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

A Prospective, Exploratory Study of Retlirafusp Alfa Combined With Famitinib and AG-Chemotherapy as First-Line Therapy for Unresectable Pancreatic Cancer

This is a single-arm, prospective, multicenter, open-label clinical trial, which aims to observe and evaluate the efficacy and safety of Relafen-α combined with famitinib and AG chemotherapy as first-line therapy in patients with unresectable pancreatic cancer.

The study enrolls patients with unresectable locally advanced and metastatic pancreatic cancer.

Progression-free survival (PFS) is set as the primary efficacy endpoint. Approximately 88 patients with unresectable locally advanced and metastatic pancreatic cancer will be recruited. After adequate informed consent and signature of the informed consent form, eligible screened subjects will receive Relafen-α in combination with famitinib plus nab-paclitaxel/gemcitabine.

Treatment regimen： Relafen-α (1800 mg, q3w, Cycle 1); Famitinib (15 mg, qd, q3w); nab-paclitaxel (125 mg/m², d1, d8, Q3W, for 6 cycles) combined with gemcitabine (1000 mg/m², d1, d8, Q3W, for 6 cycles). Treatment will be continued until disease progression or intolerable toxicity, whichever occurs first.

Inclusion Criteria:

1. Aged between 18 and 80 years, of any gender;

2. Histopathologically-confirmed diagnosis of pancreatic ductal adenocarcinoma;

3. 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;

4. Eastern Cooperative Oncology Group (ECOG) performance status: 0-1;

5. Expected survival ≥ 12 weeks;

6. No prior systemic anti-cancer treatment;

7. Adequate function of major organs;

8. 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;

9. 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;

10. Subjects voluntarily participate in this study, provide written informed consent, have good compliance, and are willing to complete follow-up assessments.

Exclusion Criteria:

1. Subjects with hypersensitivity to Retlirafusp alfa, famitinib, gemcitabine, albumin-bound paclitaxel or their excipients;
2. Histopathologically-confirmed other pancreatic malignancies, such as pancreatic acinar cell carcinoma, pancreatic neuroendocrine tumor;
3. 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;
4. History of organ transplantation (including autologous bone-marrow transplantation and peripheral stem-cell transplantation);
5. Prior receipt of systemic anti-cancer therapy;
6. 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;
7. Subjects with a history of psychoactive substance abuse that cannot be discontinued, or with psychiatric disorders;
8. 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 %);
9. Presence of uncorrectable coagulation disorders;
10. 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 %;
11. 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;
12. 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;
13. 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;
14. 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;
15. 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);
16. Uncontrolled hypertension despite medication, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg;
17. Major surgery (excluding biopsy) performed within 28 days prior to enrollment, or incompletely-healed surgical incision;
18. Receipt of any other investigational product or participation in another interventional clinical trial within 4 weeks before informed-consent signature;
19. Pregnant women (positive pregnancy test before drug administration) or breastfeeding women;
20. Subjects deemed unsuitable for enrollment at the investigator's discretion.