Clinical trials

FMG2025 continues the previous efforts to propose treatment for patients based on the molecular characteristics of their tumor at treatment failure in cancer precision medicine trials within standard of care in France. However, whereas FMG2025 is a descriptive effort providing the basis for clinical decisions, MAPPYACTS 2 will translate these findings to clinical actions. The symbiosis is critical to advance patient care. Since 2012, the molecular profiling trials "MOlecular Screening for CAncer Treatment Optimization" (MOSCATO-01) and "MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification" (MAPPYACTS) have included pediatric and adolescent patients with recurrent or refractory malignancy that underwent on-purpose biopsy or surgical intervention. Whole Exome Sequencing of tumor and normal tissue and RNA Sequencing of tumor tissue have been applied to detect genomic alterations that could lead to an adapted targeted treatment. Furthermore, ancillary studies were associated exploring circulating tumor DNA, the immune contexture of tumors and developing Patient-Derived Xenografts (PDX). The FMG2025 project transfers the molecular profiling of advanced pediatric cancers into a global approach that is now considered standard of care in France. Subsequent clinical recommendations and decisions will be made based on discussions with biologists, scientist and physicians in the molecular and clinical molecular tumor boards. Associated ancillary research studies and links to clinical interventional studies remain essential elements of the program to provide clinical, translational and basic research in order to improve scientific knowledge. The program is articulated in two main parts that are closely interacting: FMG2025 - Cancers et leucémies pédiatriques en échec de traitement or equivalent international projects that cover the sequencing of tumor and blood samples and provide molecular reports. The clinical study MAPPYACTS 2 that provides clinical and therapeutic discussions of the sequencing results and therapy recommendations via the clinical molecular tumor board (CMTB) reports. It collects molecular and comprehensive clinical data of the patients registered in FMG2025 or equivalent international projects and thereby constitutes the critical link to clinical interventional studies and its sponsors ensuring facilitated access to these trials. It also covers and coordinates ancillary research studies. Due to the delay in opening of the MAPPYACTS 2 trial, clinical and molecular data for patients whose tumors were sequenced within FMG2025 or equivalent and not included in MAPPYACTS 2 before CMTB or equivalent, will be collected retrospectively after a specific patient/legal representative information and will contribute to the endpoints of the trial as adequate.

The BIOMEDE 2.0 study is the second stage of the BIOMEDE multi-arm, multistage rolling programme (adaptive platform protocol). It is a multicenter, randomized, open-label, controlled phase-3 trial evaluating efficacy of ONC201 in comparison with everolimus (primary objective based on internal comparison) and subsequently to historical controls. Two treatment groups will be compared. A switch between treatment groups is allowed after confirmation of the disease progression (real-time central review blinded to the treatment arm allocation). Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity or consent withdrawal. The final conclusion of the trial will be successful for ONC201, if ONC201 is found significantly superior to everolimus in terms of centrally-reviewed PFS (Progression-free survival) from randomization (internal comparison) either overall, considering ND-DMG and DIPG-patients together, or in the subgroup of ND-DMG patients alone. In other cases, Everolimus will remain the standard arm unless it appears associated with an excess of toxicity compared to ONC201 which could then be discussed as a new standard.

CAMPSIS is a preliminary feasibility study of the TheraOne medical device (IIb). TheraOne is an active, non-invasive medical device intended to deliver transcranial FUS in combination with intravenous microbubbles in order to transiently and locally induce the BBB permeability. This study aims to evaluate the safety of cerebral sonication (TheraOne) in the management of patients with recurrent grade 4 glioma (wild-type IDH, technically resectable) or brain metastases originating from an extracranial solid tumor. Patients enrolled in the study will undergo a single sonication session during a protocol visit and will be monitored for up to 30 days after the sonication through the various scheduled protocol visits. Blood samples will be collected at the start of the study, during the sonication, and during the post-sonication follow-up visit for all patients enrolled in the study.

UNLOCK ASP3082 is an open label, single arm, multicenter, phase 2 platform study that aims to evaluate the mechanisms of action and resistance to ASP3082 in metastatic/locally advanced Non-Samll-Cell Lung Cancer (NSCLC) and Pancreatic Ductal Adenocarcinoma (PDAC) with the presence of KRAS G12D mutation. The two cohorts of patients are the following : i. cohort NSCLC : patients with NSCLC with KRAS G12D mutation. ii. cohort PDAC : patients with PDAC with KRAS G12D mutation. Patients enrolled in the both cohorts will receive treatment with ASP3082 at the dose of 600 mg QW thereafter in a 21-day cycle. ASP3082 will be administred in intravenous route until disease progression, unacceptable toxicity, or consent withdrawal. Tumor and blood samples will be collected at baseline, on-treatment and at the end of treatment visit only from patients who develop acquired resistance (acquired resistance is defined as a best response of CR, PR, or SD lasting more than 6 months, followed by PD).

