Efficacy and Safety of Becotatug Vedotin Combined With Cetuximab in the Later-line Treatment of Metastatic RAS Wild-type Colorectal Cancer: A Single-arm, Open-label, Single-center Phase II Clinical Study
Efficacy and Safety of Becotatug Vedotin Combined With Cetuximab in the Later-line Treatment of Metastatic RAS Wild-type Colorectal Cancer: A Single-arm, Open-label, Single-center Phase II Clinical Study
This is a single-arm, single-center, exploratory study aimed at exploring the treatment of RAS wild-type recurrent/metastatic colorectal cancer with the combination of becotatug vedotin and cetuximab as a salvage therapy
Inclusion Criteria:
1) previously received chemotherapy based on oxaliplatin and/or irinotecan 2) received anti-vascular endothelial growth factor (VEGF) treatment or anti-epidermal growth factor receptor (EGFR) treatment for left-sided colorectal cancer 3) for patients diagnosed with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), they also need to have received treatment with programmed death protein-1 (PD-1) or its ligand (PD-L1) inhibitors 4) subjects without BRAF mutations. 5. According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), subjects must have at least one measurable lesion (lesion with a longest diameter ≥10mm). 6. Within 7 days before the first dose, physical condition score according to the Eastern Cooperative Oncology Group (ECOG) standard is 0 or 1. 7. Expected survival ≥12 weeks. 8. Have appropriate organs and hematopoietic function (no blood transfusion or use of any cell growth factors within 14 days before the first use of study drugs), according to the following laboratory tests: 1) Neutrophil count (NEUT#) ≥1.5×10^9/L platelet count ≥75×10^9/L 2) Hemoglobin ≥85g/L 3) Serum creatinine ≤1.5 times the upper limit of normal (ULN) 4) AST, ALT ≤2.5 times ULN (can be relaxed to ≤5 times ULN for patients with liver metastasis) 5) Total bilirubin (TBIL) ≤1.5 times ULN 6) International normalized ratio (INR) ≤1.5 times ULN, activated partial thromboplastin time (APTT) ≤1.5 times ULN (except for patients undergoing anticoagulant therapy).
9. For female patients with reproductive capacity, blood pregnancy test results should be negative within 7 days before treatment 10.Female subjects of childbearing age and male subjects whose partners are female subjects of childbearing age must agree to use highly effective contraceptive methods (such as oral contraceptives, intrauterine devices, abstinence, or barrier contraception combined with spermicide) for contraception from the time they sign the informed consent form until one year after the last administration of study medication. Subjects must have good compliance.
Exclusion Criteria:
2) Receiving study drugs from other clinical trials within 28 days prior to the first dose
3) Receiving radiotherapy within 28 days prior to the first dose or palliative radiotherapy for bone metastases within 2 weeks
4) Receiving any anti-tumor drugs within 3 weeks prior to the first dose (whichever is shorter, with a washout period of ≥14 days for oral fluoropyrimidine derivatives, folinic acid derivatives, and weekly intensive paclitaxel chemotherapy, and a washout period of ≥42 days for nitrosoureas and mitomycin). 4. Known active central nervous system metastases and/or carcinomatous meningitis. Treated brain metastasis subjects may participate in the study, provided that their condition is stable and they do not have any of the following conditions: 1) Progressive or new-onset neurological deficits, seizures, evidence of increased intracranial pressure, vomiting, or headache
2) Evidence of recurrence/progression on MRI at least 4 weeks prior to the first dose of study treatment, and any neurological symptoms have not returned to baseline levels
3) Evidence of new brain metastases or enlargement of brain metastases, requiring the use of corticosteroids at least 3 days prior to the administration of study drugs. 5. Known history of malignant tumors (excluding subjects who have successfully undergone definitive surgery for cutaneous basal cell carcinoma, superficial bladder cancer, cutaneous squamous cell carcinoma, or cervical carcinoma in situ), unless the subject has received potentially curative treatment and has not experienced disease recurrence within 5 years since the start of treatment. 6. Uncontrolled pleural effusion, pericardial effusion, or recurrent ascites requiring ≥1 drainage per month
7. Tumor invasion into important arteries leading to high-risk bleeding risk, with significant perforation risk or already formed fistulas
