Phase I study of YKYY031 for injection in patients with advanced solid tumors

This is a open-label, dose-escalation and dose-expansion Phase 1 clinical study to evaluate the pharmacokinetic (PK) profile, safety, tolerability, and preliminary antitumor activity of YKYY031 Injection in subjects with advanced solid tumors who have failed standard therapy and have no effective treatment options, including but not limited to colorectal cancer and pancreatic cancer.

Inclusion criteria： Participants meeting all the following criteria may be enrolled

1. Male or female patients aged 18 to 75 years old at the time of signing the informed consent form.

2. Histologically or cytologically confirmed advanced or metastatic solid tumors that have failed standard therapy and have no effective treatment options, including but not limited to colorectal cancer, pancreatic cancer, etc.

   For colorectal cancer (CRC) patients, prior receipt of at least second-line standard therapy failure and no effective treatment options; adjuvant/neoadjuvant chemotherapy failure during or within 6 months after the last treatment is considered first-line failure.

   For pancreatic cancer patients, prior receipt of at least first-line standard therapy failure and no effective treatment options; adjuvant/neoadjuvant chemotherapy failure during or within 6 months after the last treatment is considered first-line failure.

3. Patients must have human leukocyte antigen (HLA) subtype HLA-A*11:01.

4. Patients must test positive for at least one of the tumor-specific antigens (TSA) targeted by YKYY031, including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G13D, KRAS G12R, KRAS G12S, PIK3CA E542K, TP53 R248Q, PIK3CA E545K, BRAF V600E, PIK3CA H1047L, FBXW7 R465C.

5. Eastern Cooperative Oncology Group (ECOG) performance status score: 0-1.

6. Expected survival duration ≥ 3 months.

7. At least one measurable lesion (non-nodal lesions with longest diameter ≥10 mm, nodal lesions with shortest diameter ≥15 mm) according to RECIST V1.1.

8. Major organ function is good, meeting the following requirements:

   Hemoglobin ≥90 g/L, absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥80×10⁹/L within 14 days prior to the first dose, without the use of hematopoietic growth factors, blood transfusions, blood products, albumin, or blood products.

   Total bilirubin ≤1.5× upper limit of normal (ULN); if liver metastasis or Gilbert's syndrome is present, total bilirubin ≤3×ULN.

   Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3×ULN; if liver metastasis is present, ALT or AST ≤5×ULN.

   Serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula).

   Prothrombin time ≤1.5×ULN (unless using warfarin anticoagulation). International normalized ratio (INR) ≤1.5×ULN (unless using warfarin anticoagulation).

   Left ventricular ejection fraction (LVEF) ≥50% as assessed by cardiac Doppler ultrasound/MUGA.

9. Participants with childbearing potential or male participants must have no plans for conception, egg donation, or sperm donation from the date of signing the informed consent form until 6 months after the last study treatment, and must agree to use effective contraception (including one or more non-pharmacological contraceptive measures) or safety measures during this period.

10. Agree to comply with all requirements and procedures of the clinical trial and voluntarily sign the informed consent form.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded

1. Allergy to the investigational product (including any excipients). History of severe allergy to any drug, food, or vaccine, such as anaphylactic shock, angioneurotic edema, allergic dyspnea, anaphylactoid purpura, thrombocytopenic purpura, Arthus reaction, etc.

2. History of other malignancies, except for cured skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ, etc., that have not recurred within 5 years prior to screening, as judged by the investigator to be eligible for enrollment.

3. Symptomatic central nervous system metastasis or meningeal metastasis, or other evidence indicating uncontrolled central nervous system metastasis or meningeal metastasis, as judged by the investigator to be unsuitable for enrollment. Patients with stable brain metastases (no imaging progression within 4 weeks, and not requiring corticosteroid treatment for at least 4 weeks before the first dose of the study drug) may be enrolled.

