MRG003 With Gemcitabine for Second-line Advanced PDAC

This is a Phase Ib/II clinical study aimed to evaluate the tolerability of becotatugvedotin in combination with gemcitabine, determine the clinically recommended dose for the combination regimen, and assess the efficacy and safety of becotatugvedotin combined with gemcitabine in patients with advanced second-line pancreatic ductal adenocarcinoma (PDAC). The study plans to enroll 27-30 patients, including 3-6 patients in the first stage (Phase I) and 24 patients in the second stage (Phase II). The study consists of three periods: screening period (including baseline), treatment period, and follow-up period (safety follow-up and survival follow-up). Eligible patients must have locally advanced unresectable or metastatic pancreatic cancer confirmed by histopathology. Phase I: After the screening period, patients will receive treatment with becotatugvedotin and gemcitabine. Becotatugvedotin will be administered at doses of 1.5 mg/kg or 2.0 mg/kg once every 3 weeks (Q3W) using a 3+3 dose escalation design. Gemcitabine will be given at 1000 mg/m² on days 1 and 8 of each 3-week cycle (Q3W). Treatment will continue until disease progression, dose-limiting toxicities (DLTs), withdrawal of informed consent, death, pregnancy, investigator decision to discontinue treatment, or study termination, whichever occurs first. Upon completion of Phase I, the study will proceed to Phase II. Phase II: After the screening period, patients will receive treatment with becotatugvedotin and gemcitabine. The dose of becotatugvedotin will be the recommended Phase II dose (RP2D) selected based on the results from Phase I, while gemcitabine will be administered at 1000 mg/m² on days 1 and 8 of each 3-week cycle (Q3W). Treatment will continue until disease progression, intolerable toxicity, withdrawal of informed consent, death, pregnancy, investigator decision to discontinue treatment, or study termination, whichever occurs first. Tumor imaging assessments will be performed using RECIST v1.1 every 6 weeks (i.e., every 2 treatment cycles). Safety assessments will be conducted using the NCI-CTCAE version 5.0 criteria from the first dose through 30 days after the last dose.

Inclusion Criteria: ECOG performance status score of 0-2; Histopathologically confirmed locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC); Failure of prior first-line systemic therapy: 1. Radiographic progression or worsening of clinical symptoms; disease progression occurring within 6 months after completion of neoadjuvant/adjuvant therapy is also considered first-line treatment failure. 2. Intolerance to first-line therapy, as fully assessed by the investigator, may also allow enrollment into the study. Intolerance to prior study treatment is defined as follows: i. Any grade ≥3 hematologic toxicity (per NCI-CTCAE v5.0) that does not recover to grade 1 or pre-treatment level after 14 days of best supportive care; ii. Any grade ≥3 non-hematologic toxicity (excluding alopecia and asymptomatic laboratory abnormalities) per NCI-CTCAE v5.0 that does not recover to normal after 14 days of best supportive care. Adequate organ and bone marrow function; Estimated life expectancy \> 3 months; Subjects must agree to provide sufficient tumor tissue samples for EGFR and PD-L1 immunohistochemistry (IHC) expression testing, next-generation sequencing (NGS), and multi-omics analysis. This includes archived tumor samples (paraffin blocks or unstained sections meeting the testing requirements specified in the study); if no archived tumor tissue sample is available, the subject agrees to undergo re-biopsy of the tumor lesion. Exclusion Criteria: * Failure of first-line gemcitabine-based therapy. Other histologic types of pancreatic tumors, such as neuroendocrine tumors, acinar cell carcinoma, cystic carcinoma, etc. Prior treatment with an MMAE-loaded ADC (antibody-drug conjugate). Congenital or acquired immunodeficiency (e.g., HIV infection), active hepatitis B (HBV-DNA ≥ 10⁴ copies/mL), or hepatitis C (positive HCV antibody with HCV-RNA above the lower limit of detection of the assay). Known hypersensitivity to the study drug or any of its excipients, or a history of severe allergic reactions to other monoclonal antibodies. Occurrence of the following within 6 months before randomization: myocardial infarction, severe/unstable angina pectoris, New York Heart Association (NYHA) Class ≥2 cardiac insufficiency, or symptomatic congestive heart failure. Vaccination with a live vaccine within 4 weeks before the first dose of study drug. Inactivated virus vaccines for seasonal influenza (administered by injection) are permitted, but live attenuated influenza vaccine administered via the intranasal route is not allowed. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation. Known history of substance abuse (psychoactive drugs) or drug addiction. Pregnant or breastfeeding women. Diagnosis of any other malignancy within 5 years before study entry, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma that have been treated with local therapy and cured. Presence of any other serious physical or psychiatric illness, or laboratory abnormalities that may increase the risk of study participation, interfere with the study results, or render the patient unsuitable for participation in the opinion of the investigator. Note: Subjects with hepatitis B meeting the following criteria may also be enrolled: HBV viral load \< 1000 copies/mL (\ 140 mmHg, diastolic blood pressure \> 90 mmHg). Active tuberculosis. Active or uncontrolled infection requiring systemic therapy. Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction. Liver disease such as cirrhosis, decompensated liver disease, or acute or chronic active hepatitis. Poorly controlled diabetes mellitus (fasting blood glucose \> 10 mmol/L). Urinalysis showing proteinuria ≥ 2+, with confirmed 24-hour urine protein \> 1.0 g. Psychiatric disorders that prevent the patient from cooperating with treatment. History or evidence of disease, treatment, or laboratory abnormalities that could interfere with the study results or prevent the subject from completing full participation in the study, or any other condition that, in the investigator's opinion, makes the subject unsuitable for enrollment, including potential risks that are not explicitly listed above.