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:

• 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);
• 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.

Inclusion criteria

• Patients must meet all of the following criteria to be eligible for enrollment:

• Pancreatic cancer-specific inclusion criteria:
• Histologically or cytologically confirmed locally advanced or metastatic pancreatic ductal adenocarcinoma according to the TNM staging system of the International Association of Pancreatology and the 8th edition of the American Joint Committee on Cancer (AJCC);
• No prior systemic antitumor therapy for recurrent or metastatic disease;
• Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or immunotherapy for non-metastatic disease is allowed, provided that at least 6 months have elapsed since completion of the last treatment without disease recurrence;
• At least one measurable lesion according to RECIST version 1.1 (previously irradiated lesions may be considered measurable only if there is clear evidence of disease progression after radiotherapy).

• Fulfillment of Fearon criteria for cachexia or pre-cachexia:

(1) Cachexia stage according to Fearon criteria: fulfillment of any of the following criteria in combination with decreased appetite (FAACT-A/CS 12 score ≤ 37) or systemic inflammation (CRP > 5 mg/L):

① Unintentional weight loss > 5% within the past 6 months;

• Body weight loss > 2% in patients with a BMI < 18.5 kg/m². (2) Pre-cachexia stage according to Fearon criteria: all of the following three conditions must be met:

① Unintentional weight loss ≤ 5% within the past 6 months;

• Systemic inflammation (CRP > 5 mg/L);

③ Decreased appetite (FAACT-A/CS 12 score ≤ 37). 3. General inclusion criteria:

• Good compliance and provision of written informed consent;
• Age 18-75 years, regardless of sex;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
• Expected survival greater than 4 months;
• Adequate organ function, defined as follows:

• Hematologic function: absolute neutrophil count ≥ 1.5 × 10⁹/L, hemoglobin ≥ 9 g/dL, platelet count ≥ 100 × 10⁹/L;

• Hepatic function: total bilirubin ≤ 1.5 × upper limit of normal (ULN) (patients with known Gilbert's syndrome may be enrolled if serum bilirubin ≤ 3 × ULN), AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN in the presence of liver metastases), and alkaline phosphatase ≤ 3 × ULN (≤ 5 × ULN in the presence of liver or bone metastases); serum albumin ≥ 3 g/dL;

• Coagulation function: international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;

• Renal function: creatinine clearance ≥ 60 mL/min as calculated by the Cockcroft-Gault formula;
• Urinary protein: urine protein ≤ 1+ on dipstick or 24-hour urine protein < 1.0 g;
• Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%.
• Women of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to first dosing (if a urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required and shall prevail). Women of childbearing potential who engage in sexual activity with non-sterilized male partners must use an acceptable method of contraception from screening and agree to continue contraception for 120 days after the last dose of study medication; decisions regarding discontinuation of contraception after this time point should be discussed with the investigator. Male patients who engage in sexual activity with women of childbearing potential must use effective contraception from screening until 120 days after the last dose of study medication; decisions regarding discontinuation of contraception after this time point should be discussed with the investigator.

Exclusion criteria

• Patients meeting any of the following criteria will be excluded from this study:

• Cancer-specific exclusion criteria:
• Active or untreated CNS metastases (e.g., brain or leptomeningeal metastases) as determined by CT or magnetic resonance imaging (MRI) during screening or based on prior imaging assessments. Patients with previously treated brain or leptomeningeal metastases may be eligible if the disease has been stable for ≥ 2 months and systemic corticosteroid therapy (>10 mg/day prednisone or equivalent) has been discontinued for > 4 weeks prior to randomization.
• Uncontrolled tumor-related pain;

(1) History of thromboembolic disease, ascites, or lower extremity edema within the past 6 months; (3) History of malignancy other than pancreatic cancer within 5 years prior to randomization, except for malignancies with negligible risk of metastasis or death (e.g., expected 5-year overall survival > 90%) and considered curable after appropriate treatment, such as adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer treated with curative surgery, and ductal carcinoma in situ treated with curative surgery; (4) Unresolved toxicity from prior anticancer therapy, defined as failure to recover to NCI CTCAE version 5.0 grade 0 or 1 (except alopecia) or failure to recover to levels specified in the inclusion/exclusion criteria; (5) Patients with peritoneal metastases will be excluded. 2. General medical exclusion criteria:

• Women who are pregnant, breastfeeding, or planning to become pregnant during the study period;
• Patients with hepatitis B or hepatitis C:

① Patients with a history of hepatitis B virus (HBV) infection must undergo HBV deoxyribonucleic acid (DNA) testing; only patients with negative HBV DNA (HBV DNA < 1000 copies/mL or < 200 IU/mL or below the upper limit of normal) are eligible for participation in this study;

② Among patients who are positive for hepatitis C virus (HCV) antibodies, only those with negative HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) testing are eligible to participate in this study;

• Patients with a positive test result for human immunodeficiency virus (HIV);
• Major surgery (excluding diagnostic procedures) within 28 days prior to randomization, or anticipated major surgery during the study period;
• Significant cardiovascular disease, such as heart disease defined as New York Heart Association class II or higher, myocardial infarction within 3 months prior to randomization, unstable arrhythmia, unstable angina, cerebrovascular accident, or transient ischemic attack. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be receiving optimal stable therapy as determined by the treating physician; consultation with a cardiologist may be obtained if necessary;
• Severe infection occurring within 4 weeks prior to first dosing, including but not limited to infections with complications requiring hospitalization, sepsis, or severe pneumonia; or active infection requiring systemic anti-infective therapy within 2 weeks prior to first dosing (excluding antiviral therapy for hepatitis B or C).

• Drug-related exclusion criteria:
• Conditions affecting gastrointestinal absorption, including dysphagia, malabsorption, or uncontrolled vomiting; difficulty in food intake or requirement for tube feeding or parenteral nutrition; anorexia nervosa; anorexia caused by psychiatric disorders or pain-related inability to eat;
• Current or planned use of other medications that increase appetite or body weight, such as corticosteroids (except short-term dexamethasone use during chemotherapy), androgens, progestins, thalidomide, olanzapine, anamorelin, or other appetite stimulants;
• Cushing's syndrome, adrenal or pituitary insufficiency; poorly controlled diabetes mellitus; or current hypertension with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg despite treatment with oral antihypertensive agents;
• History within 6 months prior to first dosing of esophageal or gastric varices, severe ulcer disease, gastrointestinal perforation and/or fistula, gastrointestinal obstruction (including incomplete obstruction requiring parenteral nutrition), intra-abdominal abscess, or acute gastrointestinal bleeding;
• Known hypersensitivity to any component of the study drug;
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in the study.