A Clinical Study of BioTTT001 in Combination With Toripalimab and Regorafenib in Patients With Colorectal Cancer

This is a phase I, open-label clinical study of BioTTT001 in combination with Toraplizumab and Regorafenib in patients with liver metastases from colorectal cancer.

This study includes a dose escalation phase and a dose expansion phase. The dose escalation phase will adopt a 3+3 design. Subjects were first treated with BioTTT001 monotherapy (hepatic artery infusion, administered every 2 weeks, D1 and D15 for a total of two doses) after enrollment. If the subject does not develop dose-limiting toxicity (DLT) in the monotherapy stage and is judged to be safe and tolerable by the investigator, the subject will enter the treatment phase of BioTTT001 in combination with toripalimab and regorafenib( toripalimab 80mg iv. D1 and D15 , BioTTT001 5×10\^7 viral particle (VP)/5×10\^8 VP/5×10\^9 VP/1×10\^10 VP hepatic arterial infusion (HAI.) D2 and D16 , regorafenib 80 mg Po. D1-D21; 4 weeks per cycle), and the dose of BioTTT001 will be determined according to the safety observation results in the monotherapy phase. In the dose expansion phase, different dose groups can be expanded, and the total number of enrolled subjects is expected to be 30 for further safety, tolerability, pharmacokinetics and preliminary efficacy evaluation.

Eligibility Criteria:
Inclusion Criteria:

1. Age range from 18 to 70 years old (including the threshold), no gender restrictions;
2. Patients with a definitive histopathological or cytological diagnosis of colorectal cancer with hepatic metastases who have received and failed at least second-line standard therapy in the past, or who have been assessed by the investigator to be unsuitable for standard therapy;
3. At least one assessable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;
4. WBC≥3.0×10\^9/L; ANC≥1.5×10\^9/L (without cytokine therapy within one week before the screening ); Hb≥90g/L(without blood transfusion within one week before the screening);PLT≥90×10\^9/L(without Platelet transfusion or thrombopoietin (TPO) within one week before the screening)；ALT and AST≤5×ULN；Cr≤1.5×ULN or CCr\>50mL/min; TBIL≤1.5×ULN; APTT≤1.5×ULN and INR/PT≤1.5×ULN；
5. ECOG 0\~2；
6. Expected survival ≥ 3 months;
7. Consent to contraception；
8. Understand and voluntarily sign a written ICF and be willing to comply with all trial requirements.

Exclusion Criteria:

1. Known allergy to the investigational drug or its components;
2. Previous treatment with other adenovirus drugs;
3. Patients with active autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, etc.), except type 1 diabetes, hypothyroidism that only needs hormone replacement therapy, and skin diseases that do not need systemic treatment (such as vitiligo, psoriasis or alopecia);
4. Received treatment with nitrosourea or mitomycin C within 6 weeks before the first dose of BioTTT001; received oral fluorouracil and small molecule targeted drug therapy within 2 weeks or 5 half-lives of the drug within 2 weeks before the first dose of BioTTT001; received traditional Chinese medicine therapy with anti-tumor indications within 2 weeks before the first dose of BioTTT001; received chemotherapy, radiotherapy, biological therapy other than the drugs mentioned above within 28 days before the first dose of BioTTT001；
5. Patients who have not recovered from the adverse reactions of previous treatments (the treatment-related toxicity ≤ grade 2, except for alopecia, pigmentation or other tolerable events judged by the investigator ).
6. History of other malignancies (except cured basal cell skin cancer, cervical carcinoma in situ, Papillary carcinoma of thyroid gland, low-risk GIST etc.) within 5 years before study drug administration;
7. Patients who have undergone any major surgery (except needle biopsy, etc.) or severe trauma within 4 weeks before the first dose of BioTTT001;
8. Patients who have been treated with high-dose systemic corticosteroids (prednisone \> 10 mg/day or equivalent doses) or other immunosuppressants within 2 weeks before the first dose of BioTTT001;
9. NYHA≥grade 3; LVEF\<50%; male QTc\>450 mms, female QTc\>470 mms;
10. Patients with active tuberculosis or drug-induced interstitial lung disease；
11. Patients with active infection requiring systemic anti-infective therapy;
12. In a state of immunosuppression, such as severe combined immunodeficiency disease or concurrent opportunistic infections;
13. HBsAg positive, and blood HBV DNA≥100 IU/mL; anti-HCV positive; HIV positive; active syphilis;
14. Patients with pleural effusion and ascites with clinical symptoms that require repeated drainage;
15. Patients with central nervous system metastases or meningeal metastases with clinical symptoms;
16. Patients with contraindications to hepatic arterial perfusion therapy;
17. Pregnant or lactating women;
18. Patients with prior organ transplants;
19. Other reasons judged by the investigator.