Clinical trials

The goal of this observational study is to learn whether a blood test can show the same biological features as the tumor in people with head and neck cancer that is not caused by HPV. These cancers often have different biological types, and these types may help predict how the cancer will behave. Today, these types can only be found by studying tumor tissue. This study wants to see if a simple blood sample can give the same information. The main questions the study aims to answer are: * Can a blood test identify the same tumor type that researchers find by studying tumor tissue under a microscope and through genetic testing? * Can these blood test results help predict how people may do after finishing treatment? Researchers will not assign treatments. All participants will receive the treatments recommended by their own care team as part of routine care. Participants will: * Give a blood sample before starting treatment. * Give another blood sample about 3 months after finishing treatment. * Allow researchers to use a sample of their tumor (already collected as part of standard care) for genetic testing. * Continue routine follow-up visits with their care team. About 300 adults with locally advanced, HPV-negative head and neck cancer (affecting the mouth, throat, voice box, or hypopharynx) will take part. Only people who are receiving treatment to cure their cancer can join. People with returning cancer or cancer that has already spread cannot join. Researchers will study: * Gene activity in tumor tissue * Gene activity in blood * Patterns in blood fragments and small molecules * Digital images of tumor samples using computer-based tools The study will compare these different types of information to see whether a blood test can reliably show the tumor's biological type. If it can, this could make it easier to monitor the cancer after treatment and may help guide future care. This study does not test any new drug or treatment. It collects information that may help improve care for people with HPV-negative head and neck cancer in the future.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. The study design is a registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE. The objectives are to improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. It is an hospital-based registry established in centres with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. The data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual. This registry has been developed with the support of EHE Rare Cancer Charity UK, STATER (Grant Agreement number: 947604, HP-PJ-2019) and EURACAN 2022 (Grant Agreement number: 101085486, EU4H-2022-ERN-IBA) European Health and Digital Executive Agency (HaDEA)

Cancer care for head and neck cancers is multidisciplinary and complex and knowledge on the rare ones is limited. There is a wide consensus that to support clinical research on rare cancers, clinical registries should be developed within networks specializing in rare cancers. Our hypothesis is that our head and neck cancer registry established in the framework of the European reference network on rare adults solid cancers will help to: describe the natural history of rare head and neck cancers; evaluate factors that influence prognosis; assess treatment effectiveness; measure indicators of quality of care. The registry is a prospective observational real-world registry. It collects data from already available registries/database and/or directly from expert health care providers (HCP). Information are prospectively collected on patient characteristics; exposure, outcomes and potential confounders (https://euracan.eu/research/starter/rare-head-and-neck-cancer-registry/#codebook). The registry if federated (i.e. data are stored by the data provider). Analyses will be performed using the federated learning approach which split computations into a local part and a central part. The data providers will share sub-computations only. Data quality checks are envisioned to assess whether data value are present, valid and believable. Validity and plausibility checks are embedded in the electronic case report form (CRF) in the form of alerts and errors during the data input. Additional checks are implemented in R and run using the federated learning to ensure a central data quality monitoring. The data analyses will include descriptive statistics showing frequency and patterns of patients' and cancers' variables; analytical analyses investigating the association of patients/disease and/or treatment characteristics and health outcomes. Fondazione IRCCS Istituto Nazionale dei Tumori (INT) is the coordinator of the EURACAN registry as well as a data provider. At the INT, and at each HCP involved, responsible investigators ensure that the EURACAN registry will be implemented in compliance with the protocol, following the instructions and procedures described herein. Each HCP is a controller and will identify a data processor. The processing of patients' personal data taking part in the registry is compliant with local privacy legislation and the General Data Protection Regulation 2016/679 of the EU.

