Advanced Pancreatic Ductal Adenocarcinoma, Cancer Anorexia-Cachexia Syndrome
Conditions
Keywords
Pancreatic ductal adenocarcinoma, Cancer anorexia-cachexia syndrome, Nanocrystalline megestrol acetate, Body weight and body composition, Appetite improvement
Brief summary
Cancer anorexia-cachexia syndrome is a common and severe complication in patients with advanced cancer, with a particularly high prevalence in pancreatic cancer. It is associated with systemic inflammation, metabolic disturbances, and dysregulation of central appetite control, leading to reduced quality of life, poor tolerance to anticancer therapy, and shortened survival. Anticancer treatments, including chemotherapy and immunotherapy, may further exacerbate the development and progression of cachexia. Megestrol acetate is recommended as a first-line treatment for cancer-related anorexia-cachexia syndrome by multiple international and national guidelines, based on its proven effects on appetite stimulation, weight gain, and quality of life improvement. The nanocrystalline formulation of megestrol acetate significantly enhances bioavailability and achieves effective plasma concentrations even in the fasting state, making it particularly suitable for patients with cancer cachexia. This randomized, controlled, prospective study aims to evaluate the efficacy and safety of nanocrystalline megestrol acetate in patients with advanced pancreatic cancer complicated by cancer anorexia-cachexia syndrome. The study will assess improvements in appetite, body weight, nutritional status, and quality of life, and explore the clinical value of early anti-cachexia intervention in the era of immuno-chemotherapy, providing evidence to optimize comprehensive treatment strategies for advanced pancreatic cancer.
Detailed description
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.
Interventions
DRUGNano-crystalline megestrol acetate
Nano-crystalline megestrol acetate is administered as an oral suspension at a dose of 625 mg once daily (5 mL, 125 mg/mL) starting concurrently with first-line chemotherapy and continued for up to 12 weeks. Unlike conventional megestrol acetate formulations, the nano-crystalline formulation utilizes reduced particle size to enhance oral bioavailability and improve weight gain outcomes. In this study, nano-crystalline megestrol acetate is used as an early supportive intervention in treatment-naïve patients with advanced pancreatic cancer-related anorexia-cachexia syndrome, rather than as salvage therapy. The intervention is delivered in combination with standard first-line chemotherapy regimens (AG, FOLFIRINOX, or NALIRIFOX). Administration of nano-crystalline megestrol acetate may be continued even if modifications, delays, or discontinuation of chemotherapy occur, in accordance with the study protocol. Safety and efficacy are prospectively monitored throughout treatment and follow-up.
Participants in the control group will receive first-line chemotherapy alone, without nano-crystalline megestrol acetate. Chemotherapy regimens, including AG, FOLFIRINOX, or NALIRIFOX, will be selected and managed according to standard clinical practice.
Sponsors
Shandong Cancer Hospital and Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a randomized, controlled, prospective, multicenter study evaluating nano-crystalline megestrol acetate plus first-line chemotherapy in patients with advanced pancreatic cancer-related anorexia-cachexia syndrome. Treatment-naïve patients with locally advanced or metastatic pancreatic ductal adenocarcinoma meeting pre-cachexia or cachexia criteria will be randomized 1:1 to receive nano-crystalline megestrol acetate (625 mg/day for up to 12 weeks) with chemotherapy or chemotherapy alone. The primary endpoint is ≥5% weight gain at Week 12. Secondary endpoints include appetite, OS, PFS, body composition, quality of life, and safety. Open-label follow-up is up to one year.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients must meet all of the following criteria to be eligible for enrollment: 1\. Pancreatic cancer-specific inclusion criteria: 1. 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); 2. No prior systemic antitumor therapy for recurrent or metastatic disease; 3. 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; 4. 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). 2\. 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: 1. Good compliance and provision of written informed consent; 2. Age 18-75 years, regardless of sex; 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; 4. Expected survival greater than 4 months; 5. 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%. 6. 