A Clinical Study of Intraperitoneal T3011 Given as a Single Agent in Patients With Malignant Ascites Induced by Advanced Colorectal Cancer

Inclusion Criteria:

1. Male or female age ≥ 18 years and ≤ 75 years at the time of informed consent.
2. Histologically or cytologically confirmed advanced unresectable or metastaticcolorectal cancer;
3. Anticipated life expectancy ≥3 months
4. Associated with medium amount of malignant ascites (defined as the amount of ascites ≥3cm by B ultrasonography in lying position accompanied by clinical symptomes likeabdonimal distension and cytology tests possitive for tumor in ascites); Noparacentesis performed with 28 days before first dosing; and the ascites can not becontrolled by SOC according to PI judgement.
5. ECOG performance status 0-2 (including threshold);
6. Weight ≥40kg
7. Hematology:

• White blood cell (WBC) ≥ 3.0×10^9/L;
• Neutrophil (ANC) ≥ 1.5×10^9/L;
• Platelet (PLT) ≥ 75×10^9/L;
• Hemoglobin (Hb) ≥ 8.0g/dL

8. Hepatic and renal function:

• Total bilirubin ≤ 1.5 × ULN;
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN forpatient without liver metastasis, ≤ 5 × ULN for patients with liver metastasis;
• Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 50 mL/min as determined bythe Cockcroft-Gault equation;
• Abumin≥30 g/L

9. Coagulation:

• INR≤1.5 x ULN;
• APTT≤1.5 x ULN;

10. For women of childbearing potential (WCBP), serum pregnancy test should be negativewithin 14 days before dosing. WCBP patients, as well as male patients with partners ofWCBP, should consent to use at least one medically approved contraceptive method (e.g.surgical sterilization, oral contraceptives, intrauterine devices, abstinence orbarrier contraception combined with spermicides) during the study and for at least 6months after the last dosing;
11. Willingness to attend this study, to sign informed consent, to have good compliance,and to cooperate with follow-up visit.

Exclusion Criteria:

1. Previously diagnosed with decompensated cirrhosis, and with portal vein and branchinvolvement or cancer embolus;
2. Pregnant or lactating, or plan to pregnant or give birth during the trial;
3. Persistent or active infection that are not controlled by treatment including but notlimited to: active tuberculosis, non-negative HIV antibody, HBsAg positive and HBV DNA ≥LOQ, HCV ab positive and HCV DNA ≥LOQ;
4. Patients with imageological confirmed brain metastasis or brain metastasis history (except patients with stable disease within 3 months before screening and not requiresystemic glucorticoid therapy according to PI), pia meningeal disease, spinal cordcompression;
5. Autoimmune disease or related symptoms, or previously suffered from autoimmunedisease;
6. History of splenectomy or organ transplantation;
7. Prior treatment with Oncolytic virus (OV) (including but not be limited to T-VEC,T3011), gene therapy, cellular therapy or tumor vaccines;
8. Requires oral or intravenous therapy against herpes virus (including but not limitedto acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet,cidofovir). Topical use of drugs (eg. external use) are allowed;
9. Patients are scheduled to receive other therapy against malignant ascites (includingbut not limited to chemotherapy, target therapy, immunotherapy), and the bestsupportive treatment for malignant ascites is permitted (e.g., albumin supplements,etc.);
10. Patients with a known psychiatric disorder that would interfere with cooperation withthe requirements of the trial;
11. History of narcotics (recreational use) and substance abuse (including alcohol) within 1 year prior to signing informed consent;
12. History of allergic reactions attributed to compounds of similar biologicalcomposition to HSV-1, IL-12, or anti-PD-1 monoclonal antibody or any excipients forT3011;
13. History or evidence of high risk cardiovascular disease, including but not limited to:

• Severe cardiac rhythm or conduction abnormalities, such as ventriculararrhythmias requiring clinical intervention, II-III degree atrioventricularblock, QT interval corrected using the Fridericia formula (QTcF) ≥ 450 msec (male) or ≥ 470 msec (female);
• Acute myocardial infarction, unstable angina pectoris, or stroke occurred within 6 months before the first administration of the experimental drug;
• Coronary angioplasty or stent implantation within 6 months prior to firstadministration of the experimental drug;
• Rating of heart function as defined by the New York Heart Association (NYHA)standards>grade II; Cardiac valve abnormalities recorded by echocardiography (≥grade 2). Note: Subjects with grade 1 cardiac valve abnormalities (such as mildregurgitation/stenosis) were admitted, but subjects with moderate valvethickening were excluded;
• Left ventricular ejection fraction (LVEF) < the center lower limit. If no lowerlimit existed, LVEF<50%;
• Poor blood pressure control after antihypertensive treatment (i.e. systolic bloodpressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);

14. History of another malignant tumor, except the following:

• Undergo potentially curative therapy and for ≥5 years prior to the first dose ofstudy treatment and no malignancies with known active disease and low potentialrecurrence risk;
• Adequately treated non-melanoma skin cancer or lentigo with no evidence ofmalignancy;
• Adequately treated carcinoma in situ without evidence of disease;

15. Received live and attenuated vaccines within 4 weeks prior to initiation of studytreatment, or plan to be vaccined during the study;
16. Previous history of immunotherapy induced non-infectious pneumonitis/ interstitiallung disease (including but not limited to ≥3 grade irAE) or intolerance toimmunotherapy (including but not limited to anti-PD-(L)1 monoclonal Ab), exceptendocrine-related irAE that can be stably controlled by hormone replacement therapy;
17. Unexplained >38.5℃ fever (except for tumor induced fever judged by PI) occurs duringthe screening period, baseline period or on the day of administration, which in thejudgment of investigator, would interfere with patient participation in the study orpatient's efficacy evaluation;
18. Any condition that PI considered may confuse the trial results, interfere with theparticipant's participation in the trial, or is not in the participant's best interestto participate in the trial, or a history of treatment or laboratory abnormalities, orother ineligibility for enrollment