The goal of this observational study is to better understand why some people with metastatic adenoid cystic carcinoma (ACC) of the head and neck have slow-growing disease while others have faster-growing or more aggressive disease. Researchers want to learn how the biology of the tumor relates to each person's clinical risk group, which is based on a published prediction tool (a nomogram). The main question the study aims to answer is: Do people in the high-risk and low-risk groups have different biological tumor types (called ACC-I and ACC-II) when their primary tumor is tested? The study will also look at other important questions, such as: * Do metastatic tumors show the same biological type as the original tumor? * Do biological types differ based on where metastases grow or how early or late they appear? * Are biological types linked to how well systemic treatments work? * Can blood tests (including DNA fragments or small RNA molecules in the blood) show the same tumor biology and help track how the cancer changes over time? Participants will: * Allow researchers to study samples of tumor tissue taken in the past during standard care. * Give blood samples at study entry and then every 6 months for up to 2 years. * Continue all medical treatments and follow-up visits as decided by their own care team. * Receive no study treatment; this study only collects information and samples. About 114 adults with metastatic ACC of the head and neck will join the study. People with only local or regional recurrence (without metastases) or those whose primary tumor started outside the head and neck cannot take part. The information gathered may help researchers understand why ACC behaves differently from person to person, identify new biological markers in blood, and support future personalized treatment strategies for people with metastatic ACC.

The EHE observational study was developed to obtain a high number of datas such as clinical presentation, natural history, and treatment outcomes, cto identificate cytokines and hormones as biomarkers and generate patient-derived preclinical models as a tool to assess the activity of anticancer agents and validate novel therapeutic targets

This observational study aims to characterize the molecular, phenotypic, and functional inflammatory and immunological profile of patients with sporadic desmoid-type fibromatosis undergoing either active surveillance or systemic therapy. The study includes analysis of the tumor immune microenvironment (TIME), circulating immune and inflammatory molecules, immune cell subsets, and circulating tumor DNA (ctDNA). The goal is to identify biomarkers associated with spontaneous or treatment-induced tumor regression and to evaluate potential correlations with specific ß-catenin mutations.

An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs. Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients. Moving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC. The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. Upon completion of the phase 1b part, the phase 2 part of the study will start.

Endometrial cancer, the most common gynecologic malignancy in high-income countries, is increasing among reproductive-age women. While hysterectomy prevents pregnancy, hormonal therapies offer fertility-sparing options for select early-stage cases, with \~80% achieving complete response (CR). Molecular classifications (POLEmut, p53abn, MMRd/MSI-H, NSMP) reveal subtype-specific prognostic differences, with NSMP showing higher CR rates and lower recurrence, while p53abn and MMRd/MSI-H fare worse. Recent studies emphasize molecular profiling's potential to guide personalized fertility-sparing treatments. This study explores the prognostic role of these classifications in treatment outcomes.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Therapeutic outcomes for HNC remain unsatisfactory and heterogeneous, with 5-year survival rates ranging from 28% to 67% overall. Moreover, HNC patients experience side effects during treatment, including inflammation and ulceration of the oral mucosa caused by radiation or cytotoxic agents (oral mucositis), which represents a limiting factor for both the escalation of radiotherapy dosage and the duration of treatment. Several observational studies have highlighted statistical associations between the oral microbiota and numerous factors related to HNC and its therapeutic course. The working hypothesis of this study is that it is possible to establish causal relationships between the functional traits of the human oral microbiota and the effectiveness of radiotherapy in HNC treatment, directly from the analysis of data collected in observational cohorts, by leveraging the statistical framework of causal inference. The oral microbiota of HNC patients enrolled in the study will be characterised through metagenomic sequencing of saliva samples collected from each patient, at radiotherapy-baseline, at 2 weeks from radiotherapy start and at radiotherapy end. Main Objectives of the Study: * Creation of a dataset of the oral microbiota in HNC patients, including both bacterial and viral components, as well as data linked to treatment effectiveness and side effects. * Estimation of the causal effect of the functional traits of the oral microbiota on the modulation of radiotherapy in HNC. * Development of predictive models for local tumour control and for oral mucositis, based on the oral microbiota of HNC patients. Clinical Relevance: The causal relationships inferred between the functional/metabolic traits of the microbiota and radiotherapy effectiveness will help build interpretable predictive models and reveal strategies to reprogram the microbiota functionality of patients with head and neck cancer. This will increase the likelihood of tumour eradication or control while reducing the risk of radiation-induced side effects.

Duodenal cancer is the leading cause of cancer-related mortality in patients with familial adenomatous polyposis (FAP), yet the current Spigelman staging system provides limited predictive accuracy for advanced neoplasia. The DRACO study (Duodenal Risk Assessment in adenomatous polyposis Coli -Oncogene) is a multicenter, STROBE- and CONSORT-compliant cohort study that analyzes upper endoscopies from genetically confirmed FAP patients across independent cohorts to develop, validate, and externally test two multivariable risk models.

