| Eligibility |
Inclusion Criteria:
- Aged = 18 years old and = 75 years old.
- Expected survival time = 18 weeks.
- Diagnosis of pMMR confirmed by PCR for microsatellite stability (MSS) or low
microsatellite instability (MSI-L), or by immunohistochemistry for DNA mismatch repair
(MMR) proteins, including MLH1, MSH2, MSH6 and PMS2 protein expression, which result
in no protein deletion.
- Subjects with histologically and/or cytologically confirmed locally advanced
unresectable or metastatic colorectal adenocarcinoma with liver metastasis (excluding
adenosquamous carcinoma mixed with other pathological types).
- ECOG PS score is in the range of 0~1.
- Failure of previous treatment with fluorouracil, oxaliplatin, and irinotecan based
chemotherapy, with imaging evidence (such as CT scans) or clinical evidence (such as
cytological reports of new ascites or pleural effusion) demonstrating disease
progression during or after treatment, or discontinuation of treatment due to toxicity
intolerance.
- Subjects having adequate organ and bone marrow functions with laboratory test values
within 7 days prior to enrollment meeting the following requirements, as follows:
1. Blood routine: absolute neutrophil count (ANC) = 1.5×109/L; platelet count (PLT)
= 100×109/L; hemoglobin level (HGB) = 9.0 g/dL.
2. Liver function: serum total bilirubin (TBIL) = 1.5 × upper limit of normal (ULN);
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3.0 × ULN
in subjects without liver metastases, and ALT and AST = 5.0 × ULN in subjects
with liver metastases; serum albumin = 25 g/L.
3. Renal function: serum creatinine (Cr) = 1.5 x ULN. 4) Patients with routine urine
results showing urine protein <2+ or routine urine testing showing urine protein
= 2+ at baseline should undergo 24-hour urine collection and 24-hour urine
protein quantification < 1 g.
5) Coagulation function: international normalized ratio (INR) = 1.5×ULN and activated
partial thromboplastin time (APTT) = 1.5×ULN.
Exclusion Criteria:
- Prior exposure to any anti-PD-1 antibody, anti-PD-L1 antibody, HDAC inhibitor, or
irinotecan.
- Receiving any investigational drug within 4 weeks prior to the first dose of the study
drug.
- Concurrent participation in another interventional clinical study, except in an
observational (non-interventional) clinical study or in the follow-up phase of an
interventional study.
- Receiving the last dose of antitumor therapy (chemotherapy, targeted therapy, tumor
immunotherapy, or tumor embolization) within 3 weeks prior to the first dose.
- Receiving radiotherapy within 4 weeks prior to the first dose.
- Patients who have received radiotherapy more than 4 weeks prior to the first dose with
any radiotherapy-related toxic reactions, such as radiation pneumonia, radiation
hepatitis, radiation enteritis, including clinical symptoms only, or requiring
glucocorticoid therapy.
- Use of immunosuppressive drugs within 4 weeks prior to the first dose, excluding
topical glucocorticoids by nasal spray, inhalation or other routes or physiological
doses of systemic glucocorticoids (i.e., no more than 10 mg/day prednisone or
equivalent doses of other glucocorticoids).
- Receiving live attenuated vaccine within 4 weeks prior to the first dose or planning
to receive during the study period.
- Major surgical procedure (craniotomy, thoracotomy or open heart surgery) or unhealed
wound, ulcer or fracture within 4 weeks prior to the first dose.
- Presence of toxicity (excluding alopecia, non-clinically significant and asymptomatic
laboratory abnormalities) from prior antineoplastic therapy not recovered to = grade 1
by NCI common terminology criteriafor adverse events (CTCAE) Version 5.0 (NCI CTCAE
Version 5.0) prior to the first dose.
- Known presence of symptomatic CNS metastases and/or carcinomatous meningitis. Subjects
with prior treatment for brain metastases may participate in the study provided that
the brain metastases have remained stable for at least 4 weeks prior to the first dose
of study treatment; and that neurological symptoms have recovered to = grade 1 by NCI
CTCAE version 5.0.
- Active autoimmune disease requiring systemic therapy (e.g., use of disease-relieving
drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose.
Alternative therapies (e.g., thyroxine, insulin, or physiologic corticosteroids for
adrenal or pituitary insufficiency) are allowed. A known history of primary
immunodeficiency. For patients with only positive autoimmune antibodies, the presence
of autoimmune diseases should be confirmed at the discretion of the investigator.