8. Residual toxic reactions (excluding hair loss, fatigue, and Grade 2 hypothyroidism) or clinically significant laboratory test abnormalities above Grade 1 (CTCAE v5.0) due to previous anti-tumor treatment (including biologics, targeted therapy, chemotherapy, or radiotherapy)
9. History of severe cardiac dysfunction, stroke, or transient ischemic attack (TIA) within 6 months prior to enrollment. History of ventricular tachycardia or torsade de pointes arrhythmia. Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting electrocardiogram (ECG), such as QTc > 450 ms in males and QTc > 470 ms in females, presence of complete left bundle branch block or third-degree atrioventricular block. Presence of clinically significant cardiac diseases, including acute myocardial infarction, Grade III or IV congestive heart failure (New York Heart Association classification), unstable angina pectoris, or arrhythmias requiring treatment, occurring within 6 months prior to the first study treatment. Note: Subjects with arrhythmias may be enrolled if they are receiving antiarrhythmic drug therapy and the screening electrocardiogram (ECG) shows a controlled rhythm
10. Pulmonary embolism or deep vein thrombosis within 3 months prior to the first dose of study drug
11. Uncontrolled or poorly controlled hypertension (e.g., systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg) or hyperglycemia
12. Active acute or chronic inflammatory skin diseases, previous history of Steven-Johnson syndrome, toxic epidermal necrolysis
13. Known hypersensitivity to any component or excipient of Vibecotar (citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride, and polysorbate 80), or known hypersensitivity to other previous anti-EGFR drugs (including the investigational study drug) or other monoclonal antibodies with a grade ≥3 reaction
14. Known active hepatitis B or C. Active hepatitis B is defined as known HBsAg positivity and HBV DNA ≥500 IU/mL. Active hepatitis C is defined as known hepatitis C antibody positivity and known quantitative hepatitis C virus (HCV) RNA result greater than the lower limit of detection. Presence of other severe liver diseases, including chronic autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis, alcoholic liver disease, or non-alcoholic steatohepatitis (NASH)
15. Concurrent severe, uncontrolled infection or known human immunodeficiency virus (HIV) infection, or diagnosis of acquired immune deficiency syndrome (AIDS) or uncontrolled autoimmune disease
16. Subjects with active bacterial, viral, fungal, rickettsial, or parasitic infections requiring intravenous anti-infective therapy (unless treated and resolved prior to study drug administration)
17. Subjects with moderate to severe dyspnea at rest due to advanced cancer or its complications, or severe primary lung disease (currently requiring continuous oxygen therapy and with oxygen saturation <93% without supplemental oxygen), or any history of interstitial lung disease (ILD) (including ILD requiring oral or intravenous corticosteroids) or non-infectious pneumonia
18. Subjects undergoing immunology-based therapy for any reason, including long-term systemic steroid use equivalent to >10 mg/day of prednisone within 7 days prior to the first dose of study drug or at any time during the study participation. Note: Inhaled or topical steroids equivalent to ≤10 mg/day of prednisone, or short-term use of corticosteroids equivalent to >10 mg/day of prednisone (e.g., as prophylaxis before contrast media administration) is permitted
19. Subjects with chronic autoimmune or inflammatory diseases requiring systemic treatment or undergoing systemic treatment within the past 2 years, including but not limited to inflammatory bowel disease, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (exceptions: vitiligo, hypothyroidism undergoing stable hormone replacement therapy, controlled asthma, type I diabetes, Graves' disease, and Hashimoto's thyroiditis)
20. Subjects who test positive for pregnancy or are breastfeeding. Female and male subjects who do not plan to use adequate contraception during the treatment period and within 180 days after the last dose of study treatment any other diseases or clinically significant laboratory parameter abnormalities, severe medical or psychiatric conditions/conditions, and substance abuse including alcohol abuse, that the investigator believes may compromise subject safety, study integrity, affect subject participation in the study, or interfere with study objectives and outcome analysis.
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