Serplulimab Plus Decitabine and CAPOX Before Surgery for Locally Advanced Colorectal Cancer

A Single-Arm, Single-Center, Phase II Exploratory Clinical Study of Serplulimab Combined With Decitabine Plus CAPOX as Neoadjuvant Therapy for Locally Advanced Colorectal Cancer

Title:A Single-Arm, Single-Center, Phase II Exploratory Study of Serplulimab Combined with Decitabine plus CAPOX as Neoadjuvant Therapy for Locally Advanced Colorectal Cancer Background:Colorectal cancer is one of the most common gastrointestinal malignancies worldwide. Patients with locally advanced colorectal cancer remain at high risk of recurrence and distant metastasis after surgery. Although perioperative chemotherapy has improved clinical outcomes, the pathological complete response rate remains limited. Immune checkpoint inhibitors have shown remarkable efficacy in dMMR/MSI-H colorectal cancer; however, most pMMR/MSS tumors respond poorly to immunotherapy alone. Decitabine, a DNA methyltransferase inhibitor, may enhance tumor immunogenicity by promoting tumor antigen expression, improving antigen presentation, increasing immune cell infiltration, and reshaping the tumor immune microenvironment. CAPOX chemotherapy may further induce immunogenic cell death and enhance antitumor immune responses. Therefore, the combination of serplulimab, decitabine, and CAPOX may provide a synergistic neoadjuvant treatment strategy for locally advanced colorectal cancer.

Objective:This study aims to evaluate the efficacy and safety of serplulimab combined with decitabine plus CAPOX as neoadjuvant therapy for patients with locally advanced colorectal cancer. The primary endpoint is pathological complete response rate. Secondary endpoints include R0 resection rate, tumor downstaging, objective response rate, disease-free survival, and safety outcomes.

Methods:This is a prospective, single-center, single-arm, phase II exploratory clinical study. A total of 35 patients with previously untreated locally advanced colorectal adenocarcinoma will be enrolled. Eligible patients are adults aged ≥18 years with histologically or pathologically confirmed cT3/cT4N+M0 colorectal adenocarcinoma according to the AJCC/UICC 8th edition, at least one measurable lesion according to RECIST 1.1, ECOG performance status of 0-1, adequate organ function, and an expected survival of more than 3 months.

The study includes a safety lead-in stage and a dose-expansion stage. In the safety lead-in stage, decitabine dose escalation will follow a conventional 3+3 design, with two planned dose levels: 10 mg and 15 mg intravenously on Days 1-2 of each 3-week cycle. Serplulimab will be administered at 300 mg intravenously on Day 1 of each 3-week cycle. CAPOX consists of oxaliplatin 130 mg/m² intravenously on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14 of each 3-week cycle. The maximum tolerated dose or recommended phase II dose of decitabine will be determined based on dose-limiting toxicity.

In the dose-expansion stage, patients will receive serplulimab combined with decitabine and CAPOX for four cycles as neoadjuvant therapy. Patients without distant metastasis and considered suitable for surgery will undergo radical colorectal cancer resection 2-4 weeks after completion of neoadjuvant treatment. Postoperative adjuvant therapy will be determined by the investigator according to pathological findings and clinical practice.

Endpoints and Analysis:The primary endpoint is pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor and resected lymph nodes after neoadjuvant therapy. Secondary endpoints include R0 resection rate, tumor downstaging rate, objective response rate assessed by RECIST 1.1, and disease-free survival. Safety assessments include adverse events, serious adverse events, immune-related adverse events, laboratory abnormalities, vital signs, 12-lead ECG, ECOG performance status, thyroid function, and physical examination findings. Adverse events will be graded according to NCI-CTCAE version 5.0.

Descriptive statistics will be used for analysis. Continuous variables will be summarized by mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency and percentage. Time-to-event outcomes will be analyzed using the Kaplan-Meier method.

