Rauber Conrad, Roberti Maria Paula, Vehreschild Maria Jgt, Tsakmaklis Anastasia, Springfeld Christoph, Teufel Andreas, Ettrich Thomas, Jochheim Leonie, Kandulski Arne, Missios Pavlos, Mohr Raphael, Reichart Alexander, Waldschmidt Dirk T, Sauer Lukas D, Sander Anja, Schirmacher Peter, Jäger Dirk, Michl Patrick, Dill Michael T
Department of Gastroenterology, Hepatology, Infectious Diseases and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
BMJ Open. 2025 Sep 9;15(9):e097802. doi: 10.1136/bmjopen-2024-097802.
Combined vascular endothelial growth factor/programmed death-ligand 1 blockade through atezolizumab/bevacizumab (A/B) is the current standard of care in advanced hepatocellular carcinoma (HCC). A/B substantially improved objective response rates compared with tyrosine kinase inhibitor sorafenib; however, a majority of patients will still not respond to A/B. Strong scientific rationale and emerging clinical data suggest that faecal microbiota transfer (FMT) may improve antitumour immune response on PD-(L)1 blockade. Early trials in melanoma with FMT and reinduction of immune checkpoint blockade (ICI) therapy in patients with anti-PD-1-refractory metastatic melanoma were reported in 2021 and demonstrated reinstatement of response to ICI therapy in many patients. Due to anatomical vicinity and the physiological relevance of the gut-liver axis, we hypothesise HCC to be a particularly attractive cancer entity to further assess a potential benefit of FMT in combination with ICI towards increased antitumour immunity. Additionally, HCC often occurs in patients with liver cirrhosis, where liver function is prognostically relevant. There is evidence that FMT may increase hepatic function and therefore could positively affect outcome in this patient population.
This prospective, multicentre, randomised, placebo-controlled, double-blind phase II clinical trial has been designed to assess immunogenicity and safety of FMT via INTESTIFIX 001 combined with A/B in advanced HCC in comparison to A/B with placebo. Primary endpoints are measured as tumour CD8+ T cell infiltration after 2 cycles of treatment with vancomycin, A/B+INTESTIFIX 001 in comparison to vancomycin-placebo, A/B+INTESTIFIX 001-placebo and safety of the therapeutic combination in advanced HCC. INTESTIFIX 001 is an encapsulated FMT preparation by healthy donors with a high alpha-diversity in their gut microbiome for oral administration, manufactured by the Cologne Microbiota Bank (CMB). Sample size was calculated to achieve a specific expected accuracy for the primary immunological endpoint. 48 subjects will be randomised to reach a goal of 42 usable measurements in the modified intention-to-treat set. Subjects will be randomised in a 2:1 ratio to A/B or placebo (28 A/B, 14 placebo).
The study was approved by ethics committee review and the German Federal Ministry of Drugs and Medical Devices. The trial is registered under EU CT no. 2023-506887-15-00. The outcome of the study will be disseminated via peer-reviewed publications and at international conferences.
NCT05690048.
通过阿替利珠单抗/贝伐珠单抗（A/B）联合阻断血管内皮生长因子/程序性死亡配体1是晚期肝细胞癌（HCC）当前的标准治疗方案。与酪氨酸激酶抑制剂索拉非尼相比，A/B显著提高了客观缓解率；然而，大多数患者对A/B仍无反应。强有力的科学依据和新出现的临床数据表明，粪便微生物群移植（FMT）可能会改善PD-（L）1阻断治疗的抗肿瘤免疫反应。2021年报道了在黑色素瘤患者中进行的FMT早期试验以及对难治性抗PD-1转移性黑色素瘤患者重新引入免疫检查点阻断（ICI）治疗，结果显示许多患者恢复了对ICI治疗的反应。由于肠道与肝脏在解剖位置上相邻且存在生理关联，我们推测HCC是一个特别有吸引力的癌症类型，可进一步评估FMT联合ICI在增强抗肿瘤免疫力方面的潜在益处。此外，HCC常发生于肝硬化患者，而肝功能对预后具有重要意义。有证据表明FMT可能会改善肝功能，因此可能对该患者群体的预后产生积极影响。
本前瞻性、多中心、随机、安慰剂对照、双盲II期临床试验旨在评估与A/B联合安慰剂相比，通过INTESTIFIX 001进行的FMT联合A/B在晚期HCC中的免疫原性和安全性。主要终点指标为使用万古霉素、A/B + INTESTIFIX 001治疗2个周期后肿瘤CD8 + T细胞浸润情况，与万古霉素 - 安慰剂、A/B + INTESTIFIX 001 - 安慰剂进行比较，以及该治疗组合在晚期HCC中的安全性。INTESTIFIX 001是由科隆微生物群库（CMB）生产的一种由肠道微生物群α多样性高的健康供体提供的用于口服的封装FMT制剂。计算样本量以达到主要免疫学终点的特定预期准确性。48名受试者将被随机分组，以在改良意向性分析集中获得42次可用测量结果的目标。受试者将按2:1的比例随机分配至A/B组或安慰剂组（28例A/B组，14例安慰剂组）。
本研究已获得伦理委员会审查和德国联邦药品与医疗器械管理局批准。该试验已在欧盟临床试验注册号为2023 - 506887 - 15 - 00下注册。研究结果将通过同行评审出版物和国际会议进行传播。
NCT05690048。