This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019). The aims of the trial are: 1. To determine the recommended phase II dose (RP2D) of a specific anticancer agent and/or a relevant combination in a pediatric population, to document its tolerability and 2. To explore first signals of activity in a molecularly enriched study population.

* PDOs are tridimensional multicellular structures expanded in vitro which retain the genotypic and phenotypic features of their tissue or tumor of origin. PDOs can be exposed to a panel of drugs (chemotherapy, hormonal therapy, targeted therapy) in order to study their sensitivity to each agent (or combination of agents) tested ('chemogram'). Recent studies showed that PDOs can accurately predict the response to treatment of solid tumors and could therefore inform clinical decision on the best therapeutic option for each patient. * ORGANOTREAT is a multicenter prospective study program of organoid-based precision oncology encompassing 3 studies: ORGANOTREAT-01, a pilot study restricted to advanced CRC, and ORGANOTREAT-02A and -2B, two Phase 2 studies in advanced solid cancers.

This phase II clinical trial is evaluating whether adding KRC-01 injections to standard chemoradiotherapy may improve treatment outcomes in patients with locally advanced rectal cancer without metastases. KRC-01 is an investigational product designed to improve the effectiveness of radiotherapy by increasing oxygen levels inside tumors, which may help radiation work better. KRC-01 contains hydrogen peroxide and sodium hyaluronate and is injected directly into the tumor before radiotherapy sessions. Previous clinical experience in Japan, including studies in several types of cancer, suggested that this approach may improve tumor oxygenation and enhance the effect of radiotherapy. The main objective of the K-BOOST study is to evaluate how many patients achieve a complete clinical response after treatment with chemoradiotherapy combined with intratumoral KRC-01 injections, potentially allowing some patients to avoid surgery. Surgery may still be recommended depending on the individual response to treatment. Approximately 24 patients will participate in this multicenter French study. The experimental treatment period lasts approximately 26 weeks, and participants will be followed for up to 2 years.

A prospective, non-interventional study involving the collection of biological samples with associated anonymised data. Biological samples will be collected at the time of diagnosis and/or as the disease progresses, with or without treatment, always in conjunction with tests scheduled as part of routine care or within the context of a clinical trial.

ADJUPANET is an open label, double arm, multicenter, phase 3 trial that aims to investigate the efficacy of systemic chemotherapy in locally resected aggressive pancreatic neuroendocrine tumors. The two arms of patients are the following : i. control arm : active surveillance only, standard of care. ii. experimental arm : adjuvant chemotherapy with 6 cycles of CAPECITABINE-TEMOZOLOMIDE (per os) and active surveillance. Patients enrolled in the experimental arm will receive Capecitabine CAPECITABINE per os 750 mg/m² (twice a day: D1 to D14) D1=D28 and TEMOZOLOMIDE per os 200 mg/m² (once a day: D10 to D14) D1=D28.

The current standard of patients with de novo metastatic hormone sensitive prostate cancer (mHSPC) is to offer androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI). In addition, upfront 6 cycles of docetaxel, if patient is eligible, and prostate radiotherapy for those with low-volume disease are recommended. BRCA mutations (BRCAm) and neuroendocrine differentiation (NED) confer a poor prognosis in mHSPC and the current standard of care for these patients remains suboptimal. While PARP inhibitors have shown efficacy in BRCAm castration-resistant prostate cancer, concerns exist about their toxicity and resistance when used earlier in the mHSPC setting. Carboplatin has demonstrated activity in BRCAm and neuroendocrine tumors but has not been extensively studied in mHSPC. The combination of carboplatin and docetaxel is expected to enhance treatment efficacy and delay progression.

The U-TRANS study was initiated by Gustave Roussy, which is its sponsor\*. It is part of the Interception Program and aims to reduce the consumption of ultra-processed foods in order to improve the overall quality of the diet among people at high risk of cancer (WCRF score ≤ 5, corresponding to low adherence to nutritional cancer prevention recommendations: eating a diet rich in whole grains, vegetables, fruit and fibre, and limiting ultra-processed foods, red meat, processed meats, sugary drinks and alcohol). It assesses the impact of a digital intervention (based on the use of the Open Food Facts app) as a complement to the nutritional education provided by the Interception program.