Expected Significance:This study will explore whether the combination of PD-1 blockade, epigenetic modulation, and CAPOX chemotherapy can improve pathological response while maintaining acceptable safety in locally advanced colorectal cancer. The results may provide preliminary evidence for a new neoadjuvant treatment strategy and support future multicenter clinical studies.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Adenocarcinoma; Locally Advanced Colorectal Cancer
• Intervention / Treatment: Drug: Serplulimab + Decitabine + CAPOX (Oxaliplatin + Capecitabine)

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rui Liu; Phone Number: 86+022-23340123; Email: liurui9003@163.com

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China
      • Tianjin Medical University Cancer Institute & Hospital
      • Contact: Rui Liu; Phone Number: 86+022-23340123; Email: liurui9003@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Voluntarily signs written informed consent before screening.
• Male or female, aged 18 years or older.
• Has at least one measurable lesion according to RECIST version 1.1.
• ECOG performance status score of 0 to 1.
• Histologically or pathologically confirmed colorectal adenocarcinoma with no prior antitumor treatment, staged as cT3/cT4N+M0 locally advanced colorectal cancer according to the AJCC/UICC 8th edition based on contrast-enhanced CT or MRI, with colonoscopy and/or diagnostic laparoscopy if clinically indicated.
• Planned to undergo surgery after neoadjuvant therapy according to clinical staging.
• Expected survival of more than 3 months.
• Adequate major organ function, meeting all of the following criteria:
• Hematology: neutrophil count ≥1.5 × 10^9/L, platelet count ≥100 × 10^9/L, hemoglobin ≥90 g/L, and white blood cell count ≥3.5 × 10^9/L, without blood transfusion, granulocyte colony-stimulating factor, or other hematopoietic growth factors within 14 days before screening.
• Hepatic function: ALT and AST ≤2.5 × upper limit of normal, and total bilirubin ≤1.5 × upper limit of normal, or ≤3 × upper limit of normal for patients with Gilbert syndrome.
• Renal function: serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥60 mL/min.
• Coagulation function: activated partial thromboplastin time, international normalized ratio, and prothrombin time ≤1.5 × upper limit of normal.

Exclusion Criteria:

• Prior treatment with any antitumor therapy, including chemotherapy, radiotherapy, hormonal therapy, or molecular targeted therapy.
• Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody, or any other antibody or drug targeting T-cell co-stimulation or immune checkpoint pathways.
• History of another malignancy within 5 years or concurrent malignancy, except cured carcinoma in situ of the cervix, non-melanoma skin cancer, or other malignancy treated with curative intent with no evidence of disease for at least 5 years.
• Pre-existing peripheral neuropathy of grade 2 or higher according to NCI-CTCAE version 5.0.
• Known active central nervous system metastasis and/or carcinomatous meningitis.
• History of severe hypersensitivity reaction to any component of a product or formulation similar to the study PD-1 antibody, or known severe hypersensitivity reaction to other monoclonal antibodies, oxaliplatin, capecitabine, or related compounds, defined as NCI-CTCAE version 5.0 grade 3 or higher.
• Known history of hereditary bleeding disorder or coagulation disorder associated with bleeding risk.
• Major surgery within 4 weeks before enrollment.
• Has not recovered from complications of prior surgery to grade 1 or lower according to CTCAE version 5.0, except alopecia and fatigue.
• Requires immunosuppressive medication within 2 weeks before enrollment or during the study, except intranasal, inhaled, topical, or local steroid injections; systemic corticosteroids at physiological doses equivalent to prednisone ≤10 mg/day; or short-term use of steroids for prevention or treatment of non-autoimmune allergic conditions for no more than 7 days.
• Active autoimmune disease or history of autoimmune disease with potential recurrence.
• Known history of interstitial lung disease or non-infectious pneumonitis.
• Known history of active tuberculosis.
• History of human immunodeficiency virus infection, other acquired or congenital immunodeficiency disease, organ transplantation, or stem cell transplantation.
• Positive hepatitis B surface antigen with HBV DNA ≥10^4 copies/mL or ≥2000 IU/mL at screening, or active hepatitis C defined as positive HCV antibody with HCV RNA above the lower limit of detection.
• Active or uncontrolled infection requiring systemic treatment within 2 weeks before enrollment.
• Receipt of a live viral vaccine within 4 weeks before enrollment.
• Intestinal obstruction, inflammatory bowel disease, extensive intestinal resection with chronic diarrhea, Crohn's disease, ulcerative colitis, or chronic diarrhea.
• Breastfeeding, or planning pregnancy during treatment and within 6 months after completion of treatment.
• Unwillingness to use effective contraception during treatment and within 6 months after completion of treatment, including male participants capable of fathering a child, female participants, and their male partners.
• Any other condition that, in the investigator's judgment, may affect protocol compliance or assessment of study endpoints and makes the participant unsuitable for this study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Serplulimab plus Decitabine and CAPOX(Oxaliplatin + Capecitabine); Patients will receive serplulimab combined with decitabine and CAPOX as neoadjuvant therapy. Serplulimab will be administered at 300 mg intravenously on Day 1 of each 3-week cycle. Decitabine will be administered intravenously on Days 1-2 of each 3-week cycle, with dose escalation in the safety lead-in stage from 10 mg to 15 mg using a 3+3 design to determine the MTD/RP2D. CAPOX consists of oxaliplatin 130 mg/m² intravenously on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14 of each 3-week cycle. Patients will receive 4 cycles of neoadjuvant treatment, followed by radical colorectal cancer surgery 2-4 weeks after completion of treatment if eligible. Postoperative adjuvant therapy will be determined by the investigator.

Drug: Serplulimab + Decitabine + CAPOX (Oxaliplatin + Capecitabine); Serplulimab will be administered at 300 mg intravenously on Day 1 of each 3-week cycle. Decitabine will be administered intravenously on Days 1-2 of each 3-week cycle. In the safety lead-in stage, decitabine dose escalation will follow a 3+3 design, with planned dose levels of 10 mg and 15 mg to determine the MTD/RP2D. CAPOX consists of oxaliplatin 130 mg/m² intravenously on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14 of each 3-week cycle. Patients will receive 4 cycles of neoadjuvant treatment before radical colorectal cancer surgery if eligible.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response Rate	Pathological complete response rate is defined as the proportion of participants with no residual viable tumor cells in the primary tumor and resected lymph nodes in surgical specimens after neoadjuvant therapy.	2 to 4 weeks after completion of four cycles of neoadjuvant therapy, approximately 14 to 16 weeks after the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 Resection Rate	R0 resection rate is defined as the proportion of participants who undergo complete tumor resection with microscopically negative surgical margins and no residual tumor.	2 to 4 weeks after completion of four cycles of neoadjuvant therapy, approximately 14 to 16 weeks after the first dose
Tumor Downstaging Rate	Tumor downstaging rate is defined as the proportion of participants with any reduction in pathological T stage or N stage after neoadjuvant therapy compared with baseline clinical staging.	2 to 4 weeks after completion of four cycles of neoadjuvant therapy, approximately 14 to 16 weeks after the first dose
Objective Response Rate	Objective response rate is defined as the proportion of participants who achieve complete response or partial response according to RECIST version 1.1.	Every 3 weeks during neoadjuvant therapy, up to approximately 12 weeks after the first dose
Disease-Free Survival	Disease-free survival is defined as the time from enrollment to local or distant tumor recurrence or death from any cause, whichever occurs first. Disease-free survival will be analyzed only in participants who undergo R0 resection.	Up to approximately 24 months after enrollment
Incidence and Severity of Adverse Events	Safety will be assessed by the incidence, type, severity, duration, and relationship to study treatment of adverse events and serious adverse events. Safety assessments include laboratory abnormalities, vital signs, 12-lead electrocardiogram, ECOG performance status, thyroid function, and physical examination findings. Adverse events will be graded according to NCI-CTCAE version 5.0.	From the first dose of study treatment through 28 days after the last dose, up to approximately 16 weeks