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: 1\. Cancer-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Achieving >5% Weight Gain From Baseline(weight in kilograms,Kg) | 12 weeks | The proportion of patients with advanced pancreatic cancer-related anorexia-cachexia syndrome who achieve a body weight increase of more than 5% compared with baseline(Kg) during first-line treatment combined with or without nano-crystalline megestrol acetate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Appetite Assessed by Functional Assessment of Anorexia/Cachexia Therapy-Anorexia/Cachexia Subscale (FAACT-A/CS 12) | 12 weeks | Change from baseline in appetite as assessed by the Functional Assessment of Anorexia/Cachexia Therapy-Anorexia/Cachexia Subscale (FAACT-A/CS 12) in patients with advanced pancreatic cancer.The A/CS-12 Scale maintains the reliability, validity, and assessment accuracy of the FAACT questionnaire while reducing the number of items from 18 to 12. Each item is scored from 0 to 4, with a total score ranging from 0 to 48. Lower scores indicate poorer appetite in patients. When using the A/CS-12 Scale, it is recommended to use a total score ≤ 37 as the criterion for determining appetite loss in patients. |
| Change in Body Composition Assessed by L3-CT | 12 weeks | Change from baseline in body composition parameters, including skeletal muscle and adipose tissue area, assessed by computed tomography at the third lumbar vertebra (L3) level.A single cross-sectional image of the third lumbar vertebra (L3) is obtained via CT/MRI scanning. The skeletal muscles (psoas major, erector spinae, quadratus lumborum, transversus abdominis, external oblique, internal oblique) and adipose tissue in the L3 image are identified and quantified. Image analysis software such as Slice-O-Matic or Image J is used to calculate the total skeletal muscle area(skeletal muscle area in square centimeters,cm²) at this level. This area is then divided by the square of the patient's height(height in meters,m) to obtain the L3 Skeletal Muscle Index (L3-SMI,L3-SMI =skeletal muscle area (cm²) / (height(m))².Compare the changes in Skeletal Muscle Index (SMI) from baseline to the end of the study between the two groups (Megestrol Acetate group vs. control group). |
| Change in Physical Function Scale | 12 weeks | Change from baseline in physical function assessed using standardized functional assessment methods in patients with advanced pancreatic cancer.Physical Functioning Scale is assessed using a 4-point scale（from 1 to 4）, where a higher score on the functional scale indicates better function. |
| Change in Quality of Life Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | 12 weeks | Change from baseline in health-related quality of life assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).The Overall Quality of Life Scale is divided into 7 levels, with scores ranging from 1 to 7. Higher scores indicate better overall quality of life. |
| Incidence and Severity of Adverse Events | 12 weeks | Incidence, nature, and severity of adverse events and serious adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. NCI CTCAE version 5.0 classifies the severity of adverse events into Grades 1 through 5, with a higher grade indicating greater severity. Adverse events (AEs) for each subject will be followed up until 30 days after the last dose of nanocrystalline megestrol acetate or until the initiation of new antitumor therapy, whichever occurs first. Serious adverse events (SAEs) will be followed up until 90 days after the last dose or until the initiation of new antitumor therapy, whichever occurs first. Safety assessments of the drug will be conducted according to the schedule outlined in the study protocol, including a series of examinations such as vital signs, physical examinations, clinical laboratory evaluations, electrocardiograms (ECG), and echocardiograms. |
| Chemotherapy Compliance | 12 weeks | Compliance with planned first-line chemotherapy regimens, assessed by dose intensity, treatment delays, and discontinuations during the study period. |
| Overall Survival (OS) | 1 year | The time interval from enrollment to death from any cause for patients in the intent-to-treat population. For patients who were still alive at the time of analysis or lost to follow-up, the date of the last known survival status was used as the endpoint date. |
| Progression-Free Survival (PFS) | 1 year | The time interval from enrollment to disease progression or death from any cause, whichever occurs first. For patients without documented progression at the time of study discontinuation, the date of the last tumor assessment will be used as the endpoint date. |
| Overall Response Rate (ORR) | 1 year | The percentage of subjects in the intent-to-treat population who achieve a complete response (CR) or partial response (PR) as their best overall response according to RECIST 1.1 criteria during the study period. |
| Disease Control Rate (DCR) | 1 year | The percentage of subjects in the intent-to-treat population who achieve a best overall response of complete response (CR), partial response (PR), or stable disease (SD) lasting for at least 6 weeks, as assessed per RECIST 1.1 criteria. |
Countries
China
Contacts
CONTACTJinbo Yue, Dorcter
PRINCIPAL_INVESTIGATORJinbo Yue, Dorcter
Shandong Cancer Hospital and Institute
Outcome results
None listed