Fruquintinib Combined With Sintilimab ± Radiotherapy for Third-line Treatment of Colorectal Cancer With Liver Metastases

Fruquintinib Combined With Sintilimab ± Radiotherapy for Third-line Treatment of Colorectal Cancer With Liver Metastases: A Randomized, Controlled, Multicenter Phase II Trial

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. Its early clinical manifestations are often subtle, leading to late-stage diagnosis in about 30% of cases with distant metastases. Liver metastases are widespread and associated with poor prognosis, especially in terms of response to immunotherapy. This prospective study will evaluate the efficacy of combined therapy involving sintilimab, fruquintinib, and radiotherapy in CRC with liver metastases. The primary objectives are to assess progression-free survival, overall survival, and treatment response rates. This study aims to provide valuable insights into optimizing third-line and subsequent therapies for CRC with liver metastases by elucidating the efficacy and safety of this combined treatment approach.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Radiotherapy; Immunotherapy; Targeted Therapy; Liver Metastasis
• Intervention / Treatment: Drug: Immunotherapy (Sintilimab); Drug: Targeted Therapy Agent (Fruquintinib); Radiation: Radiotherapy (SBRT and LDRT)

Detailed Description

CRC is a significant cause of morbidity and mortality worldwide. Its early clinical manifestations are often subtle, leading to late-stage diagnosis in about 30% of cases with distant metastases. Liver metastases are widespread and associated with poor prognosis, especially in terms of response to immunotherapy. This prospective study will evaluate the efficacy of combined therapy involving sintilimab, fruquintinib, and radiotherapy in CRC with liver metastases. The primary objectives are to assess progression-free survival, overall survival, and treatment response rates. The rationale for this study stems from the intricate interplay between immunotherapy, targeted therapy, and radiotherapy in CRC management. Previous data suggest a negative correlation between liver metastases and immunotherapy efficacy, necessitating a comprehensive approach integrating multiple treatment modalities. Radiotherapy, particularly stereotactic body radiation therapy, has shown promise in controlling liver tumors and modulating the tumor microenvironment, potentially enhancing immunotherapy responses. This study aims to provide valuable insights into optimizing third-line and subsequent therapies for CRC with liver metastases by elucidating the efficacy and safety of this combined treatment approach.

• Study Type: Interventional
• Enrollment (Estimated): 62
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jin Bo Yue, dorctor; Phone Number: 0531-67626442 0531-67626442; Email: Len.Xu@hotmail.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250000
      • Recruiting
      • Jinbo Yue
      • Contact: Jin Bo Yue; Phone Number: 0531-67626442 0531-67626442; Email: Len.Xu@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ECOG PS 0-2
• Histologically confirmed colorectal adenocarcinoma with liver metastases (8th edition AJCC)
• MSS/pMMR subtype
• Previously received standard first- and second-line systemic anti-tumor therapy
• At least one measurable lesion as defined by RECIST 1.1 criteria
• Access to tumor samples for biomarker assessment
• Expected survival of ≥3 months
• Normal function of major organ systems (within 14 days before enrollment)
• No systemic corticosteroid treatment within 7 days before treatment initiation, excluding physiological corticosteroid replacement therapy.
• Fertile males or females with the potential for pregnancy must use highly effective contraception methods during the trial.

Exclusion Criteria:

• Patients diagnosed with malignancies other than colorectal cancer within 3 years prior to enrollment.
• Participating in an interventional clinical study or receiving other investigational drugs or treatments with study devices within the past 4 weeks before enrollment.
• Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs, or drugs targeting another T cell co-stimulatory or co-inhibitory receptor (e.g., CTLA-4, OX-40, CD137), fruquintinib, etc.
• Received traditional Chinese medicine or immune-modulating drugs with anti-tumor indications within the past 2 weeks before enrollment (excluding local use for controlling pleural effusion).
• Experienced active autoimmune diseases requiring systemic therapy within the past 2 years before enrollment. Replacement therapy is not considered systemic therapy.
• Diagnosed with immune deficiency or received systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of investigational treatment. After consultation with the sponsor, the use of physiological doses of corticosteroids may be approved.
• Received liver radiotherapy within the past 2 weeks before enrollment.
• Known presence of central nervous system metastases and/or carcinomatous meningitis.
• Received systemic corticosteroid therapy within 7 days before enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immunotherapy, targert therapy, and radiotherapy; For liver oligometastases, high-dose stereotactic body radiation therapy (SBRT) irradiation will be administered to all lesions with a dose fractionation pattern of 40-50 Gy/5F, 60-70 Gy/10F, or 65 Gy/13F. For multiple liver metastases, SBRT plus low-dose radiation therapy (LDRT) will be performed to all lesions. One or more suitable lesions (which will be selected by the physician based on proximity to organs at risk) will undergo SBRT with a dose fractionation pattern of 40-50 Gy/5F, 60-70 Gy/10F, or 65 Gy/13F, and the remaining lesions will undergo LDRT at a total dose of 1-10 Gy at 0.5-2.0 Gy/F. Extrahepatic lesions will be not treated with radiotherapy. Targeted therapy and immunotherapy will be administered one week after the end of radiation therapy. A 21-day treatment cycle of sintilimab (200 mg, D1, once every 3 weeks) will be given intravenously on day 1 of each cycle, and fruquintinib will be given on days 1 to 14.	Drug: Immunotherapy (Sintilimab); Sintilimab; Drug: Targeted Therapy Agent (Fruquintinib); Fruquintinib; Radiation: Radiotherapy (SBRT and LDRT); SBRT and LDRT
Active Comparator: Immunotherapy and targert therapy; A 21-day treatment cycle of sintilimab (200 mg, D1, once every 3 weeks) will be given intravenously on day 1 of each cycle, and fruquintinib will be given on days 1 to 14.	Drug: Immunotherapy (Sintilimab); Sintilimab; Drug: Targeted Therapy Agent (Fruquintinib); Fruquintinib
Active Comparator: Targert therapy; Treatment with fruquintinib (5 mg, po, D1-21, once every 4 weeks) will be given on days 1 through 21 in a 28-day treatment cycle.	Drug: Targeted Therapy Agent (Fruquintinib); Fruquintinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Time from initial drug administration to first radiographic disease progression or death (whichever occurs first).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	The proportion of subjects achieving complete response (CR) and partial response (PR) among the total subjects; includes assessment of both irradiated and non-irradiated lesions.	1 year
Disease control rate (DCR)	The proportion of subjects achieving complete response (CR), partial response (PR), and stable disease (SD) among the total subjects.	1 year
Overall survival (OS)	Time from initial drug administration to death of the subject for any reason.	3 year
The incidence and grade of adverse events	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death.	2 year

