Retlirafusp Alfa Combined With Famitinib, Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Unresectable Pancreatic Cancer

Inclusion criteria

• Aged between 18 and 80 years, of any gender;
• Histopathologically-confirmed diagnosis of pancreatic ductal adenocarcinoma;
• Unresectable disease or distant metastasis confirmed by imaging evidence. Unresectable pancreatic ductal adenocarcinoma is defined as patients with distant metastasis, or a subset of locally advanced pancreatic cancer (LAPC) with invasion of surrounding major blood vessels that cannot be resected and reconstructed;
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-1;
• Expected survival ≥ 12 weeks;
• No prior systemic anti-cancer treatment;
• Adequate function of major organs;
• Baseline hematology and blood biochemistry shall meet the following criteria:

White blood cell count ≥ 3.0 × 10⁹/L; hemoglobin ≥ 90 g/L; absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); total bilirubin ≤ 2 × ULN; serum creatinine ≤ 1.5 × ULN; albumin ≥ 30 g/L;

• Females of child-bearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, condoms) throughout the study and for 6 months after study completion, have a negative serum or urine pregnancy test within 7 days prior to enrollment, and shall not be breastfeeding. Male subjects must agree to use effective contraception throughout the study and for 6 months after the end of study treatment;
• Subjects voluntarily participate in this study, provide written informed consent, have good compliance, and are willing to complete follow-up assessments.

Exclusion criteria

• Subjects with hypersensitivity to Retlirafusp alfa, famitinib, gemcitabine, albumin-bound paclitaxel or their excipients;
• Histopathologically-confirmed other pancreatic malignancies, such as pancreatic acinar cell carcinoma, pancreatic neuroendocrine tumor;
• Moderate-to-large pleural effusion, pericardial effusion or ascites with clinical symptoms, which requires frequent drainage (≥ 1 time per week) as judged by the investigator;
• History of organ transplantation (including autologous bone-marrow transplantation and peripheral stem-cell transplantation);
• Prior receipt of systemic anti-cancer therapy;
• Active or uncontrolled severe infection (≥ Grade 2 infection according to CTCAE 5.0), including but not limited to hospitalization due to infectious complications, bacteremia or severe pneumonia; unexplained fever > 38.5 °C before the first dose;
• Subjects with a history of psychoactive substance abuse that cannot be discontinued, or with psychiatric disorders;
• History of or concurrent other malignant tumors requiring active treatment within the past 5 years (except for fully-treated basal-cell or squamous-cell skin cancer, carcinoma in situ of the cervix and carcinoma in situ of the breast with an expected 5-year survival rate > 90 %);
• Presence of uncorrectable coagulation disorders;
• Clinically significant cardiovascular diseases, including but not limited to acute myocardial infarction, severe/unstable angina or coronary-artery bypass grafting within 6 months prior to enrollment; New York Heart Association (NYHA) class ≥ 2 congestive heart failure; ventricular arrhythmias requiring pharmacotherapy (including baseline QTc interval calculated by Fridericia's correction formula (QTcF): ≥ 450 ms for males and ≥ 470 ms for females); left-ventricular ejection fraction (LVEF) < 50 %;
• Subjects with radiologically-confirmed tumor invasion into major blood vessels, or those judged by the investigator to be at high risk of life-threatening massive hemorrhage due to subsequent tumor invasion of major blood vessels during the study;
• Subjects with active autoimmune disease, immunodeficiency, or a medical history including, but not limited to, autoimmune hepatitis, interstitial pneumonia, uveitis, rheumatoid arthritis, inflammatory bowel disease, hypophysitis, vasculitis, nephritis are excluded. Exceptions: subjects with a history of autoimmune hypothyroidism receiving thyroid-hormone replacement therapy are eligible. Subjects with type 1 diabetes mellitus whose blood-glucose level is well-controlled with insulin regimens may be enrolled;
• Subjects receiving immunosuppressants or systemic corticosteroids for immunosuppressive purposes (> 10 mg/day prednisone or equivalent dose of other glucocorticoids) and continuing such treatment within 2 weeks before enrollment;
• Arterial or venous thromboembolic events within 3 months prior to the first dose, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral embolism), deep-vein thrombosis and pulmonary embolism;
• Gastrointestinal diseases or conditions that, in the investigator's opinion, may affect drug absorption, including but not limited to active gastric/duodenal ulcer, ulcerative colitis, un-resected gastrointestinal tumor with active bleeding, or other conditions at risk of gastrointestinal bleeding or perforation as assessed by the investigator; multiple factors interfering with oral-drug administration (e.g. inability to swallow, post-gastrointestinal resection, chronic diarrhea, intestinal obstruction);
• Uncontrolled hypertension despite medication, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg;
• Major surgery (excluding biopsy) performed within 28 days prior to enrollment, or incompletely-healed surgical incision;
• Receipt of any other investigational product or participation in another interventional clinical trial within 4 weeks before informed-consent signature;
• Pregnant women (positive pregnancy test before drug administration) or breastfeeding women;
• Subjects deemed unsuitable for enrollment at the investigator's discretion.