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

January 24, 2024 updated by: Peking University

Targeted Treatment Based on ctDNA Genotyping Combined With Tislelizumab and HAIC as Salvage Treatment for Advanced Colorectal Cancer Liver Metastasis Failed From Standard Systemic Treatment (SALVLIV Trial)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / 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 Type

Interventional

Enrollment (Estimated)

47

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China, 100142
        • Recruiting
        • Peking Univerisity Cancer Hospital
        • Contact:
        • Sub-Investigator:
          • Xiaodong Wang, M.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment Arm
HAIC combined with targeted therapy and PD-1 inhibitor
Drug: HAIC+targeted therapy+PD-1 inhibitor

HAIC regimen: doublet or triplet regimen based on the response and adverse events occurred in the previous standard treatment (depended on the decision of researchers)-oxaliplatin (85 mg/m2, split into d1 and d2, 0-2h,) and 5-fluorouracial (2g/m2, split into d1 and d2, 2-24h)/ oxaliplatin (65 mg/m2, 0-2h, d1), irinotecan (100 mg/m2, 0-2h, d2), and 5-fluorouracial (2g/m2, split in d1 and d2, 2-24h), repeated every 4 weeks; drug-eluting TACE will be performed at 3rd-4th cycles if the lesions in liver is abundant with blood supply.

Tislelizumab (a PD-1 inhibitor): 200 mg, intravenous drip for 30-60 minutes before 24h of HAIC, q4w.

Cetuximab (Group A, KRAS/NRAK/BRAF/EGFR wide type and interrupt cetuximab more than 3 months): 500 mg/m2, intravenous drip before HAIC, q4w.

Fruquintinib (Group B, KRAS/NRAS/BRAF/EGFR mutation type and wide type but treated with cetuximab in last 3 months): 3 mg/d, d3-23, then suspend for 1w.

Other Names:
  • HAIC+Fruquintinib/Cetuximab+Tislelizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS rate at 6 months
Time Frame: 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.
From the date of treatment begining to the date of 6 months after the treatment begining.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with treatment-related adverse events
Time Frame: 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.
Through study completion, an average of once per 1 month.
PFS
Time Frame: 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
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
OS
Time Frame: 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
From date of treatment beginning until the date of death from any cause, assessed up to 100 months
intrahepatic PFS
Time Frame: 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
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
ORR
Time Frame: 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.
Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.
DCR
Time Frame: 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.
Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking University

Investigators

  • Study Director: Xiaodong Wang, M.D., Peking University Cancer Hospital & Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 23, 2024

Primary Completion (Estimated)

January 23, 2026

Study Completion (Estimated)

January 23, 2027

Study Registration Dates

First Submitted

December 24, 2023

First Submitted That Met QC Criteria

January 9, 2024

First Posted (Actual)

January 10, 2024

Study Record Updates

Last Update Posted (Estimated)

January 25, 2024

Last Update Submitted That Met QC Criteria

January 24, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PekingUCHI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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