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Publications and helpful links

General Publications

• Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, Chen W. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022 Feb 9;135(5):584-590. doi: 10.1097/CM9.0000000000002108.
• Wang Y, Deng W, Li N, Neri S, Sharma A, Jiang W, Lin SH. Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions. Front Pharmacol. 2018 Mar 5;9:185. doi: 10.3389/fphar.2018.00185. eCollection 2018.
• Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, Liu WY, Chen SL, Li S, Lu NN, Cai Y, Li YH, Zhu Y, Cheng GH, Zhang HY, Wang X, Zhu SY, Wang J, Li GF, Yang JL, Zhang K, Chi Y, Yang L, Zhou HT, Zhou AP, Zou SM, Fang H, Wang SL, Zhang HZ, Wang XS, Wei LC, Wang WL, Liu SX, Gao YH, Li YX. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022 May 20;40(15):1681-1692. doi: 10.1200/JCO.21.01667. Epub 2022 Mar 9.
• 张剑威，邓艳红. 微卫星稳定或错配修复正常结直肠癌的新辅助免疫治疗［J］.中华胃肠外科杂志，2022, 25(3):193-198.
• Hasegawa J, Nishimura J, Mizushima T, Miyake Y, Kim HM, Takemoto H, Tamagawa H, Noura S, Fujii M, Fujie Y, Kato T, Miwa H, Takemasa I, Ikeda M, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M. Neoadjuvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer. Cancer Chemother Pharmacol. 2014 May;73(5):1079-87. doi: 10.1007/s00280-014-2417-9. Epub 2014 Mar 5.
• Lin Z, Cai M, Zhang P, Li G, Liu T, Li X, Cai K, Nie X, Wang J, Liu J, Liu H, Zhang W, Gao J, Wu C, Wang L, Fan J, Zhang L, Wang Z, Hou Z, Ma C, Yang K, Wu G, Tao K, Zhang T. Phase II, single-arm trial of preoperative short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer. J Immunother Cancer. 2021 Nov;9(11):e003554. doi: 10.1136/jitc-2021-003554.
• Bando H, Tsukada Y, Inamori K, Togashi Y, Koyama S, Kotani D, Fukuoka S, Yuki S, Komatsu Y, Homma S, Taketomi A, Uemura M, Kato T, Fukui M, Wakabayashi M, Nakamura N, Kojima M, Kawachi H, Kirsch R, Yoshida T, Suzuki Y, Sato A, Nishikawa H, Ito M, Yoshino T. Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer. Clin Cancer Res. 2022 Mar 15;28(6):1136-1146. doi: 10.1158/1078-0432.CCR-21-3213.
• Tanaka S, Hosokawa M, Ueda K, Iwakawa S. Effects of Decitabine on Invasion and Exosomal Expression of miR-200c and miR-141 in Oxaliplatin-Resistant Colorectal Cancer Cells. Biol Pharm Bull. 2015;38(9):1272-9. doi: 10.1248/bpb.b15-00129. Epub 2015 Jul 15.
• Taib N, Merhi M, Inchakalody V, Mestiri S, Hydrose S, Makni-Maalej K, Raza A, Sahir F, Azizi F, Nizamuddin PB, Fernandes Q, Yoosuf ZSKM, Almoghrabi S, Al-Zaidan L, Shablak A, Uddin S, Maccalli C, Al Homsi MU, Dermime S. Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy. J Transl Med. 2023 Mar 31;21(1):235. doi: 10.1186/s12967-023-04073-y.
