Grenoble

This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of elenestinib (BLU-263) + symptom directed therapy (SDT) with placebo + SDT in participants with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by SDT. Parts 1 and 2 will enroll participants with ISM. Participants enrolled in Part 2 will roll over onto Part 3 to receive treatment with elenestinib in an open-label fashion following completion of the earlier Part. Part K will enroll participants with ISM who have previously received an approved selective KIT inhibitor. The study also includes pharmacokinetic (PK) groups that will enroll participants with ISM.

Robot-assisted partial nephrectomy (RAPN) is the standard treatment for localized kidney tumors. New 3D modeling and reconstruction technologies have enabled the development of real time imageguided surgery using virtual reality (VR). In view of advances in artificial intelligence and surface recognition based on deep-learning, augmented reality (AR) by merging a 3D reconstructed virtual image onto the real per-operative view represents the next step in image-guided surgery. 3D IG-RAPN using Synapse 3D (Fujifilm) and DaVinci Tile-Pro display (Intuitive Surgical) vs conventional RAPN without 3D navigation in 12 high-volume urological centers from the UroCCR Network. Outcoume : Primary endpoint is a composite validated score (TRIFECTA) evaluating peri-operative complications as well as oncological safety and long-term renal function preservation. Secondary endpoints assess long-term survival, ergonomics and surgeon satisfaction. A medico-economic evaluation will be performed. Methodology: ACCURATE is a nation-wide, single-blind, multicentric, prospective randomized controlled trial enrolling 694 patients with a single complex renal mass, defined as RENAL NS≥7. Randomization (1:1) between the experimental and the conventional group will take place on day of inclusion and will be stratified by center.

This study is a multicenter, open label phase I dose escalation trial designed to define the Maximum Tolerated Dose (MTD) of 177Lu-DOTATATE in children with refractory or recurrent neuroblastoma. 177Lu-DOTATATE will be delivered intravenously for 2 cycles, 6 weeks apart. The duration of study participation of each patient will be 5 months.

Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC. This collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned: i. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to: * Evaluate its positive and negative predictive value. * Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy. ii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring). iii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.

The goal of this observational study is to evaluate a new classification system for obstructive sleep apnoea in patients with newly diagnosed obstructive sleep apnoea and monitor for long-term objective and subjective improvement.

Food protein induced enterocolitis syndrome (FPIES), is a non-IgE mediated food allergy (FA) which seems to expand, and occurring in infancy. Prevalence of FPIES is unknown. In 2011, Katz published cumulative incidence of cow 'milk FPIES of 3 per 1000 new-borns, from prospective birth cohort in Israel. The offending food depend on the country, probably in relation to eating habits. Cow's milk (CM) is most commonly incriminated and can lead to a chronic digestive disease or in its acute form with potentially life-threatening vomiting/diarrhoea/dehydration, confusing with anaphylaxis. Rice and oat in US, or fish and egg in France are the solid food most often implicated. This disease is usually unknown by clinicians. Its diagnostic is based on clinical history, and differential diagnosis elimination. In 2017, an international workgroup of American Academy of Allergy, Asthma and Immunology published clinical criteria to specify the diagnosis and management. According to this last definition (JACI 2017), patient have to meet the major criterion and at least 3 minor criteria. Major criterion is vomiting in the 1- to 4-h period after ingestion of the suspect food and absence of classic IgE-mediated allergic skin or respiratory symptoms. Minor criteria are : 1. A second (or more) episode of repetitive vomiting after eating the same suspect food, 2. Repetitive vomiting episode 1-4 h after eating a different food 3. Extreme lethargy with any suspected reaction 4. Marked pallor with any suspected reaction 5. Need for emergency department visit with any suspected reaction 6. Need for intravenous fluid support with any suspected reaction 7. Diarrhea in 24 h (usually 5-10 h) 8. Hypotension 9. Hypothermia Skin prick test et IgE antibody are negative except atypical FPIES. Acute management begins with clinical evaluation, then administer normal saline bolus quickly. Parenteral ondansetron can be used to stop vomiting. Nutritional management implicate elimination of the offending foods. Only the oral food challenge in hospital can be done to determine resolution of FPIES after a long time of no symptom. The age of tolerance, depend of the food. The average age of acquiring tolerance for cow's milk changes in the literature, around 8-10 months in Korea, around 1 year in Israel, around 5 years in the United States. There is no data in France on the recovery age of CM-FPIES. However, there is a lack of information in literature for describe the evolution and atypical phenotypes. In addition, no prospective French series has been published to date. Our work is a national prospective study, which will collect news cases of acute FPIES diagnosis in sixteen French centres. Main objective: To determine the rate of acquisition of tolerance by food at 1 year, 2 years, 3 years post inclusion. Secondary objectives: * Description of a population of children with newly diagnosed FPIES. 2. Describe the rate of patients with FPIES progressing to IgE sensitization whatever the food at 1 year, 2 years, 3 years post inclusion. 3\. Determine per food the rate of FPIES patients evolving towards IgE sensitization at 1 year, 2 years, 3 years post inclusion. 4\. Describe the rate of patients with FPIES progressing to clinical symptoms of IgE-mediated allergy, whatever the food, at 1 year, 2 years, 3 years post inclusion. 5\. Determine, by food, the rate of FPIES evolving towards clinical symptoms of IgE-mediated allergy at 1 year, 2 years, 3 years post inclusion. 6\. Describe the rate of patients with multiple FPIES at each time point of the study. 7\. Describe at each time the rates of patients with personal atopic comorbidities. The inclusion period will last three years, and the follow up of each patient will last three years. Allergologist will see the patient at inclusion visit, then one time a year. If the patient does not acquire tolerance, an oral food challenge (OFC) in hospital will lead to answer. The aim of our work will help allergologist to manage FPIES children, with French specificities in offending food, and tolerance.