This is a 2x2 factorial randomized, multicenter, international, open phase III trial. The primary objective is to evaluate the benefit of acetylsalicylic acid and atorvastatin on overall survival (OS) (main endpoint) for patients with castrate-resistant prostate cancer starting first line treatment for CRPC

TRANSCEND-XR is a European research project designed to better support adolescents and young adults who have been cured of testicular cancer. Even after treatment has ended, many young people continue to face physical, psychological, or social difficulties that are often poorly understood and insufficiently addressed. The project aims to develop an innovative digital tool using extended reality (XR) to help these young people better understand the potential long-term effects of the disease and its treatments, recognize signs that require medical attention, and become more active participants in their own health follow-up. TRANSCEND-XR first includes a pilot phase to test feasibility and improve the tool, followed by a larger clinical study comparing its use with usual medical follow-up. Researchers will assess, in particular, its impact on patients' knowledge, quality of life, and ability to seek help. The ultimate goal is to sustainably improve information, autonomy, and well-being among young survivors of testicular cancer through a digital approach tailored to their needs and daily practices.

Rational, objective and design: Some cancer-protecting genes are inactivated when the EZH2 enzyme is too active or the SWI/SNF complex is less active. The EZH1/2 enzymes and the SWI/SNFs complex play opposing roles in gene expression: we hypothesize that valemetostat, an inhibitor of the EZH1/2 enzymes, will stop/slow down the growth of cancer cells by reactivating these genes. Numerous clinical trials are currently underway worldwide to optimize the development of valemetostat tosylate and potentially offer a new targeted therapeutic option for patients suffering from various cancer pathologies. The aim of this research is to evaluate the efficacy of valemetostat on solid tumors, which have an alteration in certain genes: SMARC (B1/A4/A2/C1/C2), ARID (1A/1B), PBRM1, BAP1 and other SWI/SNF sub-units. The research will be conducted in two phases: 1) Pre-selection of patients with the desired alterations. 2) Treatment with valemetostat, 200mg/day, for a maximum of 2 years, with examinations every 28 days. This is a multicenter, international, phase II open-label, multicenter modular study exploring the efficacy and safety of valemetostat. Module 1 will be the SWI/SNF basket monotherapy study describe below. Such design will allow the study to evolve considering signals for further monotherapy and/or combination modules. The Primary endpoint of the study is Overall Response Rate at 24 weeks, defined as the proportion of patients with a confirmed best overall response. Trial population: Adult patients with histologically/cytologically confirmed progressive metastatic or recurrent solid tumor, who have selected chromatin remodeling deficiency in at least one of the following genes: SMARCB1, SMARCA4, SMARCA2, SMARCC1, SMARCC2, ARID1A, ARID1B, PBRM1, BAP1and other SWI/SNF sub-units; or molecularly (Wildtype) and phenotypically-selected Clear cell endometrial or ovarian carcinoma cancers. Patients must be using an effective method of contraception and have signed the consent form. They must not participate in another clinical study with an investigational product during the last 3 weeks, during the study treatment and not have a contraindication to the study treatment (…) Intervention: After confirmation by IHC of the loss of expression in tumors cells of SMARCB1, SMARCA4, SMARCA2, SMARCC1, SMARCC2, ARID1A, ARID1B, PBRM1, BAP1and other SWI/SNF sub-units and validation of inclusion/exclusion criteria patients will included in different cohorts (refer to investigation scheme). All patients will receive Valemetostat (200 mg per day), divided into 28-day periods called treatment cycles, for a maximum of two years. The main interventions scheduled are blood samples (to evaluate biological parameters and for translational research), electrocardiogram, echocardiography and CTscan. For patients who have consented, sequential biopsies will be performed as follow: at baseline, on treatment and at progression. Ethical consideration: This research will make it possible to collectively evaluate the interest of EZH1/2 inhibitor in solids tumors with SWI/SNF defect. Individually, by participating in this research, patients could benefit from these treatments based on cell-based results and in the treatment of relapsed/refractory peripheral T-cell lymphomas, with an improvement in symptoms and quality of life. As with any research, the investigational drug and other procedures that take place may involve risks, some of which are already known and others not yet described. The main risks (described in the consent form) are side effects of the valemetostat. If they agree, patients will also be monitored more closely with their safety assessed through patient-reported outcomes (PRO), the evaluation of their experience through qualitative interviews \& assessment of quality of care and the evaluation of their biometric physiological via a wearable device.

This is an open-label, single-dose, prospective, monocenter, Phase I interventional study (not first-in-human) to assess the safety, tolerability, and preliminary efficacy of autologous anti-CD19 CAR-T cells as an advanced therapy medicinal product in adult patients; with severe and refractory systemic autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's disease (SjD), systemic sclerosis (SSc) and idiopathic inflammatory myositis (IIM).