Collaborators and Investigators

• Sponsor: Shandong Cancer Hospital and Institute
• Investigators: Principal Investigator: Jin Bo Yue, Shandong Cancer Hospital and Institute

Publications and helpful links

General Publications

• Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, Yoshii T, Kotani D, Tamura H, Mikamoto Y, Hirano N, Wakabayashi M, Nomura S, Sato A, Kuwata T, Togashi Y, Nishikawa H, Shitara K. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol. 2020 Jun 20;38(18):2053-2061. doi: 10.1200/JCO.19.03296. Epub 2020 Apr 28.
• 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.
• 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.
• 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.
• Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021 Feb 16;325(7):669-685. doi: 10.1001/jama.2021.0106.
• Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, Rizvi SM, Qin A, Waninger JJ, Lang X, Chopra Z, El Naqa I, Zhou J, Bian Y, Jiang L, Tezel A, Skvarce J, Achar RK, Sitto M, Rosen BS, Su F, Narayanan SP, Cao X, Wei S, Szeliga W, Vatan L, Mayo C, Morgan MA, Schonewolf CA, Cuneo K, Kryczek I, Ma VT, Lao CD, Lawrence TS, Ramnath N, Wen F, Chinnaiyan AM, Cieslik M, Alva A, Zou W. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021 Jan;27(1):152-164. doi: 10.1038/s41591-020-1131-x. Epub 2021 Jan 4.
• Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, Garcia-Alfonso P, Kocsis J, Cubillo Gracian A, Sartore-Bianchi A, Satoh T, Randrian V, Tomasek J, Chong G, Paulson AS, Masuishi T, Jones J, Csoszi T, Cremolini C, Ghiringhelli F, Shergill A, Hochster HS, Krauss J, Bassam A, Ducreux M, Elme A, Faugeras L, Kasper S, Van Cutsem E, Arnold D, Nanda S, Yang Z, Schelman WR, Kania M, Tabernero J, Eng C; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023 Jul 1;402(10395):41-53. doi: 10.1016/S0140-6736(23)00772-9. Epub 2023 Jun 15.
• Bouchalova M, Gerylovova A. [Evolution of body weight as influenced by social conditions and life style of the children in the 1st 3 years of life]. Cesk Pediatr. 1971 Jan;26(1):7-9. No abstract available. Czech.
• Leung MK, Stefano GB. Isolation and identification of enkephalins in pedal ganglia of Mytilus edulis (Mollusca). Proc Natl Acad Sci U S A. 1984 Feb;81(3):955-8. doi: 10.1073/pnas.81.3.955.
• Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Trifluridine/Tipiracil (TAS-102) Monotherapy in Asian Patients With Previously Treated Metastatic Colorectal Cancer: The TERRA Study. J Clin Oncol. 2018 Feb 1;36(4):350-358. doi: 10.1200/JCO.2017.74.3245. Epub 2017 Dec 7.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: April 5, 2024
• First Submitted That Met QC Criteria: April 5, 2024
• First Posted (Actual): April 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; Immunotherapy; Targeted therapy; Radiotherapy; Liver metastasis
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Stereotaxic Techniques; Neurosurgical Procedures; Biological Therapy; Immunomodulation; Radiotherapy; Radiosurgery; Immunotherapy; sintilimab; HMPL-013
• Other Study ID Numbers: SDZLEC2024-078-01

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
• product manufactured in and exported from the U.S.: No