ReInspire: A phase 2 study of mutant-selective PI3Kα inhibitor, RLY-2608, in adults and children with PIK3CA-related overgrowth spectrum and malformations driven by PIK3CA mutation

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 [email protected]