4. Significant clinically significant cardiovascular diseases, including but not limited to:

   1. Congestive heart failure (New York Heart Association [NYHA] class > II)
   2. Myocardial infarction, unstable angina, severe pericardial disease, severe myocardial disease within the past 6 months
   3. Need for treatment of valvular regurgitation or stenosis
   4. Any supraventricular or ventricular arrhythmia requiring treatment or intervention; uncontrolled malignant arrhythmia; complete left bundle branch block, second- or third-degree atrioventricular block
   5. QT interval (QTcF) >450 ms in males, >470 ms in females
   6. Uncontrolled hypertension (defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite treatment with two or three antihypertensive agents)

5. Any active autoimmune disease or history of autoimmune disease, including but not limited to immunologically related neurological diseases, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis, systemic lupus erythematosus, connective tissue disease, scleroderma, autoimmune hepatitis, toxic epidermal necrolysis, or Stevens-Johnson syndrome (except for type 1 diabetes mellitus on a stable dose of insulin, hypothyroidism on stable hormone replacement therapy, etc.).

6. Any uncontrolled clinical disease (e.g., respiratory, circulatory, neurological, hematological, genitourinary, endocrine system diseases) or psychiatric disease (e.g., depression, schizophrenia) or other major illness, as judged by the investigator to interfere with providing informed consent, interpretation of trial results, participation in the trial posing risks to the participant, or otherwise affecting the achievement of trial objectives, including uncontrolled pleural effusion, pericardial effusion, or ascites as judged by the investigator.

7. Known history of interstitial pneumonia or high suspicion of interstitial pneumonia; or presence of pulmonary abnormalities that may interfere with the detection or management of suspected drug-related pulmonary toxicity during the trial.

8. Any abnormality at the injection site that, as judged by the investigator, would hinder observation of local reactions at the injection site.

9. Presence of contraindications to intramuscular injection.

10. Received any antitumor therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or participated in another drug or device clinical trial within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose; received traditional Chinese medicine or patent Chinese medicine with clear antitumor indications within 2 weeks prior to the first dose.

11. Previous antitumor treatment-related adverse events that have not recovered to ≤ grade 1 according to CTCAE, except for toxicities judged by the investigator to have no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, hypothyroidism stabilized by hormone replacement therapy, etc.

12. Prior organ transplantation or allogeneic hematopoietic stem cell transplantation.

13. Use of corticosteroids (>10 mg/day prednisone or equivalent other glucocorticoids) or other immunosuppressants for systemic treatment within 14 days prior to the first dose of the vaccine. Inhaled or topical steroids and adrenal hormone replacement at doses ≤10 mg/day prednisone are allowed in the absence of active autoimmune disease.

14. Received live/attenuated live/inactivated vaccines within 4 weeks prior to the first dose of the vaccine.

15. Prior receipt of a therapeutic tumor vaccine targeting the same antigen.

16. Bleeding disorders (e.g., coagulation factor deficiency, coagulation dysfunction [as judged by the investigator to be unsuitable for enrollment]), or a history of significant bruising or bleeding after injection or blood draw.

17. Blood donation or significant blood loss (>450 mL) within 3 months prior to screening, or planned blood or blood component donation during the study period.

18. Major surgery within 4 weeks prior to screening (minor procedures such as catheter placement and biopsy required by the protocol are not exclusionary), or unresolved effects of surgery or trauma within 14 days prior to enrollment.

19. History of substance abuse or known medical, psychological, or social conditions, such as alcoholism or drug addiction.

20. Positive human immunodeficiency virus antibody test result, active syphilis (defined as positive syphilis antibody test and positive reagin test), active hepatitis B (defined as hepatitis B virus [HBV] DNA ≥2000 IU/mL), or active hepatitis C (defined as hepatitis C virus [HCV] RNA test positive).

21. Active tuberculosis (TB) (patients suspected of having active TB require further consultation with the infectious disease department for definitive diagnosis) or history of active TB; or severe acute or chronic infection requiring systemic treatment.

22. Pregnant or breastfeeding women.

23. Any other condition deemed by the investigator to make the participant unsuitable for participation in this trial.