Targeted Treatment Plus Tislelizumab and HAIC for Advanced CRCLM Failed from Standard Systemic Treatment

Not Applicable

Recruiting

• Conditions: Liver Metastasis Colon Cancer; Failed from Standard Treatment; CtDNA Genotype; MSS
• Interventions: Drug: HAIC+targeted therapy+PD-1 inhibitor

• Registration Number: NCT06199232
• Lead Sponsor: Peking University

Brief Summary

Hepatic arterial infuison chemothearpy (HAIC), targeted therapy, and programmed death-1 (PD-1) inhibitors have been demonstrated to be effective for colorectal cancer liver metastasis (CRCLM). Thus, the investigators will conduct a prospective trial to explore the efficacy and safety of targeted treatment based on ctDNA genotyping combined with tislelizumab and HAIC as salvage treatment for advanced CRCLM failed from standard systemic treatment, aiming to provide individualized optimized regimen for microsatellite stable (MSS) CRCLM in salvage treatment.

Detailed Description

Although surgery has been demonstrated to improve the prognosis of patients with colorectal cancer liver metastasis (CRCLM), only 20% of patients with CRCLM is candidate for surger. Irinotecan-/oxaliplatin-based doublet/triplet chemotherapy regimen combined with targeted therapy (anti vascular endothelial growth factor \[VEFG\] or anti epidermal growth factor receptor \[EGFR\]) based on the genotype are recommended as standard first- and second-line treatment for unresectabel metastatic colorectal cancer (mCRC) by NCCN guideline. RAS and BRAF are the important signal members in the EGFR signal pathway, and the mutation of them could induce the persistent activation of the downstream of the MAPK pathway, leading to the differentiation, proliferation, and growth change of the tumor cell. The status of RAS and BRAF V600E mutation will affect the efficacy of anti-EGFR therapy, but not anti-VEGF therapy.

Regorafenib, fruquintinb, and TAS-102 have been recommended as third-line treatment for mCRC, while the survivl benefits from these agents are limited, with the median progression-free survival (PFS) and median OS of 1.9-3.7 months and 6.4-9.3 months, respectively.

The efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) for CRCLM have been demonstrated by multiple trials and recommended by many guidelines worldwide. Fruquintinib, a small molecular tyrosine kinase inhibitor targeting at VEGF 1-3, has been demonstrated to change the tumor microenvironment and enhance the anti-tumor effect of programmed death-1 (PD-1) inhibitor in microsatellite stable (MSS) CRC. Anti-EGFR rechallenge (cetuximab rechallenge) was effective in patients with CRC who interrupted the anti-EGFR therapy while responsed to anti-EGFR therapy in the first-line treatment. In 2021, a phase II trial, which explore the efficacy and safety of cetuximab rechallenge combined with Avelumab for pretreated RAS wide type (WT) mCRC. Our retrospective study (unpublished) showed HAIC combined with fruquintinib and tislelizumab presented greater efficacy for MSS CRCLM.

Thus, the investigators will conduct a prospective trial to explore the efficacy and safety of targeted treatment based on ctDNA genotyping combined with tislelizumab and HAIC as salvage treatment for advanced CRCLM failed from standard systemic treatment, aiming to provide individualized optimized regimen for MSS CRCLM in salvage treatment.

Study Timeline

• Study First Submitted: 2023-12-24
• Status Verified: 2024-01
• Study First Submitted QC: 2024-01-09
• Study First Posted: 2024-01-10
• Study Start: 2024-01-23
• Last Update Submitted: 2024-12-01
• Last Update Posted: 2024-12-04
• Primary Completion: 2026-01-23
• Study Completion: 2027-01-23

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

1. 18-80 years old.

2. Colorectal cancer confirmed by histopatology.

3. The metastasis is mainly located in liver.

4. Unresectable liver metastasis is confirmed by CT/MRI scan and multidisciplinary.

5. Failed from standard first- and second-line systemic treatment.

6. At least one measurable lesion according to modified Response Evaluation Criteria in Solid Tumors guidelines (mRECIST).

