Clinical trial NCT06199232: Targeted Treatment Plus Tislelizumab and HAIC for Advanced CRCLM Failed from Standard Systemic Treatment
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Liver Metastasis Colon Cancer
CtDNA Genotype
MSS
Failed from Standard Treatment
Keywords: hepatic arterial infusion chemotherapy
targeted therapy
tislelizumab
ctDNA genotype
MSS CRCLM
Lead sponsor: Peking University
Sponsor class: OTHER
First posted: 2024-01-10
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: PFS rate at 6 months
timeFrame: From the date of treatment begining to the date of 6 months after the treatment begining.
Secondary outcomes:
measure: PFS
timeFrame: 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
measure: OS
timeFrame: From date of treatment beginning until the date of death from any cause, assessed up to 100 months
measure: intrahepatic PFS
timeFrame: 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
measure: ORR
timeFrame: Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.
measure: DCR
timeFrame: Evaluation of tumor burden based on mRECIST criteria through study completion, an average of once per 3 months.
measure: Number of patients with treatment-related adverse events
timeFrame: Through study completion, an average of once per 1 month.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking Univerisity Cancer Hospital
state: Beijing
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Xiaodong Wang, M.D.
role: STUDY_DIRECTOR
References:
citation: Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, Alexander DD, Choti MA, Poston G. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol. 2012;4:283-301. doi: 10.2147/CLEP.S34285. Epub 2012 Nov 7.
citation: Hackl C, Neumann P, Gerken M, Loss M, Klinkhammer-Schalke M, Schlitt HJ. Treatment of colorectal liver metastases in Germany: a ten-year population-based analysis of 5772 cases of primary colorectal adenocarcinoma. BMC Cancer. 2014 Nov 4;14:810. doi: 10.1186/1471-2407-14-810.
citation: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.
citation: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. doi: 10.1016/S1470-2045(15)70156-7. Epub 2015 May 13.
citation: Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, Deng Y, Chen ZD, Zhong H, Pan H, Guo W, Shu Y, Yuan Y, Zhou J, Xu N, Liu T, Ma D, Wu C, Cheng Y, Chen D, Li W, Sun S, Yu Z, Cao P, Chen H, Wang J, Wang S, Wang H, Fan S, Hua Y, Su W. Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial. JAMA. 2018 Jun 26;319(24):2486-2496. doi: 10.1001/jama.2018.7855.
citation: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325.
citation: Cho M, Gong J, Fakih M. The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Rev Anticancer Ther. 2016;16(2):229-45. doi: 10.1586/14737140.2016.1129277. Epub 2016 Jan 13.
citation: Wang Y, Wei B, Gao J, Cai X, Xu L, Zhong H, Wang B, Sun Y, Guo W, Xu Q, Gu Y. Combination of Fruquintinib and Anti-PD-1 for the Treatment of Colorectal Cancer. J Immunol. 2020 Nov 15;205(10):2905-2915. doi: 10.4049/jimmunol.2000463. Epub 2020 Oct 7.
citation: Li Q, Cheng X, Zhou C, Tang Y, Li F, Zhang B, Huang T, Wang J, Tu S. Fruquintinib Enhances the Antitumor Immune Responses of Anti-Programmed Death Receptor-1 in Colorectal Cancer. Front Oncol. 2022 Mar 17;12:841977. doi: 10.3389/fonc.2022.841977. eCollection 2022.