A Clinical Study of T3011 in Combination With Toripalimab and Regorafenib in Patients With Colorectal Cancer

This is a phase I, open-label clinical study of T3011 in combination with Toraplizumab and Regorafenib in patients with liver metastases from colorectal cancer.

This trial is a prospective, open-label, investigator-initiated clinical study in patients with liver metastasis from colorectal cancer, aiming to evaluate the safety and efficacy of T3011 herpes virus injection alone or in combination with toripalimab and regorafenib in patients with liver metastasis from colorectal cancer. In this study, the lead-in period of T3011 and the combination therapy period were designed, and the 3+3 dose escalation design was carried out in the lead-in period.

Eligibility Criteria:
Inclusion Criteria:

1. Men or women aged ≥18 years at the time of signing the Informed Consent Form (ICF);
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. Patients with at least one measurable lesion (as defined by RECIST v1.1) that has not been previously treated with radiotherapy (unless definite progression of the lesion has occurred after radiotherapy);
4. Eastern Cooperative Oncology Group(ECOG) score 0 or 1;
5. Expected survival ≥ 12 weeks;
6. For female subjects with childbearing potential, a negative serum pregnancy test within 7 days prior to the first dose of study drug; Acceptance of using medically accepted and effective contraception for at least 6 months after signing the ICF and until the last dose of study drug;
7. Male subjects with childbearing potential agree to use medically accepted and effective contraception from the date of signing the ICF to the date of at least 6 months after the last dose; in addition, the male subject must agree that he will not donate sperm during this period;
8. Understand and voluntarily sign a written ICF and be willing to comply with all trial requirements.

Exclusion Criteria:

1. Patients allergic to the study drug (including its components) or other similar products;
2. Patients who have been treated with oncolytic virus therapy, interleukin-12 (IL-12) in combination with anti PD-1/ PD-L1;
3. Patients who have not recovered from the adverse reactions of previous treatments (the treatment-related toxicity ≤ grade 2, except for alopecia, fatigue or other tolerable events judged by the investigator);
4. Patients with brain metastases that have progressed within 3 months prior to study drug administration (brain metastases that have stabilised within 3 months may be included);
5. History of other malignancies (except cured basal cell skin cancer, cervical carcinoma in situ, papillary thyroid cancer, etc.) within 5 years prior to study drug administration;
6. Patients who received any antineoplastic drug (including but not limited to chemotherapy, biologics, herbal preparations, etc.) within 4 weeks or 5 half-lives (whichever is shorter) prior to study drug administration;
7. Severe hepatic dysfunction (Child Pugh class C), or significant jaundice, hepatic encephalopathy, refractory pleural effusion, or hepatorenal syndrome; Coagulation: international normalized ratio (INR) or Prothrombin time (PT) \> 1.5 x Upper limits of normal(ULN) ; activated partial thromboplastin time (aPTT)\> 1.5 x ULN; Current comorbidity with active hepatitis: persistent or active hepatitis B (i.e. HBsAg positive or hepatitis B virus (HBV) DNA ≥ upper limit of detection), hepatitis C (HCV RNA ≥ upper limit of detection)\] or other hepatitis; Haematology: white blood cell count (WBC) \< 3.0 x 10\^9/L; platelets \< 75 x 10\^9/L; haemoglobin \< 80g/L; Renal function: serum creatinine \>1.5 ULN or creatinine clearance \<60 mL/min (Cockcroft-Gault formula calculation)
8. Serious or uncontrollable cardiac disease requiring treatment, congestive heart failure classified as grade 3 or 4 by the New York Heart Association (NYHA), unstable angina not controlled by medication, history of myocardial infarction within 6 months prior to enrolment, serious arrhythmia requiring medication (except atrial fibrillation or paroxysmal supraventricular tachycardia); History of arterial thromboembolic event, venous thromboembolic event of grade ≥3 as defined in NCI CTCAE 5.0, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to randomisation; Current major vascular disease such as aortic aneurysm, aortic coarctation aneurysm, etc. that may be life-threatening or require surgery within 6 months;
9. Previous immunotherapy (including but not limited to PD-1/PD-L1) with immune-related pneumonitis or ≥ grade 3 other immune-related adverse reactions; Current active immune disease requiring systemic treatment with immunosuppressive agents (excluding autoimmune diseases such as vitiligo that do not require intervention, or hypothyroidism that only needs hormone replacement therapy), or immune disease requiring systemic treatment with immunosuppressive agents (e.g., systemic lupus erythematosus) that is likely to recur; Patients with other diseases currently requiring systemic immunosuppressive therapy;
10. HIV Positive; Patients who are currently in the midst of an episode of orofacial herpes; Clinically significant infection or infection treated with intravenous antibiotics within 4 weeks prior to dosing;
11. Inability to swallow, malabsorption syndrome, or uncontrollable nausea, vomiting, diarrhoea or other gastrointestinal disorders that would seriously interfere with drug administration and absorption;
12. Patients who need anti-herpes simplex virus medications (including, but not limited to, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir, etc.) for the duration of the study, with the exception of topical applications;
13. History of seizures within 12 months prior to study drug administration;
14. Patients with the history of drug use or a history of substance abuse (including alcohol) within one year prior to signing the ICF;
15. Pregnant or lactating women;
16. Other reasons judged by the investigator.