Hammill, Adrienne M.

Abstract Background and Significance Somatic gain-of-function mutations in the PIK3CA gene can result in a range of vascular malformations (VMs). These rare disorders include lymphatic anomalies and PIK3CA-related overgrowth spectrum (PROS). VMs are noncancerous lesions that may be managed with treatments such as surgery, sclerotherapy, sirolimus, and non-mutant-selective PI3Kα inhibitors; however, use of systemic therapies in patients is frequently limited by drug-related adverse effects. In particular, inhibition of wild-type PI3Kα results in significant toxicity, including hyperglycemia, diarrhea and rash. RLY-2608 is a novel, allosteric, pan-mutant and isoform-selective oral PI3Kα inhibitor designed to have higher potency and improved tolerability. In a PIK3CAH1047R HUVEC xenograft mouse model, RLY-2608 demonstrated greater lesion regression and less insulin induction across clinically relevant dose levels than alpelisib (Llambi, VAC 2025). ReInspire (RLY-2608-201; NCT06789913) is an ongoing, global, multicenter study in patients with PIK3CA-driven VMs to assess the safety, pharmacokinetics, recommended adult and pediatric dosing, and efficacy of RLY-2608 based on target lesion volume and clinical outcome assessments. The design of this study, including dose selection, was informed by clinical data from the first-in-human study of RLY-2608 in adult patients with advanced solid tumors, including breast cancer (Varkaris et al, 2024). Study Design and Methods ReInspire is a 3-part study evaluating the safety and efficacy of RLY-2608 in approximately 277 patients two years of age and older with PIK3CA-driven VMs and PROS. RLY-2608 is administered orally in continuous cycles. The primary endpoints are safety, tolerability, recommended Phase 2 dose (RP2D), and efficacy of RLY-2608 per volumetric reduction on MRI (≥20% reduction from baseline to Week 24 in the sum of target lesion volumes) by blinded independent central review. Other endpoints include duration of response and change in age-appropriate clinical outcome assessments. Patients are enrolled in a staggered fashion by age, beginning with adult and adolescent participants 12 years and older (Group 1), and may be extended to pediatric participants 6 to <12 years (Group 2) and 2 to <6 years, based on review of cumulative clinical data. Part 1 is the open-label dose-finding portion, which initiates with randomization of Group 1 patients (n=45) to one of three dose levels with stratification according to prior alpelisib use, and will be followed by weight-based dose escalation using a Bayesian optimal interval (BOIN) design in Groups 2 and 3, if opened. Part 2 is a basket-style, open-label dose expansion that will evaluate the clinical activity of RLY-2608 at one or more RP2Ds in various populations in cohorts of 20 patients each based on Part 1 findings. Depending on the results of Parts 1 and 2, Part 3, a double-blinded, placebo-controlled, 2:1 randomized study (n=90), may be opened to patients 6 years of age and older. To enroll, patients are required to have a clinical diagnosis of PROS or a malformation within the ISSVA classifications, and the majority must have a documented activating PIK3CA mutation per local assessment of lesional tissue and/or cell-free DNA from the lesion or blood. Patients with other known pathogenic somatic or germline driver mutations (such as TIE2 (TEK) and AKT1) are not eligible. Patients must be a candidate for investigational systemic therapy; have severe, symptomatic, and/or progressive disease; and at least one target lesion amenable for volumetric assessment. Additionally, patients who have received disease-directed therapy must undergo a washout period for systemic treatment and local therapies including radiation, surgery and other procedures. Patients with Type 1 or 2 diabetes requiring antihyperglycemic medication or fasting plasma glucose ≥140 mg/dL, or glycosylated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) are not eligible. Statistical analyses will be primarily descriptive in nature in Parts 1 and 2, with statistical comparisons between RLY-2608 and placebo at Week 24. ReInspire is open to enrollment. Patients ≥12 years are now enrolling in Part 1. For more information, contact clinicaltrials@relaytx.com

ABSTRACT Hereditary hemorrhagic telangiectasia (HHT, Osler‐Weber‐Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease‐modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT. Additionally, with the ongoing repurposing of antiangiogenic agents and emerging development of novel HHT‐specific therapies, comparative clinical trials are expected in the future. Therefore, to end the problematic heterogeneity hindering these efforts, the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT Foundation, an international group of recognized HHT experts, convened a conference of expert HHT clinician‐investigators from within GRMAB as well as invited external experts in HHT and bleeding disorders generally, patients with HHT, and patient advocates to define standard terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT. These criteria and definitions should be adopted by regulators, investigators, and the pharmaceutical industry in the development and performance of interventional clinical trials and cohort studies to allow improved comparability between clinical trials, facilitate communication between clinicians and investigators, improve therapeutic guideline development, and provide a standardized framework for regulatory agencies. Search Strategy and Selection Criteria Evidence for this report was systematically identified and evaluated utilizing two search strategies in Ovid MEDLINE, described in full detail in the Appendix, pp.4–13. The searches were conducted on January 7, 2025. The titles and abstracts of each record were reviewed, and the inclusion criteria were applied to all search results to identify full text articles to be retrieved for further review. All retrieved full texts were then reviewed to reach a final determination if a study met the inclusion criteria. Included references were then compiled into evidence tables, which were then utilized by the International Consensus Report Working Group throughout the development of report recommendations.

Objective(s): PIK3CA-related overgrowth spectrum (PROS) is a group of disorders caused by somatic variants in the PIK3CA gene. We aimed to update recommendations on the severity classification, testing, and medical management of patients with PROS. Methods: Using validated consensus methodology, we convened a 13-member panel in 2020 and reviewed current evidence on how to diagnose and treat PROS. The panel was asked to rate the level of disease severity, and the appropriateness of whether to test for a mutation and medical therapy in 217 patient scenarios before a virtual meeting. Panelists discussed areas of disagreement and completed ratings following the meeting. Results: The panel developed clinical presentations and endorsed the disease severity framework defined by functional impairment, a reduction in quality of life, and risk of death. Panelists agreed it is appropriate to test for a PIK3CA gene variant in every moderately/severely affected patient. Panelists agreed it may be appropriate to consider an mammalian (mechanistic) target of rapamycin inhibitor in some severely affected patients and some moderately affected patients with progressive disease. Although clinical trials have only recently begun and the evidence remains limited, panelists also agreed it may be appropriate to consider treatment with phosphoinositide 3-kinase/serine/threonine protein kinase inhibitors in severely affected patients with a confirmed PIK3CA variant or without a confirmed variant but with progressive disease. Conclusion: These recommendations represent the consensus of experts informed by published literature and experience. Future research should validate this guidance using clinical data. Once validated, we hope these recommendations will improve outcomes for patients with PROS.

Abstract Background Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large‐scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. Procedure A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. Results Twenty‐nine patients with CLVM, including KTS and CLOVES, were included. Ninety‐three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D‐dimer ( p = .008) and increases in mean fibrinogen ( p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life‐threatening, and none required long‐term discontinuation of sirolimus. Conclusion Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment‐related toxicities.