7. Eastern Cooperative Oncology Group (ECOG) performance status <2.

8. Child-Pugh A or B (≤ 7).

9. Expectant survival time ≥ 3 months.

10. Adequate organ function as follows:

    1. Hemoglobin ≥ 90 g/L;
    2. Absolute neutrophil count ≥ 1.5×10^9/L;
    3. Blood platelet count ≥ 775×10^9/L;
    4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 5 times of upper limit of normal (ULN);
    5. Total bilirubin ≤ 2 times of ULN;
    6. Serum creatinine ≤ 1.5 times of ULN;
    7. Albumin ≥ 30 g/L.

11. Patients sign informed consent.

Exclusion Criteria

1. Extensive extrahepatic metastasis (>25% of tumor burden in liver).
2. HER2 (3+) or HER2 amplification.
3. MSI-H or dMMR.
4. Allergic to contrast media.
5. Pregnant or lactational.
6. Allergic to oxaliplatin or cetuximab.
7. Coinstantaneous a lot of malignant hydrothorax or ascites.
8. History of organ transplantation (including bone marrow auto-transplantation and peripheral stem cell transplantation).
9. Coinstantaneous infection and need anti-infection therapy.
10. Coinstantaneous peripheral nervous system disorder.
11. History of obvious mental disorder and central nervous system disorder.
12. Concomitant malignancy within 5 years, except for non-melanoma skin cancer and carcinoma in situ of cervix.
13. Without legal capacity.
14. Impact the study because of medical or ethical reasons.
15. Clinically severe gastrointestinal bleeding within 6 months of the start of treatment or any life-threatening bleeding events within 3 months of the start of treatment.
16. Uncorrectable coagulation disorder.
17. Obvious abnormal in ECG or obvious clinical symptoms of heart disease, like congestive heart failure, coronary heart disease with obvious clinical symptoms, unmanageable arrhythmia and hypertension.
18. History of myocardial infarction within 12 months, or Grade III/IV of heart function.
19. Severe liver disease (like cirrhosis), renal disease, respiratory disease, unmanageable diabetes or other kinds of systematic disease.
20. Any other subjects that the investigator considers ineligible.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment Arm	HAIC+targeted therapy+PD-1 inhibitor	HAIC combined with targeted therapy and PD-1 inhibitor

Primary Outcome Measures

Name	Time	Method
PFS rate at 6 months	From the date of treatment begining to the date of 6 months after the treatment begining.	Proportion of patients with 6- month progression-free survival after treatment begining in all patients.

Secondary Outcome Measures

Name	Time	Method
PFS	From date of treatment beginning until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months	The time from treatment initiation to the first documented disease progression or death due to any cause, whichever occurs firstly
intrahepatic PFS	From date of treatment beginning until the date of first documented progression in liver or date of death from any cause, whichever came first, assessed up to 100 months	The time from treatment initiation to the first documented disease progression in liver or death due to any cause, whichever occurs firstly
DCR	Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.	The proportion of participants in the analysis population who have complete response (CR), partial response (PR), or stable disease (SD) determined by investigators using mRECIST criteria at any time during the study.
Number of patients with treatment-related adverse events	Through study completion, an average of once per 1 month.	Number of patients with AE, treatment-related AE (TRAE), serious adverse event (SAE) assessed by CTCAE v5.0.
OS	From date of treatment beginning until the date of death from any cause, assessed up to 100 months	The time from treatment initiation to death due to any cause
ORR	Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.	The proportion of participants in the analysis population who have complete response (CR) or partial response (PR) determined by investigators using mRECIST criteria at any time during the study.

Trial Locations

Locations (1)

Peking Univerisity Cancer Hospital; 🇨🇳 Beijing, Beijing, China