Fecal Transplantation for Liver Cancer to Enhance the Efficacy of Immunotherapy with Atezolizumab/Bevacizumab (FLORA)

Hepatocellular carcinoma (HCC) is a malignant disease characterized by the uncontrolled proliferation of liver cells. The disease often develops in a liver that has already been damaged—for example, by cirrhosis, chronic hepatitis B or C, alcohol abuse, or fatty liver disease. For a long time, there were few treatment options available for advanced liver cancer.

In recent years, the situation has improved, primarily due to the use of immunotherapies. Immunotherapies aim to activate the body’s own immune system so that it recognizes and fights the cancer cells. In liver cancer, the combination of atezolizumab and bevacizumab has proven particularly effective. Atezolizumab is a so-called PD-L1 inhibitor that binds to the PD-L1 protein on cancer cells, thereby blocking its interaction with immune cells. This allows the body’s immune system to better recognize and fight cancer cells. Bevacizumab is an antibody used to treat various types of cancer. It binds to the vascular endothelial growth factor (VEGF), thereby inhibiting tumor growth by cutting off the blood supply to the tumors. This combination is now considered the standard of care for many patients with inoperable HCC. However, not all patients respond to immunotherapy. Research shows that the state of the immune system, the tumor microenvironment, and the gut microbiota can all influence treatment success. For this reason, new approaches are being investigated to determine how targeted modification of the gut microbiota—for example, through fecal transplantation—might enhance the effectiveness of immunotherapy.

The goal of this Phase 2 study is to investigate whether a fecal transplant in capsule form, in addition to standard treatment, can improve the immune response against the tumor and the effectiveness of immunotherapy. To this end, patients will be randomly assigned to two groups. The treatment group receives the fecal transplant, while the control group receives a placebo.

After enrollment in the FLORA study, an initial tissue sample (biopsy) will be taken from the tumor under ultrasound guidance within ten days—unless this has already been done previously. In addition, a brief colonoscopy will be performed, during which only the lower part of the large intestine will be examined (sigmoidoscopy). The actual cancer treatment with atezolizumab and bevacizumab then begins within five days after the colonoscopy. This standard immunotherapy is administered as an infusion every 21 days. Patients in the treatment group first receive an antibiotic (vancomycin) to prepare the bowel. Concurrent with the start of immunotherapy and again after 3 weeks, a stool transplant (fecal microbiome transfer, FMT) is performed. This involves administering deep-frozen capsules containing donated stool from healthy individuals, and various procedures are possible. Before the start of the third treatment cycle (between days 40 and 42), another tumor biopsy and a second sigmoidoscopy are performed. The goal is to closely examine changes in the tumor tissue and the treatment’s effect on the intestine. At the same time, the therapy’s efficacy and tolerability are closely monitored.

The study is single-blind, meaning that only the patients do not know which treatment they are receiving. The primary endpoint of the study is the assessment of immunogenicity after 6 weeks—that is, how strongly and in what way the immune system reacts to a specific substance or therapy. Follow-up visits as part of the study will take place for up to 1 year, during which the efficacy of the therapy, the occurrence of side effects from the various medications, the course of the disease, and the patients’ quality of life will be assessed.

Adults aged 18 and older who have been diagnosed with advanced hepatocellular carcinoma that can no longer be surgically removed (BCLC Stage C) are eligible to participate.

Study Facts:

1. Disease: Hepatocellular carcinoma
2. Cancer characteristics: Advanced (BCLC Stage C), inoperable, good liver function
3. What the study investigates: Fecal microbiota transplantation as part of immunotherapy vs. placebo + immunotherapy
4. Study objective: To improve the immune response within the tumor and treatment tolerability
5. Study duration: primary observation period of approximately 6 weeks, follow-up for up to 48 months
6. Study characteristics: Phase 2 study, randomized, two treatment arms, single-blind, placebo-controlled