Clinical Research Directory

A Study to Evaluate the Efficacy and Safety of Everolimus in Patients With Teratment-refractory Vascular Anomalies

Background and Objectives Vascular anomalies are a heterogeneous group of disorders classified into vascular tumors and vascular malformations according to the ISSVA classification. Although most follow a benign course, a subset causes serious complications including organ dysfunction, chronic pain, thrombocytopenia, and hemorrhage. Kaposiform hemangioendothelioma (KHE) complicated by Kasabach-Merritt Phenomenon (KMP) carries a mortality rate of 14-24%. Surgical resection is the primary treatment when organ damage is not anticipated; however, when surgery is not feasible, pharmacologic therapy is considered. Agents such as interferon, corticosteroids, vincristine, cyclophosphamide, and propranolol have been used with variable efficacy, and no established therapy exists for patients refractory to these treatments. The PI3K-Akt-mTOR and RAS-MEK-ERK pathways have been identified as key molecular mechanisms underlying vascular anomalies. Targeted therapies against these pathways are emerging, including anti-VEGF antibodies, PI3K/Akt inhibitors (e.g., alpelisib, miransertib), and mTOR inhibitors. Sirolimus has demonstrated clinical benefit in 50-80% of patients with vascular anomalies, with a 96% symptom response rate in KMP-associated vascular tumors. Everolimus, another mTOR inhibitor, is already approved and established for tuberous sclerosis-associated angiomyolipoma and SEGA in pediatric patients, with a well-characterized safety profile. Given its shared mechanism with sirolimus and emerging case reports supporting efficacy in KHE with KMP, this phase 2 study aims to evaluate the efficacy and safety of everolimus in patients with treatment-refractory vascular anomalies. Study Design This is a single-center, open-label, uncontrolled phase 2 clinical trial enrolling 67 patients over 60 months from IRB approval, stratified into two cohorts: Cohort 1 (sirolimus-naïve, n=39) and Cohort 2 (prior sirolimus failure, n=28). Everolimus is administered orally at age- and CYP3A4/P-gp inducer-adjusted doses, with maintenance dosing titrated to a target trough level of 5-15 ng/mL. The primary endpoint is overall response rate (ORR) at 6 months. Secondary endpoints include toxicity per NCI CTCAE v4.0, ORR at 12 months, platelet recovery rate at 4 weeks (KMP patients), 1-year overall survival, and 3-year progression-free survival.

A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations

Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).

Institution of an Italian Registry and Biobank for Biological Sample Collection

Lymphatic malformations (ML), are benign non-neoplastic, rare, resulting from an embryologic abnormal development of the lymphatic system. Sometimes they may be associated with other vascular malformations (venous or arterial)1,2. ML usually appear at birth, in early childhood or during the first years of life (congenital vs. acquired) and are mainly localized in the region of the head and neck, armpits, groin, retroperitoneal tissues, tongue and mucous membranes of the oral cavity since these areas contain a plethora of lymphatic structures1. The main complications due to their location are airway obstruction, difficulty in eating, and bleeding3-5. Infection and bleeding can promote the sudden, progressive and accelerated growth of these lesions1. The location, speed of growth, and the subsequent complications associated with ML, determine the overall severity of the clinical picture and require generally the referral of the affected patient to a specialized center that can ensure a multidisciplinary care3,5. Recently, the International Society for the Study of Vascular Anomalies (ISSVA), has revised and updated the classification of such malformations, emphasizing the distinction between isolated forms and ML in the context of more complex syndromes with multisystem involvement2. Until a few years ago, the only treatment strategies available for ML were scleroembolization, cryotherapy, transcutaneous laser photocoagulation, and surgical resection of the malformation. The recent identification of genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/target mammalian pathway of rapamycin (mTOR), which underlies many isolated and syndromic ML pictures6-9, has opened up important prospects for personalized treatment with repurposed drugs6,7,10-20. Over the years, the rarity and complexity of ML management have resulted in a fragmented nature of available information and poor nationwide sharing of diagnostic-clinical-assistance-therapeutic protocols (PDTAs) with the consequent need for many families to undertake multispecialty consultations in various provinces or regions before identifying a suitable Referral Center. In addition, recent acquisitions in genetics have forced specialists, a further reevaluation of those complex clinical pictures of ML, whether isolated or syndromic, that could be candidates for personalized drug treatments. The institution of a national Registry of pathology promoted by the Association of Patients with Lymphatic Malformations, which supports clinicians and families in filling unmet information and clinical care gaps, is a priority project in order to improve the quality of life of patients and the level of care offered to them. In addition, the establishment of a collection of biological specimens, processed according to high quality standards, within a Research Biobank provides the opportunity for patients and their families to maximize the visibility of the specimens, promoting their use in national and international research projects dedicated to ML, in compliance with ELSI (Ethical, Social, and Legal Issues) criteria. The study primary Objective is To create a computerized registry for ML that collects both retrospective and prospective data in order to estimate the incidence and prevalence of ML, in different phenotypes. As secondary objectives. (i) Establish a collection of biological specimens (Fresh and fixed biopsy tissue; DNA extracted from whole blood, saliva and where possible from biopsy tissue) within the FPG Research Biobank, intended for future research purposes and available to the entire scientific community; ii) Genetically profile patients who have never undergone molecular diagnostics or who have been tested with restricted panels of genes (PIK3CA, AKT, MTOR, PTEN, KRAS and BRAF) (activity performed on patients per clinical practice); (iii) Define the natural history of ML in different phenotypes and genotypes from prenatal to adult age; (iv) Evaluate the clinical outcomes of different treatments (e.g., experimental drug therapy, maxillofacial surgery, vascular surgery, laser therapy, sclerotherapy, compression therapy, etc.) and different modes of care (type and frequency of visits performed) in the short and long term; (v) Assess the impact of ML on the lives of patients and caregivers; (vi) Support the drafting/updating of national recommendations and standards of care; vii) to promote and facilitate the implementation of research projects dedicated to ML, fostering the advancement of scientific knowledge on this specific disease area;