Malignant hypertension is the most severe form of high blood pressure, fatal if left untreated. It has not disappeared, with an increasing incidence. Patients with the disease, mainly young (35 to 55 years of age), have an unfavorable cardiovascular prognosis (14% of cardiovascular and renal events at 4 years). Despite these facts, scientific research on the subject remains limited. The definitions and diagnostic criteria have not changed since 1929, and the therapeutic recommendations remain empirical. This first prospective and multicentric registry will increase and modernize the knowledge of the disease. From these data, diagnostic and therapeutic recommendations based on solid scientific evidence could be developed. The investigators want to first recruit 500 patients and define their prognosis at 5 years. The impact of the patient's phenotype, type and number of target organs affected will be studied. A modern definition, adapted to these results, could be proposed. The epidemiology of the disease, the care pathways, the target organ disorders and the management carried out in the centers will be described in detail.

Despite remarkable clinical results with the use of CDK4/6i, breast cancer patients will experience progression of disease requiring alternative treatment options. The optimal sequence of therapy after progression on CDK4/6i has not been established and it depends on multiple factors, including previous regimens, mutational profile, comorbidities, patient preference or disease burden (NCCN v4, 2023). Thus, new targeted treatment modalities are needed for treatment of patients with endocrine-resistant mBC. The purpose of this Phase I/II study conducted in participants with ER+/HER2-, gastrin releasing peptide receptor positive (GRPR+) mBC after progression on CDK4/6i-based therapy is: In the Phase I (dose escalation part) to determine the recommended doses and regimens of \[177Lu\]Lu-NeoB in combination with capecitabine in post-menopausal women and men not requiring gonadotropin releasing hormone agonist. In the Phase II (dose optimization part) to evaluate preliminary efficacy across 2 different dose levels and regimens of \[177Lu\]Lu-NeoB in combination with capecitabine in adults including pre/peri-menopausal and post-menopausal women, and men, regardless of their need of a gonadotropin releasing hormone agonist (GnRha). During screening, study participants will receive the radioligand imaging agent \[68Ga\]Ga-NeoB for a positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI). An additional \[68Ga\]Ga-NeoB for PET/CT or PET/MRI will be performed after their last administration of \[177Lu\]Lu-NeoB for phase II participants only. During the treatment period participants will be required to attend a site visit approximately every 3 weeks for the first 9 months and every 6 weeks thereafter, on the first day of every cycle (defined as a period of 3 weeks) or every other cycle, respectively, to undergo study treatment administration or dispensing, dosimetry and safety assessments. Tumor assessments are performed every 9 weeks (+/- 7 days) until M18, then every 12 weeks until M36, and thereafter as clinically indicated until documented disease progression, death, withdrawal of consent, loss to follow-up, participant/guardian decision. After study treatment discontinuation, participants will be followed up for safety for 8 weeks after their last study treatment administration. Beyond the initial 8 weeks of safety follow-up, all participants will be followed up as per the Schedule of Assessments, for a total of 5 years from their last \[177Lu\]Lu-NeoB administration, or until death, lost to follow-up, participant/guardian's or investigator's decision or withdrawal of consent (WoC). The end of study is defined as the date of the last visit, scheduled procedure or follow up (or date of death, participant/guardian's or investigator's decision, WoC or lost to follow up, whichever occurs first) of the last participant in the study globally, or at 5 years from the last \[177Lu\]Lu-NeoB administration to the last study participant, whichever occurs last. This study includes \[177Lu\]Lu-NeoB and capecitabine as study treatment and \[68Ga\]Ga-NeoB as an imaging agent. Participants will receive \[177Lu\]Lu-NeoB in combination with capecitabine (and a GnRHa, where applicable, as per local clinical practice, for pre-/peri-menopausal women and men in the Phase II part only). \[68Ga\]Ga-NeoB is a PET imaging agent being investigated in studies with \[177Lu\]Lu-NeoB treatment in patients with tumors overexpressing GRPR, including mBC patients. \[68Ga\]Ga-NeoB has shown favorable technical and diagnostic performance to identify GRPR-expressing malignancies, both in preclinical and in clinical studies, with good image quality that allows