A Study of Dose Escalation of ES502 in Patients With Advanced Pancreatic Cancer

A Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Preliminary Antitumor Activity of ES502 Injection in Patients With Advanced Pancreatic Cancer

ESSIGHT-HJG-ES502-01 is a dose-escalation study of ES502 in patients with advanced pancreatic cancer. The study will enroll patients with advanced, RAS G12V positive pancreatic cancer who have no effective treatment options available (HLA genotyping required).

The study will adopt the standard "3+3" design., with a first-in-human (FIH) dose of 20 μg administered once every four weeks (Q4W). Subsequent dosing frequency will be adjusted based on pharmacodynamics and pharmacokinetics data. The primary objectives of this study are to evaluate the safety and tolerability of ES502 and to determine its maximum tolerated dose (MTD). The secondary objectives are to evaluate its antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD).

Inclusion Criteria:

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To be enrolled in this study, participants must meet all of the following inclusion criteria:

1. Age ≥18 years, regardless of gender;
2. Available fresh or archived tumor tissue samples (within the past 5 years) for testing at screening;
3. Individuals with histologically or cytologically confirmed advanced solid tumors for whom no standard therapy exists, who are refractory to standard therapy, or who are deemed unsuitable for standard therapy by the investigator. Tumor types include but are not limited to: pancreatic cancer, colorectal cancer, non-small cell lung cancer, intrahepatic cholangiocarcinoma, gallbladder cancer, ovarian cancer, endometrial cancer, and intestinal cancer;
4. RAS G12V mutation (KRAS/NRAS/HRAS) and positivity for HLA-DPB1*03:01, *14:01, *25:01, or *104:01;
5. Individuals with at least one measurable lesion (defined per RECIST v1.1 as a lesion with the longest diameter ≥10 mm, or a lymph node with a short axis of ≥15 mm); lesions that have undergone radiotherapy or other local therapies are not considered target lesions unless they demonstrate clear progression;
6. ECOG score: 0-1;
7. Expected survival greater than 3 months;
8. Adequate hematological and organ function, as evidenced by the following laboratory tests (the individual must not have received a blood transfusion, long-acting EPO or long-acting G-CSF within 14 days before study treatment, or not have received short-acting EPO or short-acting G-CSF within 7 days before study treatment): 1) hematology: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, hemoglobin (Hb) ≥90 g/L; 2) liver function test: both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit of normal (ULN), total bilirubin (TBIL) ≤1.5 × ULN. Exceptions: liver metastasis, AST and/or ALT ≤5 × ULN; Gilbert's syndrome, TBIL ≤3 × ULN; pancreatic head cancer or biliary obstruction, TBIL ≤3 × ULN; 3) kidney function test: creatinine clearance (CrCL) ≥50 mL/min (by Cockcroft-Gault formula); 4) coagulation function test: activated partial thromboplastin time (APTT) ≤1.5 × ULN and international normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN; 5) echocardiography: left ventricular ejection fraction (LVEF) ≥50%; eligibility for enrollment of individuals with out-of-range laboratory results should be determined at the investigator's discretion.
9. Women of childbearing potential who agree to use at least one medically recognized method for contraception (e.g., intrauterine device, contraceptive pills, or condoms) during the study treatment and for 1 year after the last treatment, and have a negative pregnancy test result at screening;
10. Prior antitumor treatment-related adverse events (AEs) (per NCI-CTCAE v6.0) have resolve to ≤ Grade 1 at screening, except for alopecia, Grade 2 hypothyroidism, and non-clinically significant or asymptomatic laboratory abnormalities;
11. Individuals who fully understand the informed consent information, agree to participate in this clinical study, and voluntarily sign the Informed Consent Form (ICF).

Exclusion Criteria:

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To be enrolled in this study, participants must not meet any of the following exclusion criteria:

To be enrolled in this study, participants must not meet any of the following exclusion criteria:

1. Individuals with the following tumors:

   • Malignant tumors other than those under investigation in this study (except for cured thyroid cancer, skin basal cell carcinoma, or cervical carcinoma in situ) within the past 5 years;
   • Meningeal metastases;
   • Brain metastases, except for individuals who have received systematic and radical therapy (radiotherapy or surgery) for brain metastases, demonstrated radiologically stable disease for at least 4 weeks, discontinued systemic corticosteroids for more than 2 weeks, and remain asymptomatic.

2. Individuals with the following conditions:

   • Received prior targeted therapy targeting RAS-G12V within 4 weeks before the first dose, or within 5 half-lives of the therapeutic agent, whichever is longer;
   • Participation in other clinical studies involving an investigational product within 4 weeks before the first dose;
   • Use of systemic antitumor therapy (including but not limited to chemotherapy, radiotherapy, biotherapy, immunotherapy, and cell therapy) within 4 weeks or 5 half-lives (whichever is shorter) before the first dose;
   • Receipt of major surgery without complete recovery within 4 weeks before the first dose, or planning to undergo major surgery during the study;
   • Receipt of systemic immunosuppressants or systemic corticosteroids within 1 week before the first dose;
   • Receipt of live-attenuated vaccines within 4 weeks before the first dose, or planning to receive such vaccines during the study;
   • Planning to receive any other systemic antitumor therapy (chemotherapy, radiotherapy, biotherapy, immunotherapy, cell therapy, etc.) during the study;

3. Symptomatic ascites, pleural effusion or pericardial effusion requiring drainage at screening, or history of drainage for serous effusion within 4 weeks before the first dose;

4. History of clinically significant cardiovascular disorders at screening, including but not limited to congestive heart failure (NYHA Class ≥ II), unstable angina, myocardial infarction, stroke or transient ischemic attack (TIA), severe arrhythmias (including but not limited to atrial fibrillation or paroxysmal supraventricular tachycardia, complete left bundle branch block or third-degree atrioventricular block with clinical significance and requiring clinical intervention), or poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) within 6 months before enrollment;

5. QT interval corrected by Fridericia's formula (QTcF) ≥470 ms;

6. History of severe infection within 4 weeks before the first dose; active infection requiring therapeutic intravenous antibiotics within 2 weeks before the first dose. Use of prophylactic antibiotics is not an exclusion criterion;

7. Active autoimmune diseases, or any conditions requiring systemic corticosteroids or immunosuppressants (prednisone at ≥20 mg/day or an equivalent dose) at screening;

8. History or evidence of clinically unstable or poorly controlled disorders (including but not limited to cardiac, pulmonary, renal, hepatic, metabolic or hematological disorders) at screening;

9. History of severe allergy or known hypersensitivity to the investigational product or its components;

10. Organ transplantation, allogeneic stem cell transplantation or renal replacement therapy in the past or at screening;

11. Pulmonary embolism, pulmonary fibrosis, interstitial lung disease or acute lung disease in the past or at screening;

12. Positivity for Treponema pallidum antibody, positivity for human immunodeficiency virus (HIV) antibody, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening. Definition of active HBV infection: positivity for hepatitis B surface antigen (HBsAg), and HBV DNA above the ULN; definition of active HCV infection: positivity for hepatitis C antibody, and HCV RNA above the ULN. Such conditions unsuitable for enrollment as judged by the investigator;

13. Other circumstances inappropriate for participation in this study as considered by the investigator.