HER2-positive and Triple-negative are subtypes of breast cancer more sensitive to systemic therapies, where the complete pathological response rate may be higher than 50%. This gave rise to doubts about the usefulness of traditional local treatments for such responders. Omission of surgery after vacuum assisted breast biopsy (VABB) as well omission of radiotherapy after conservative surgery would now seem to be reasonable alternatives to standard care for highly selected patients, in whom systemic treatments have provided the maximum response.

Italian multicenter study, will enroll \~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized to receive local treatment based on the investigator's choice ( either one between primary radiotherapy or cytoreductive prostatectomy), in addition to apalutamide, or to continue just with medical therapy.

RADIOSPHER2 study is a monocentric, retrospective, observational study aiming at identifying a radiomics signature able to predict HER2 expression (0 vs low vs overexpression) and trastuzumab deruxtecan efficacy in metastatic breast cancer patients. The study also encompasses translational analyses and inter-modal correlations in order to provide novel insights about HER2 spatial and temporal heterogeneity, at the macroscopic and microscopic levels.

Nerve-sparing radical hysterectomy aims to preserve the autonomic innervation of pelvic organs. In most studies, the preservation of the parasympathetic component of pelvic innervation is achieved by sparing the lymphovascular-neural tissue located at the base of the lateral paracervical tissue. This study explores an alternative surgical technique based on a different anatomical pathway of parasympathetic fibers, running more cranially and deeply within the pararectal space.

This is multicentric, single-arm, observational, investigator-drive study investigating the efficacy of liver transplantation after successful downstaging/disease control of unresectable perihilar cholangiocarcinoma using chemotherapy +/- immunotherapy and stereotactic body radiation therapy (SBRT).

Cervical cancer is one of the most preventable types of cancer, as it develops over an extended period, and its causative agent is well-known. Persistent infection with human papillomavirus (HPV) is the primary factor causing cervical cancer. Generally, persistent HPV infection leads to cervical dysplasia (also known as cervical intraepithelial neoplasia), which can potentially progress to cancer. Although the majority of women with HPV infection will never develop lesions, a relatively high number of women remain at risk of developing cervical dysplasia. Women with cervical dysplasia who receive appropriate follow-up and treatment are at low risk of developing cervical cancer. However, recurrent cervical dysplasia is a well-known risk factor for cervical cancer. Furthermore, recurrent cervical dysplasia can contribute to morbidity, as additional surgical treatments are associated with fertility and obstetric complications in women who wish to preserve their childbearing potential. Against this background, identifying the best treatment modality for patients with cervical dysplasia is of paramount importance. The management of residual or recurrent dysplasia after primary treatment is often challenging. Moreover, it is important to classify patients based on their risk of having persistent or recurrent dysplasia following initial treatment. Assessing these risk categories is useful in tailoring appropriate surveillance and determining the need for adjunctive treatments. Our research group has estimated the risk of developing persistent or recurrent dysplasia in several investigations, identifying positive surgical margins, surgical techniques, high-risk HPV infection at the time of diagnosis, and HPV persistence as key prognostic factors. Our findings align with a substantial body of literature investigating this issue. However, accurately estimating the risk of persistent or recurrent dysplasia for each individual patient remains challenging. Similarly, few studies have evaluated the outcomes of patients affected by vaginal intraepithelial neoplasia, and results have been inconsistent. In fact, there is no consensus on the optimal treatment modality for these patients. Treatments have included topical applications of imiquimod or 5-fluorouracil (5-FU), as well as ablative and excisional procedures performed via conventional surgery, electrosurgery, and carbon dioxide laser. The risk of developing invasive vaginal cancer in these patients remains uncertain, with estimates ranging between 2% and 12% in different series. Recently, a multi-institutional Italian study reported that more than 10% of women initially diagnosed with high-grade vaginal intraepithelial neoplasia were found to have occult invasive vaginal cancer at the time of excisional procedures, highlighting the need for histological diagnosis before proceeding with ablative or medical treatments. Additionally, the widespread implementation of HPV vaccination is expected to reduce the risk of recurrence after treatment. In this context, the investigators aim to evaluate the significance of post-treatment HPV vaccination and other prognostic factors in influencing the risk of persistent or recurrent lesions of the uterine cervix and vagina.

