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

Phase 1

Not yet recruiting

• Conditions: Colorectal Cancer Metastatic
• Interventions: Biological: BioTTT001 hepatic artery infusion; Drug: toripalimab; Drug: regorafenib

• Registration Number: NCT06283134
• Lead Sponsor: China Medical University, China

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2024-02
• Study First Submitted: 2024-02-22
• Study First Submitted QC: 2024-02-22
• Last Update Submitted: 2024-02-27
• Study First Posted: 2024-02-28
• Last Update Posted: 2024-02-29
• Study Start: 2024-04-02
• Primary Completion: 2027-12-01
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combination therapy with BioTTT001 hepatic artery infusion , Regorafenib and Toripalimab	BioTTT001 hepatic artery infusion	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 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 VP/5×10\^8 VP/5×10\^9 VP/1×10\^10 VP 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.
Combination therapy with BioTTT001 hepatic artery infusion , Regorafenib and Toripalimab	regorafenib	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 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 VP/5×10\^8 VP/5×10\^9 VP/1×10\^10 VP 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.
Combination therapy with BioTTT001 hepatic artery infusion , Regorafenib and Toripalimab	toripalimab	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 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 VP/5×10\^8 VP/5×10\^9 VP/1×10\^10 VP 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.

Primary Outcome Measures

Name	Time	Method
MTD	28 days within BioTTT001 injection in the monotherapy phase and combination therapy phase	Maximum tolerated dose (MTD)
Incidence of adverse events	From the enrollment to 28 days after the end-of-trial visit (i.e. end of treatment or early termination visit)	The incidence and severity of all types of adverse events evaluated based on NCI-CTCAE V5.0 assessment.

Secondary Outcome Measures

Name	Time	Method
Plasma adenovirus (ADV) copies	28 days within the first BioTTT001 injection dose	Pharmacokinetic Study (PK): Copies of ADV in plasma at various sampling points.
Serum neutralizing antibody level	28 days within the first BioTTT001 injection dose	Immunogenicity assessment through adenovirus neutralizing antibody detection.
Objective response rate (ORR)	Imaging was performed after completion of the monotherapy phase, and tumour assessment was performed every 4 weeks in the first 4 cycles ,then every 8 weeks during the combination therapy phase	Objective response rate (ORR) as assessed by the investigators
Overall survival(OS)	Every 3 months until consent withdraw, death, withdrawal study, or loss of follow-up, up to 100 weeks	The time from the start of treatment to death for any cause
Progression-free survival (PFS)	Every 4 weeks in the first 4 cycles ,then every 8 weeks until disease progression, consent withdraw, death or end of study during the combination therapy phase, up to 100 weeks.	The time from the start of treatment to progress disease or death for any cause
ADV copies in various sites	28 days within the first BioTTT001 injection dose	Viral Shedding Analysis: Copies of ADV in swabs of injection sites, rectal swabs, throat swabs, and urine samples at various sampling points.
Serum IL-12 level	28 days within the first BioTTT001 injection dose	Expression levels of IL-12 at various sampling points in serum.