Bevacizumab (FLORA)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 7
- 主要终点
- Assessment of immunogenicity
研究概览
简要总结
The interventional, randomized, placebo-controlled, double-blind phase II-trial FLORA will assess safety and immunogenicity of fecal microbiota transfer in combination with standard of care immunotherapy in advanced hepatocellular carcinoma (HCC) in a parallel group design.
Subjects will be randomized 2:1 into either the FMT or placebo group.
详细描述
Eligible HCC patients visiting the outpatient clinics at the study sites of the NCT Germany will be enrolled into the study after informed consent. Patients undergo 2:1 randomization into either the FMT or placebo group. Prior to the intervention, a sigmoidoscopy with mucosal biopsies will be performed. At day -3 to 0 oral Vancomycin 4x 250mg or placebo will be given. Atezolizumab/bevacizumab (A/B) will be administered as standard of care every 21 days, starting on day 0. At day 0 and 21, concurrent to the first and second cycle of A/B, encapsulated FMT or placebo will be administered on the same day. At day 40-42, before the third cycle of A/B, a tumor biopsy and a sigmoidoscopy will be performed. The first radiologic assessment will be performed after 4 cycles of A/B. Clinical efficacy and safety will be assessed as indicated per protocol analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Age 18 years or older
- •Confirmed radiologic or histological diagnosis of HCC
- •Disease not amenable to resection, liver transplantation or loco-regionary therapy
- •Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care
- •Measurable disease per RECIST 1.1
- •Preserved liver function with a Child-Pugh score A or B (maximally 7 points)
- •Performance status ECOG 0-1
排除标准
- •Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab.
- •Active or prior documented autoimmune or inflammatory disorders
- •Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-VEGF antibodies.
- •Known to have tested positive for human immunodeficiency virus (HIV) infection.
- •Co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
- •Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.
- •Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism or excretion of investigational product.
- •Uncontrolled arterial hypertension defined by a systolic pressure > 150 mm Hg or diastolic pressure > 90 mm Hg or other hypertensive cardiovascular complications despite standard medical treatment.
- •Any history of nephrotic or nephritic syndrome.
- •Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab.
- •Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab.
- •Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.
- •History of another primary malignancy.
- •Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
- •Pregnancy or lactation.
- •History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
- •Participation in other interventional clinical trials or observation period of competing clinical trials, respectively.
- •Held in an institution by legal or official order.
- •Legally incapacitated.
- •Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.
研究组 & 干预措施
Vancomycin + A/B + FMT
- Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Vancomycin orally (250 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Fecal microbiota transfer (FMT) via capsules (total 50 g of fecal matter) on day 0 and day 21.
干预措施: Fecal microbiota transfer (Drug)
Vancomycin + A/B + FMT
- Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Vancomycin orally (250 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Fecal microbiota transfer (FMT) via capsules (total 50 g of fecal matter) on day 0 and day 21.
干预措施: Vancomycin Oral Capsule (Drug)
Vancomycin + A/B + FMT
- Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Vancomycin orally (250 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Fecal microbiota transfer (FMT) via capsules (total 50 g of fecal matter) on day 0 and day 21.
干预措施: Atezolizumab + Bevacizumab (Drug)
Placebo Vancomycin + A/B + Placebo FMT
- Atezolizumab 1200mg i.v. & bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Placebo vancomycin orally (4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Placebo fecal microbiota transfer (FMT) via capsules on day 0 and day 21.
干预措施: Atezolizumab + Bevacizumab (Drug)
Placebo Vancomycin + A/B + Placebo FMT
- Atezolizumab 1200mg i.v. & bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Placebo vancomycin orally (4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Placebo fecal microbiota transfer (FMT) via capsules on day 0 and day 21.
干预措施: Placebo Vancomycin Oral Capsule (Drug)
Placebo Vancomycin + A/B + Placebo FMT
- Atezolizumab 1200mg i.v. & bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
- Placebo vancomycin orally (4xd, day -3 to 0) for reduction of original patient gut microbiota.
- Placebo fecal microbiota transfer (FMT) via capsules on day 0 and day 21.
干预措施: Placebo Fecal microbiota transfer (Drug)
结局指标
主要结局
Assessment of immunogenicity
时间窗: 6 weeks after treatment initiation
Tumoral CD8+ T cell infiltration after 2 cycles of treatment with Vancomycin, A/B + FMT in comparison to Vancomycin-placebo, A/B + FMT-placebo
Safety of the therapeutic combination in advanced HCC
时间窗: The observational period begins with the first administration of the 1st IMP (Vancomycin/Placebo) on day -3 and ends with either the Follow-up visit after 15 weeks (Day 105) or the initiation of a subsequent anticancer treatment.
Occurence of Adverse Events (AE) \& immune-related adverse events (irAE)
次要结局
- Overall survival (OS)(From start of treatment until the date of death from any cause, assessed up to 4 years.)
- Progression free survival (PFS)(From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.)
- Disease control (DC)(From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.)
- Objective Response (OR)(From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.)
- Duration of Response (DoR)(From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.)
- AFP serological response rate(From start until end of treatment (11 weeks).)
- Hepatic Function measured by model of end-stage liver disease (MELD) score(From start until end of treatment (11 weeks).)
- Hepatic Function measured by Child-Pugh score(From start until end of treatment (11 weeks).)
- Hepatic Function measured by ALBI grade(From start until end of treatment (11 weeks).)
- Hepatic Function measured by Psychometric Hepatic Encephalopathy Score (PHES)(From start until end of treatment (11 weeks).)
- Health-related quality of life - general(From start until end of treatment (11 weeks).)
- Health-related quality of life - disease-specific(From start until end of treatment (11 weeks).)
研究者
Michael Dill
Principal Investigator
University Hospital Heidelberg