Nano-Megestrol Acetate for Cancer Cachexia in Advanced Pancreatic Cancer

This is a multicenter, randomized, controlled, prospective interventional clinical study evaluating an approved formulation of nanocrystalline megestrol acetate oral suspension. The study aims to assess the efficacy and safety of nanocrystalline megestrol acetate in combination with standard first-line therapy versus standard first-line therapy alone in newly diagnosed patients with locally advanced or metastatic pancreatic ductal adenocarcinoma with cancer anorexia-cachexia syndrome, and to explore its impact on survival outcomes, quality of life, and selected biomarkers. Patients with pancreatic cancer have a high prevalence of malnutrition and cachexia. Treatment-related adverse effects from chemotherapy and immunotherapy may further worsen anorexia, weight loss, and skeletal muscle wasting, creating a vicious cycle that compromises treatment tolerance, quality of life, and prognosis. Although megestrol acetate is widely recommended as a first-line pharmacologic option for cancer-related anorexia-cachexia syndrome by multiple guidelines, prospective evidence regarding the optimal timing and the overall clinical benefit of combining megestrol acetate with contemporary first-line regimens (including immuno-chemotherapy) remains limited. The nanocrystalline formulation improves bioavailability through particle-size reduction and can achieve effective plasma exposure even in the fasting state, which may be particularly advantageous for patients with reduced oral intake. Eligible participants will be stratified by pre-cachexia versus cachexia, and randomized with stratification factors including ECOG performance status (0-1 vs 2) and planned chemotherapy regimen (AG vs mFOLFIRINOX/NALIRIFOX). Participants will be assigned to one of two arms: 1. Megestrol arm: nanocrystalline megestrol acetate 625 mg/day (125 mg/mL, 5 mL orally once daily) initiated at the start of first-line therapy and continued for up to 12 weeks, in addition to investigator-selected standard first-line systemic therapy per guidelines and routine practice (e.g., AG, FOLFIRINOX, or NALIRIFOX, with or without immunotherapy as applicable); 2. Control arm: standard first-line systemic therapy alone. If the primary anticancer regimen is modified, interrupted, or permanently discontinued during the study, nanocrystalline megestrol acetate may continue in the combination arm (per protocol) until completion of the 12-week course, allowing evaluation of the core anti-cachexia intervention. The primary assessment focuses on the proportion of patients achieving \>5% body-weight gain from baseline at Week 12 (as a key primary endpoint within the dual-endpoint framework), along with comprehensive evaluation of appetite (FAACT-A/CS 12), body composition (L3-level CT-based assessment of skeletal muscle and adipose tissue), physical function, health-related quality of life (EORTC QLQ-C30), chemotherapy adherence, and the incidence and severity of adverse events. Tumor response will be assessed at predefined intervals (approximately every 6 weeks), and survival outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) will be followed and analyzed up to one year after randomization. In addition, the study will explore changes in inflammatory markers (CRP, NLR), cytokines (IL-1, IL-6, TNF-α), and nutritional indices (albumin, prealbumin, hemoglobin) from baseline to Week 12 to support mechanistic understanding and identify potential predictive biomarkers. Safety will be monitored continuously throughout the study, with standardized collection and follow-up of adverse events (AEs) and serious adverse events (SAEs) as specified in the protocol, complemented by vital signs, physical examinations, laboratory testing, electrocardiography, and echocardiography. Overall, this study aims to validate an integrated strategy combining anticancer therapy with early anti-cachexia intervention in the immuno-chemotherapy era, and to generate high-quality evidence on the clinical value of nanocrystalline megestrol acetate in improving weight/body composition, symptom burden, quality of life, and potentially survival outcomes in advanced pancreatic cancer.