Retlirafusp Alfa Plus Apatinib and Chemotherapy as Second-Line Treatment for Pancreatic Cancer

A Prospective, Open-Label, Single-Arm Clinical Study of Retlirafusp Alfa Combined With Apatinib and Chemotherapy as Second-Line Treatment for Locally Advanced or Metastatic Pancreatic Cancer

This is a prospective, open-label, single-arm clinical study designed to evaluate the efficacy and safety of retlirafusp alfa combined with apatinib and chemotherapy as second-line treatment in patients with unresectable locally advanced or metastatic pancreatic cancer who have experienced disease progression after first-line systemic therapy. Approximately 37 participants will be enrolled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety.

Pancreatic cancer is an aggressive malignancy with a poor prognosis. Most patients are diagnosed with unresectable locally advanced or metastatic disease, and treatment options after progression on first-line systemic therapy remain limited.

Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment and dense desmoplastic stroma. TGF-β contributes to immune suppression and stromal remodeling, while PD-L1-mediated signaling promotes immune evasion. Retlirafusp alfa is a bifunctional fusion protein targeting PD-L1 and TGF-β receptor II (TGF-βRII), designed to simultaneously inhibit PD-L1/PD-1 signaling and TGF-β signaling.

This prospective, open-label, single-arm study will evaluate the efficacy and safety of retlirafusp alfa combined with apatinib and fluoropyrimidine-based chemotherapy, with the specific chemotherapy regimen selected by the investigator, as second-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer after progression on first-line systemic therapy.

Approximately 37 participants will be enrolled. Study treatment will continue until disease progression, unacceptable toxicity, withdrawal of informed consent, or other treatment discontinuation criteria are met. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety.

Inclusion Criteria:

1. Age 18 to 75 years, male or female.
2. Histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic cancer.
3. ECOG Performance Status of 0 or 1.
4. Disease progression after first-line systemic therapy.
5. At least one measurable lesion according to RECIST 1.1, as assessed by the investigator.
6. Availability of 10 archived tumor tissue sections and 10 mL of peripheral blood.
7. Adequate organ function.
8. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days before enrollment, must not be breastfeeding, and must agree to use effective contraception during the study and for 6 months after the end of study treatment. Male participants must also agree to use effective contraception during the study and for 6 months after the end of study treatment.
9. Voluntary participation in the study, provision of written informed consent, and willingness and ability to comply with study procedures and follow-up.

Exclusion Criteria:

1. Known hypersensitivity to the investigational drug or any of its excipients.

2. Major surgery, open biopsy, or significant traumatic injury within 4 weeks before study treatment.

3. Participation in another investigational drug clinical study within 4 weeks before enrollment.

4. History of other malignancy within the past 5 years, except for malignancies that have been definitively treated and are considered cured.

5. Any of the following medical conditions: Untreated or symptomatic brain metastases or spinal cord compression. Other active malignancy requiring concurrent treatment.

   Active autoimmune disease or immunodeficiency, or a history of such conditions, including autoimmune hepatitis, interstitial pneumonia, uveitis, rheumatoid arthritis, inflammatory bowel disease, hypophysitis, vasculitis, or nephritis. Exceptions include stable conditions not requiring systemic immunosuppressive therapy, such as type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, or skin diseases not requiring systemic treatment, such as vitiligo, psoriasis, or alopecia. History of substance abuse or psychiatric disorders that may interfere with study participation.

6. Severe and/or uncontrolled medical conditions, including: Uncontrolled hypertension, defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg. Grade ≥1 myocardial ischemia or myocardial infarction; clinically significant arrhythmia, including QTc ≥450 ms in males or ≥470 ms in females; congestive heart failure of NYHA class ≥II; or LVEF <50%. Decompensated diabetes mellitus or other conditions contraindicating high-dose corticosteroid therapy. Exacerbation of chronic obstructive pulmonary disease (COPD) or other severe respiratory disease requiring hospitalization. Active or uncontrolled severe infection (≥Grade 2 according to CTCAE). Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage. Cirrhosis, decompensated liver disease, active hepatitis, or chronic hepatitis requiring antiviral treatment. Renal dysfunction with urine protein ≥++ on urinalysis and confirmed 24-hour urinary protein >1.0 g.

7. Severe infection within 4 weeks before the first dose, including infectious complications, bacteremia, or severe pneumonia requiring hospitalization or intravenous antibiotics, antifungal agents, or antiviral therapy; or unexplained fever >38.5°C during screening or before the first dose.

8. Active brain metastases or leptomeningeal metastases at enrollment.

9. Acute pancreatitis meeting diagnostic criteria or subclinical pancreatitis requiring recent intervention.

10. Any other condition that, in the investigator's judgment, may prevent the participant from complying with study procedures, restrictions, or requirements.