- Patients who are known to have active tuberculosis and are receiving anti-tuberculosis
treatment or have received anti-tuberculosis treatment within 1 year prior to the
first dose.
- Known to have interstitial lung disease requiring steroid hormone therapy.
- Known to have acute or chronic active hepatitis B (HBsAg positive and HBV DNA = 200
IU/mL or = 103 copies/mL) or acute or chronic active hepatitis C (HCV antibody
positive and HCV RNA positive).
- Infected with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive), known to
be infected with syphilis.
- Severe infections that are in the active phase or poorly controlled in clinical
practice. Serious infection, including but not limited to hospitalization for
complications of infection, bacteremia or severe pneumonia, within 4 weeks prior to
the first dose.
- Significant malnutrition, such as the need for intravenous supplemental nutrient
solutions; except for malnutrition corrected more than 4 weeks prior to the first
dose.
- Symptomatic congestive heart failure (New York Heart Association class II-IV);
symptomatic or poorly controlled arrhythmias.
- Uncontrolled arterial hypertension (systolic blood pressure = 150 mmHg or diastolic
blood pressure = 100 mmHg) even with standard treatment.
- Any arterial thromboembolic event including myocardial infarction, pulmonary embolism,
and unstable angina within 6 months prior to enrollment.
- A history of deep vein thrombosis or any other serious thromboembolism (implantable IV
port or catheter-derived thrombosis, or superficial vein thrombosis is not considered
"serious" thromboembolism) within 3 months prior to enrollment.
- Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or more severe
cirrhosis.
- A history of gastrointestinal perforation and/or fistula in the previous 6 months; a
history of peptic ulcer, a history of intestinal obstruction (including incomplete
intestinal obstruction requiring parenteral nutrition), extensive bowel resection
(partial colectomy or extensive small bowel resection complicated by chronic
diarrhea), Crohn's disease, ulcerative colitis, abdominal abscess, or long-term
chronic diarrhea. Post-intestinal stent implantation.
-> 3 loose stools per day at baseline, suggesting a predisposition to colon or small
bowel disease with uncontrollable symptoms.
- A history of allergy or known intolerance to atropine sulfate or loperamide or the
appropriate antiemetic in combination with FOLFIRI.
- Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases or
secondary reactions to cancer and can lead to higher medical risk and/or uncertainty
in survival evaluation.
- A known history of inherited bleeding tendency disorders or coagulation disorders.
- Any life-threatening bleeding event within the previous 3 months, including the need
for blood transfusion therapy, surgical or local treatment, or ongoing drug therapy.
- A high risk of bleeding as determined by the investigators: cirrhosis with severe
esophagogastric fundic varices, intermittent or persistent non-fatal bleeding events
(including but not limited to intermittent bloody stools or positive occult blood due
to primary intestinal lesions, intermittent hemoptysis due to pulmonary metastases).
Cerebrovascular accident (including transient ischemic attack) in the previous 6 months.
- Use of aspirin (>325 mg/day) or other NSAIDs known to inhibit platelet function for 10
consecutive days within 10 days prior to the first dose.
- Treatment with oral or parenteral anticoagulants or thrombolytics for 10 consecutive
days within 10 days prior to the first dose. However, prophylactic use of
anticoagulants is allowed.
- Pleural fluid, ascites, and pericardial effusion with clinical symptoms or requiring
drainage, except for small amounts of pleural fluid, small amounts of ascites, and
small amounts of pericardial effusion without clinical symptoms on imaging only.
- A history of other primary malignancies, except: malignancies in complete response for
at least 2 years prior to enrollment and requiring no other treatment during the study
period; adequately treated non-melanoma skin cancer or malignant freckled nevus with
no evidence of disease recurrence; adequately treated carcinoma in situ with no
evidence of disease recurrence.
- A known history of allogeneic organ transplantation and allogeneic hematopoietic stem
cell transplantation.
- Known to be allergic to any monoclonal antibody component.
- Female subjects in the pregnancy or lactating period.
- A history of alcohol or drug abuse.
- Other acute or chronic illnesses, psychiatric disorders, or abnormal laboratory test
values that may result in the following outcomes: increasing the risk associated with
study participation or study drug administration, or interfering with the
interpretation of study results and, at the investigator's discretion, classifying the
patient as ineligible for participation in this study.
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