The goal of IMMUNOLIFE2 is to overcome primary resistance to immune checkpoint inhibitors (ICIs), such as pembrolizumab or nivolumab used alone or in combination with chemotherapy, observed in patients with advanced non-small cell lung cancer (NSCLC) following antibiotic exposure, which induces intestinal dysbiosis. The reintroduction of immunotherapy with Cemiplimab, combined with oral pooled fecal microbiotherapy (MaaT033), aims to restore gut microbiota and potentially reverse resistance to ICIs. The main objective is to determine whether the combination of MaaT033 and Cemiplimab provides a superior disease control rate compared to the current best investigator's choice as comparator. Patients will be randomized to receive either: * Experimental arm: MaaT033 administered orally for one week prior to each cycle of Cemiplimab, which will be given in hospital care every 3 weeks for 6 months, followed by Cemiplimab alone thereafter; * Control arm: Best investigator's choice

It involves collecting safety and efficacy data, under the actual conditions of use of medicines in children and adolescents, using a validated tool (Ennov EDC) and relying on the network of Interregional pediatric oncology appeal organizations (RIOs) identified by INCa since 2010 and responsible for the organization of Pluridisciplinary Pediatric Interregional (RCPPI) and National Consultative Meetings which discuss each case of relapse in order to define the best therapeutic options.

LEAH is a prospective, observational, single-centre, non-randomised, open-label study of people at increased risk of cancer or malignant disease. The main objective of LEAH is to evaluate and compare the sensitivity of different tests on body fluids to detect cancers that will occur within 3 years of inclusion in the study, in a cohort of individuals identified as being at increased risk of cancer.

The investigators therefore propose to conduct a biological study of prospectively collected patient tumour samples, ascites, blood and other residual samples (feces, urine, vaginal smear) throughout the disease course where markers (at diagnosis and their change with treatment) will be correlated to outcome in order to investigate how genetic diversity in OC prior to treatment and adaptation following treatment contribute to chemotherapy resistance. In addition freshly collected ascitic samples (and tumour samples) will be subjected to ex vivo DNA repair functional assays and isolated in primary culture (and established as xenografts) for target validation experiments.

Advanced neuroendocrine tumors (NETs) are rare cancers, characterized by prolonged survival (median\>5 years). If five medical options are now approved and 4 others are only recommended, the best sequence is still unknown. No single study on long-term cumulative toxicity of consecutive treatment interventions has been published so far. Taking into account real-world context is required for sound decision- making that cannot be answered by randomized trials. Project objectives and brief description of the methods, which will be used to achieve them: Study team will construct a longitudinal prospective cohort of consecutive non resectable or metastatic NET patients using the GTE-RENATEN network to evaluate the real world cumulative and limiting toxicities. They will expect, as primary endpoint, a difference in survival without limiting (\>grade 1 adverse event according to nci.ctc V5) persistent (\>6 months) toxicity between therapeutics classes or therapeutics sequences in the real life conditions all along the treatments lines, since metastasis diagnosis. All NET primary patients will be enrolled. Patients will be followed until the primary endpoint is reached, death or until 5 years. Based on our pilot study, we plan to enroll 1100 patients to detect 150 events and adjust for 15 cofounders and 10% of lost to follow-up. Cox model adapted to time-related dependency will be used to analyze the data and machine learning will be utilized to take into account the number of confounding factors, interactions and nonlinear relationship. The best model of prediction will be validated in a subgroup of the cohort population. Expected results: Study team will create a tool to help therapeutic decision in order to identify in a given patient the best therapeutic class or sequence with the lowest risk of persistent limiting toxicity.

Randomized, placebo-controlled phase 3 trial to evaluate nonavalent HPV vaccine as a secondary prevention in patients treated for human papilloma virus related high-grade squamous intraepithelial lesions.

To engineer immune organoids from pediatric patient tissues using induced-pluripotent stem cells (iPSC)

The objective of STING study is to perform high throughput molecular analysis (next generation sequencing +/- immunological profiling) to estimate the proportion of patients with cancer presenting at least one targetable genomic alteration.

To assess the efficacy of preventive Low-Level Laser Therapy (LLLT) for reducing the incidence of WHO's grade 3-4 oral mucositis in children and young adults receiving chemotherapy regimens associated with a high rate of mucositis: conventional chemotherapy or High Dose Chemotherapy (HDC) conditioning regimens with Hematological Stem Cell Transplantation (HSCT).

The RAINBO program is a studies group which proposes personalized treatment of patients suffering from endometrial cancer according to their molecular profile. the RAINBO-RED study allows observation or maintenance treatment with targeted therapy for one year (olaparib). This after standard therapy. The goal is to improve recurrence-free survival of patients treated with Olaparib.