| Eligibility |
Inclusion Criteria:
1. pathologically confirmed metastatic colorectal adenocarcinoma;
2. Age of 18-75 years old, both sexes;
3. predicted survival time =12 weeks;
4. Eastern Cooperative Oncology Group performance status (ECOG) score 0-2;
5. Participants who had failed second-line or higher standard-of-care systemic therapy
and should have been treated with oxaliplatin, irinotecan, and fluorouracil were
allowed to enroll if first-line therapy included three agents;
6. liver tumor burden =50% as assessed by enhanced CT or MRI;
7. There were no serious complications (perforation, obstruction, massive bleeding, etc.)
in the primary lesion;
8. According to RECIST1.1 criteria, there should be at least one measurable objective
tumor lesion, the maximum diameter of which must be =1cm by spiral CT, and the maximum
diameter of which must be =2cm by conventional CT or MRI; This procedure was performed
within 28 days before enrollment.
9. Study participants had to have adequate organ function, as assessed by the following
laboratory results within 1 week before enrollment (no blood transfusion, granulocyte
colony-stimulating factor, or other medical support within 14 days before study drug
administration) :
1. Blood routine examination: hemoglobin =90g/L; Platelet (PLT) =75×109/L; White
blood cell (WBC) =3.0×109/L; Neutrophil (ANC) =1.5×109/L;
2. Blood biochemical examination: total bilirubin (TBI) =1.5× upper limit of normal
(UNL); Serum creatinine (Cr) =1.5× upper limit of normal; Alanine
aminotransferase (ALT), aspartate aminotransferase (AST) =5×UNL;
10. study participants with active hepatitis B or active hepatitis C, who must have
received antiviral therapy for at least 14 days before the first dose of the study
drug, If they have a hepatitis B virus (HBV) DNA titer test (not higher than 500 IU/mL
or 2500 copies [cps]/mL) and a hepatitis C virus (HCV) RNA test (not higher than the
lower limit of detection of the assay), can be enrolled in the trial, and are willing
to continue to receive effective antiviral therapy during the study;
11. Patients volunteered to participate and provided written informed consent.
Exclusion Criteria:
1. a history of other malignancies with disease-free survival <5 years (except cured
basal cell carcinoma of the skin, cured carcinoma in situ of the cervix, and
gastrointestinal cancer proven cured by endoscopic mucosal resection);
2. participated in other drug clinical trials within four weeks;
3. patients with known CNS metastases or a history of CNS metastases before screening.
For patients with clinically suspected central nervous system metastasis,
contrast-enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) was
required within 28 days before informed consent to rule out central nervous system
metastasis.
4. patients with a long history of chronic diarrhea or complete intestinal obstruction;
5. urinalysis showed urinary protein =2+ or 24-hour urinary protein =1g;
6. Drug-uncontrolled hypertension (systolic blood pressure > 140 MMHG or diastolic blood
pressure > 90mmHg);
7. a history of severe bleeding (> 30ml per episode) within 3 months or hemoptysis (> 5ml
per episode) within 1 month or thromboembolic events (including pulmonary embolism,
cerebral infarction, etc.) within 12 months;
8. had undergone surgical treatment (excluding biopsy) within 6 weeks or had unhealed
surgical incisions;
9. long-term unhealed wounds or incompletely healed fractures;
10. imaging shows that the tumor has invaded the vital blood vessels or the patient's
tumor has a high possibility of invading the vital blood vessels during treatment,
which may cause fatal bleeding;
11. with a history of unstable angina pectoris; Newly diagnosed angina pectoris within 3
months before screening or myocardial infarction within 6 months before screening;
Arrhythmias (including QTcF =450 ms in men and =470 ms in women) required long-term
use of antiarrhythmic drugs and New York Heart Association (NYHA) grade =II cardiac
dysfunction.
12. patients with abnormal coagulation function and bleeding tendency (INR within the
normal range without anticoagulant therapy must be met within 14 days before the first
medication); Patients treated with anticoagulants or vitamin K antagonists such as
warfarin, heparin, or their analogues; Low-dose warfarin (1 mg orally once daily) or
low-dose aspirin (at a dose of up to 100 mg daily) for preventive purposes were
allowed if the International Normalized Ratio of prothrombin time (INR) was 1.5 or
less.
13. participants with an active or prior autoimmune disease or risk (e.g., organ
transplant requiring immunosuppressive therapy) that may relapse. However,
participants with type 1 diabetes, hypothyroidism for which they were receiving
hormone-replacement therapy only, or skin conditions for which no systemic treatment
was required (e.g., vitiligo, psoriasis, or alopecia) were allowed.
14. have had a history of interstitial lung disease or noninfectious pneumonia, such as
symptomatic disease or a previous pulmonary history that may preclude assessment or
management of study-drug-related pulmonary toxicity;
15. Participants with a history of active pulmonary tuberculosis infection within 1 year
before the first dose of the study drug and a history of active pulmonary tuberculosis
infection more than 1 year before were considered eligible if they had no evidence of
current active pulmonary tuberculosis, as assessed by the investigator;
16. severe uncontrolled medical illness or acute infection (fever > 38 ° C);
17. study participants who required systemic treatment with corticosteroids (>10 mg/ day
prednisone equivalent dose) or other immunosuppressive drugs within 14 days prior to
administration of the study drug. Note: In the absence of active autoimmune disease,
inhaled or topical steroid hormones, or adrenal hormone replacement therapy with an
equivalent dose of =10 mg prednisone per day, were allowed. Short-term (= 7 days) use
of glucocorticoids was permitted for preventive treatment (e.g., contrast allergy) or
for the treatment of nonautoimmune conditions (e.g., delayed hypersensitivity from a
contact allergen).
18. study participants who had been treated with any antibody/drug (e.g., anti-PD-1,
anti-PD-L1, anti-CTLA-4, anti-OX-40, anti-CD137, anti-TIM-3, anti-LAG-3 antibodies,
etc.) targeting a T-cell co-regulatory protein (immune checkpoint);
19. study participants with a history of allergic or hypersensitivity reactions to study
drug components;
20. have immunodeficiency diseases or HIV infection;
21. pregnant or lactating women or patients of childbearing potential (men or women who
have been without menstruation for less than 1 year) who are unwilling to use
contraception;
22. concomitant diseases that, according to the investigator's judgment, seriously
endanger the patient's safety or prevent the patient from completing the study;
23. who were deemed by the investigator to be ineligible for participation in the trial.
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