interpretation. \[177Lu\]Lu-NeoB has shown high affinity to the GRPR and its ability to target the GRPR expressing tumor has been confirmed in in vivo imaging and biodistribution studies in tumor models. \[177Lu\]Lu-NeoB is rapidly cleared from the blood, quickly eliminated through the renal system, with no retention in kidneys. \[177Lu\]Lu-NeoB is currently being evaluated as a single agent in an ongoing Phase I/IIa, open-label, multi-center study (NeoRay) which evaluates the safety, tolerability, whole-body distribution, radiation dosimetry and anti-tumor activity of \[177Lu\]Lu-NeoB administered in patients with advanced solid tumors known to overexpress GRPR who have no available therapeutic options. Data show that \[177Lu\]Lu-NeoB has shown a good tolerability and safety profile and a favorable biodistribution with low uptake in organs considered to be at risk due to GRPR-expression, such as the pancreas, or due to radioligand therapy (RLT), such as the red marrow, and the route of excretion, such as the kidneys. Capecitabine is an oral fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FU) preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase. It is one of the most frequent chemotherapy treatment choices for HR+/HER2- mBC patients post-CDK4/6i failure from 2nd line and beyond as reflected in real word data. It is also considered to be a potent radiosensitizer. The synergistic combination of chemotherapy and radionuclides has the potential to enhance efficacy. This study will enroll a total of between 36 and 58 participants, depending on the applicable scenario. In the Phase I part, about 18 participants will be either enrolled or assigned to treatment/randomized (as applicable). In the Phase II part, between 28 and 40 participants will be randomized, depending on the applicable scenario. A standalone Japanese cohort will run in parallel to the Phase II of the Study. * The screening period of 42 days is followed by the treatment period until disease progression, discontinuation of study treatment due to any other reason such as unacceptable toxicity, symptomatic deterioration, WoC, lost to follow up, investigator decision or death, whichever occurs first. The post treatment follow up period comprises the safety follow up for 8 weeks after treatment discontinuation and the long term safety and survival follow up for up to 5 years from the date of the participant's last dose of \[177Lu\]Lu-NeoB * During screening, each participant will receive \[68Ga\]Ga-NeoB for PET/CT or PET/MRI imaging to confirm eligibility. Additionally, within 4-8 weeks from the last administration of \[177Lu\]Lu-NeoB, another administration of \[68Ga\]Ga-NeoB for PET/CT or PET/MRI will be performed, in the phase II part only. * In the phase I part, participants will receive \[177Lu\]Lu-NeoB at a starting dose of 150mCi +/- 10% (iv infusion) Q6W in combination with capecitabine (tablet, 1000 mg/m2 twice daily for 14 consecutive days followed by 7 days off treatment). If dose escalation is supported, then two higher dose levels of \[177Lu\]Lu-NeoB in combination with capecitabine are planned to be explored, in a randomized way: 200mCi Q6W and 100mCi Q3W. These correspond to the same total dose given in a 6 weeks timeframe but exploring a different dose fractionation. * If dose escalation from the starting dose is not supported, then lower dose levels will be explored (100mCi Q6W and if shown safe, 100mCi Q3W). If none of these are shown safe then the study will be terminated * In the phase II part, there are four potential scenarios that may apply, depending on the outcome of the phase I part: * Scenario 1 (if both higher dose levels in phase I were shown safe) participants will be randomized to either \[177Lu\]Lu-NeoB 200mCi Q6W or 100mCi Q3W, in combination with capecitabine * Scenario 2 (if only one of the two higher dose levels in phase I were shown safe) participants will be randomized to either \[177Lu\]Lu-NeoB 200mCi Q6W / 100mCi Q3W (whichever was shown safe in phase I) or 150 mCi Q6W, in combination with capecitabine * Scenario 3 (if none of the higher doses in phase I are shown safe): participants will be randomized to either \[177Lu\]Lu-NeoB 150mCi Q6W or 100mCi Q6W, in combination with capecitabine * Scenario 4 (if dose escalation from the starting dose was no supported in phase I and lower investigational dose levels and regimens are shown safe in phase I part): participants will be randomized to either \[177Lu\]Lu-NeoB 100 mCi Q6W or 100 mCi Q3W, in combination with capecitabine. * Treatment duration with \[177Lu\]Lu-NeoB is 6 administrations for Q6W regimens and 12 administrations for Q3W regimens. Additional \[177Lu\]Lu-NeoB administrations may be considered based on an individual benefit-risk assessment performed by the Investigator, participant and Sponsor