The Serpentine (Stratify cancER PatiENTs by ImmuNosupprEssion) project, represents the most consistent effort so far attempted to translate MDSC into clinical practise by producing an off-the-shelf compliant assay for quantifying these cells in peripheral blood.

This is an interventional trial. The goal of this clinical trial is dose finding. There are two phases: phase Ib to determine the MTD and recommended phase II dose of niraparib in combination with abemaciclib in patients with advanced ovarian cancer. Target population will be patients (woman, age \> 18 years) with epithelial ovarian, fallopian tube or peritoneal cancer treated with at least 2 lines of therapy.

This is single-arm, observational, academic, investigator-driven study investigating the efficacy of liver transplantation after successful and sustained downstaging/tumor control of liver-limited unresectable intrahepatic cholangiocarcinoma. The downstaging protocol includes chemotherapy +/- immunotherapy and transarterial radioembolization (TARE) with Yttrium-90 in various combinations.

PALMARES-2 is a retrospective/prospective, observational, multicenter, population-based study, aiming at providing real-world evidences on HR+/HER2- aBC patients treated with first-line CDK4/6i plus ET. The present study has the objective to collect data coming from different sources, i.e. RWD, medical images and biological samples, from patients treated with CDK4/6i as first-line of therapy for HR+/HER2- aBC. In consideration of the complexity of data collected and different objectives of the study, this master protocol foresees different sub-studies, which encompasses different methodologies for data collection, data extraction and analyses.

The goal of this clinical trial is to evaluate the safety and efficacy of neoadjuvant capecitabine and cyclophosphamide treatment in patients affected by huge Pseudomyxoma peritonei (PMP) (peritoneal cancer index \>28). Treatment consists of metronomic (low-dose medication for a prolonged time) of capecitabine plus cyclophosphamide for 6 months followed by standard of care cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The main question the trial aims to answer is which is the proportion of patients with complete cytoreduction at CRS/HIPEC after neoadjuvant metronomic approach with oral capecitabine and cyclophosphamide in patients affected by huge PMP.

The goal of this observational study is to assess the prognostic value of a genomic classifier (S18) and its refined version (S\*) in women with early-stage HER2-positive breast cancer. The study aims to determine whether these tools can predict event-free (EFS) and disease-free survival (DFS) in patients treated with neoadjuvant and/or adjuvant trastuzumab-based therapies.

Main objectives: Qualitative and quantitative monitoring of recurrences in patients with a previous diagnosis of high-grade bladder cancer at high risk of persistence/recurrence. Endpoints: Presence or absence of mRNA in urine with a dichotomous result; concordance between Xpert BM and histopathological examination Clinical relevance: reduces by half the number of (invasive) cystoscopies during follow-up. The non-invasive nature of the test could improve patient compliance with follow-up. Interventional study because it would reduce by half the number of cystoscopies during follow-up of bladder cancer which is considered the gold standard in the follow-up of this tumor. However, these markers are already CE validated and described in the European guidelines and for this reason the risk would be low.

The clinical trial concerns the use of an innovative \"anti-emetic\" drug (that is, anti-vomiting and nausea) in subjects affected by endometrial cancer. It is addressed to patients who have never received chemotherapy before and are about to start a treatment with platinum and taxanes with or without immunotherapy for endometrial cancer. The primary objective of the study is to learn if the drug is able to avoid the occurrence of vomiting and post- nausea chemotherapy within 120 hours after cycle 1 with carboplatin and paclitaxel with or without immunotherapy. Partecipants will take the drug before the chemotherapy/immunotherapy (single dose at day one of each cycle of therapy, that is one capsule before treatment). The entire duration of participation in the study may extend to the fourth cycle of chemotherapy/immunotherapy. Patients will fill in questionnaires and keep a diary of the number and intensity of symptoms (vomiting and nausea).

The SARveillance trial is an efficient, pragmatic, multi-centre, international, stratified, partially-randomised, patient-preference trial within a registry of high versus lower intensity radiological surveillance following primary resection of retroperitoneal, abdominal and pelvic soft tissue sarcoma. The trial design is stratified by sarcoma tumour grade (high/intermediate grade and low grade).