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.

Prostate cancer (PCa) is the second most common cancer in men worldwide and genetic factors and family history significantly increase the risk of PCa. Men at increased risk for PCa often experience higher PCa-specific anxiety and distress. Comprehensive prevention strategies for men with familial or genetic PCa predisposition are lacking. Consequently, the psychological impact, facilitators and barriers for risk-adapted PCa prevention lack comprehensive study. The novel prospective registry and prevention clinic ‘ProFam-Risk’ (prevention clinic for familial PCa risk) at the University Hospital Düsseldorf offers personalised risk assessment and risk-adapted prevention recommendations for men with familial or genetic PCa predisposition. As part of this research project, this study (‘ProFam-Psych’ - risk-adapted prevention clinic for familial and genetic prostate cancer: psychosocial effects; funded by German Cancer Aid) aims to evaluate the longitudinal psychosocial trajectories associated with this novel prevention clinic.

In a longitudinal observational mixed-methods design, psychosocial outcomes will be assessed in participants of the prevention clinic (case group, CAG) and compared with urology patients without increased risk for PCa (control group, COG). Psychosocial outcomes will be collected at four time points in the CAG (T0: baseline; T1: after first visit; T2: after risk stratification consultation; T3: follow-up 6 months after T2) and at two time points in the COG (T0: baseline during inpatient stay; T1: post-inpatient stay). Recruitment started in 2023, and the recruitment target is n=225 participants (CAG) and n=118 participants (COG). Primary endpoint is the longitudinal course of PCa-specific anxiety (Memorial Anxiety Questionnaire for Prostate Cancer) in the CAG. Secondary endpoints include the comparison of T0 and T1 outcomes between the CAG and COG and the assessment of changes in perceived PCa risk and perceived personal control in the CAG. To assess facilitators and barriers to participation in the risk-adapted PCa prevention clinic, a minimum of n=12 semi-structured qualitative interviews will be conducted, with recruitment continuing until data saturation is reached. Qualitative data will be analysed using qualitative content analysis.

Ethics approval from the Medical Faculty of the Heinrich Heine University Düsseldorf was obtained (2023-2551). Results of the main objective and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

DRKS.de, DRKS00032350. Prospectively registered with the German Clinical Trials Register (DRKS) on 14 September 2023.

Neoadjuvant (chemo)radiotherapy (n(C)RT) followed by resection with total mesorectal excision (TME) constitutes the standard treatment for patients with locally advanced rectal cancer of the middle and lower third. However, n(C)RT has demonstrated no significant impact on overall survival but is associated with adverse effects, including impaired sphincter and sexual function. We hypothesise that omitting n(C)RT in selected patients with a clear circumferential resection margin (CRM) >1 mm as determined through preoperative MRI is not inferior regarding local recurrence rate within 3 years after surgery. That treatment approach may show fewer adverse effects and be more cost-effective.

Selective neoadjuvant therapy of rectal cancer patients (SELREC) is a randomised controlled, parallel-group, open, multicentre, non-inferiority trial. The experimental intervention involves performing TME surgery without n(C)RT. In contrast, the control intervention adheres to German S3-guidelines, incorporating neoadjuvant radiotherapy (nRT) with a dosage of 5x5 Gy or a total of 50.4 Gy. Additionally, if applicable, concomitant chemotherapy (CT) based on 5-fluorouracil is administered, followed by TME surgery within less than 12 weeks. Adjuvant treatment according to guidelines is allowed depending on the (y)pTNM stage.

The inclusion criteria for this study encompass adult patients with primary adenocarcinoma of the rectum in whom the main tumour mass is located less than 12 cm away from the anal verge, as assessed via proctoscopy. Additionally, eligible participants are required to have a preoperative tumour stage determined by MRI of either T1 or T2 with lymph node involvement (N1) or T3 with no lymph node involvement (N0) or with lymph node involvement (N1) and no distant metastases (M0). The assessment of a clear CRM >1 mm, based on MRI, is another prerequisite for inclusion. A total of 1074 patients in approximately 35 centres are planned to be allocated to the trial.

The primary endpoint of the trial is local recurrence within 3 years after surgery. The primary estimand is based on the full analysis set using a logistic mixed model (margin 3%). The first secondary endpoint is no/minor low anterior resection syndrome (LARS) score at 2 years after surgery, and further secondary endpoints include survival outcomes and quality of life. Safety analysis involves describing the frequencies of major intervention-specific complications, such as the acute toxicity of n(C)RT according to CTCAE and perioperative morbidity and mortality according to Clavien-Dindo criteria.

SELREC is financially supported by the German Federal Ministry of Education and Research.

This trial has been prospectively registered in the German Clinical Trials Register.

Previously, the study had been approved by the responsible ethics committee of Heidelberg and the local ethics committees of the collaborating institutions before patient enrolment. Any protocol deviation that has an impact on relevant parameters such as study design, endpoints or patient safety will be reported to the responsible ethics committees.

The results will be published in a peer-reviewed scientific journal and on institutional websites.

German Clinical Trials Register DRKS00030567.