IFCT-2202 ROSIE study aims to incorporate a broad-panel centralized NGS testing at baseline in all patients with completely resected NSCLC with common EGFR mutation after confirmation of an optimal preoperative extension assessment and with a centralized review of the quality of the surgical excision. Furthermore, the IFCT-2202 ROSIE study also aims to study the molecular events associated with relapse on, or after osimertinib exposure, that should result in the opportunity to accede to optimal treatment in case of metastatic relapse.

As pegcetacoplan is a new product on the market, with a new mechanism of action, there is an urgent need to provide data to treaters, payers and the PNH community on the real-world usage and effectiveness of pegcetacoplan. This study aims to fill part of that knowledge gap and to add to the knowledge base regarding the use of pegcetacoplan in routine medical practice. Another important rationale for this study is to provide information on RBC transfusions and health care resource utilization pre and post pegcetacoplan treatment initiation. The study plans to include approximately 200 patients at 70 sites in Europe, Middle East, Canada and Australia. Additional countries may be added in the study if necessary. Patients meeting the eligibility criteria will be enrolled in the study and followed prospectively for approximately 36 months. Patient data will be collected from start of pegcetacoplan treatment to end of follow-up. Retrospective data on pegcetacoplan will be captured from the time of pegcetacoplan treatment initiation. Pegcetacoplan treatment data will be collected for a minimum of approximately 36 months and up to a maximum of approximately 72 months, including retrospective period depending on when the patient started pegcetacoplan treatment. After pegcetacoplan treatment discontinuation, patients will remain in the study for 8 weeks to capture any AEs. Patients will come to their routine visits and the available data from each visit will be collected. The scope of the study is to collect both retrospective and prospective data. The main part of the study will be prospective, collecting data on effectiveness, safety, patient- and clinician-reported outcomes and health care resource use. The study will also collect retrospective data before pegcetacoplan treatment start, which will consist of information on PNH treatment, blood transfusions and healthcare resource use. Data will be collected for up to 12 months prior to pegcetacoplan treatment start. As patients may have been treated with pegcetacoplan for up to 12 months prior to enrollment, retrospective data may be collected for up to 24 months. This means that the total data collection period including both the retrospective and the prospective part is up to 48 (+/- 3) months.