• Huang KC, Chiang SF, Chen WT, Chen TW, Hu CH, Yang PC, Ke TW, Chao KSC. Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer. Cancers (Basel). 2020 Feb 17;12(2):462. doi: 10.3390/cancers12020462.
• Yu G, Wu Y, Wang W, Xu J, Lv X, Cao X, Wan T. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell Mol Immunol. 2019 Apr;16(4):401-409. doi: 10.1038/s41423-018-0026-y. Epub 2018 Apr 5.
• Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, Fromm PD, Hart DN, Van Tendeloo VF, Berneman ZN. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy. Pharmacol Rev. 2015 Oct;67(4):731-53. doi: 10.1124/pr.114.009456.
• Harris JE, Ryan L, Hoover HC Jr, Stuart RK, Oken MM, Benson AB 3rd, Mansour E, Haller DG, Manola J, Hanna MG Jr. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol. 2000 Jan;18(1):148-57. doi: 10.1200/JCO.2000.18.1.148.
• Takei S, Tanaka Y, Lin YT, Koyama S, Fukuoka S, Hara H, Nakamura Y, Kuboki Y, Kotani D, Kojima T, Bando H, Mishima S, Ueno T, Kojima S, Wakabayashi M, Sakamoto N, Kojima M, Kuwata T, Yoshino T, Nishikawa H, Mano H, Endo I, Shitara K, Kawazoe A. Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer. J Immunother Cancer. 2024 Feb 8;12(2):e008210. doi: 10.1136/jitc-2023-008210.
• Yu B, Kang J, Lei H, Li Z, Yang H, Zhang M. Immunotherapy for colorectal cancer. Front Immunol. 2024 Aug 21;15:1433315. doi: 10.3389/fimmu.2024.1433315. eCollection 2024.
• Hu H, Zhang J, Li Y, Wang X, Wang Z, Wang H, Kang L, Liu P, Lan P, Wu X, Zhen Y, Pei H, Huang Z, Zhang H, Chen W, Zeng Y, Lai J, Wei H, Huang X, Chen J, Chen J, Tao K, Xu Q, Peng X, Liang J, Cai G, Ding K, Ding Z, Hu M, Zhang W, Tang B, Hong C, Cao J, Huang Z, Cao W, Li F, Wang X, Wang C, Huang Y, Zhao Y, Cai Y, Ling J, Xie X, Wu Z, Shi L, Ling L, Liu H, Wang J, Huang M, Deng Y; OPTICAL study group. Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial. J Clin Oncol. 2024 Sep 1;42(25):2978-2988. doi: 10.1200/JCO.23.01889. Epub 2024 Apr 2.
• Saraf A, Roberts HJ, Wo JY, Parikh AR. Optimal Neoadjuvant Strategies for Locally Advanced Rectal Cancer by Risk Assessment and Tumor Location. J Natl Compr Canc Netw. 2022 Oct;20(10):1177-1184. doi: 10.6004/jnccn.2022.7061.
• Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Wu X, Peng J, Ren D, Wang J. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 2019 Dec 1;37(34):3223-3233. doi: 10.1200/JCO.18.02309. Epub 2019 Sep 26.
• Yu Xin，Wang Qiao-Xuan，Xiao Wei-Wei，Chang Hui，Zeng Zhi-Fan，Lu Zhen-Hai，等. 奥沙利铂和卡培他滨联合贝伐单抗加放疗的新辅助方案治疗局部晚期直肠癌:单中心Ⅱ期研究结果[J]. 癌症, 2018, 37(08): 346-355.
• 姚宏伟，李心翔，崔龙，等. 中国结直肠癌手术病例登记数据库2022年度报告：一项全国性登记研究［J］. 中国实用外科杂志，2023，43(1): 93-99.

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: July 1, 2026
• First Submitted That Met QC Criteria: July 8, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Uracil; Pyrimidinones; Azacitidine; Deoxyribonucleosides; Fluorouracil; Decitabine; Capecitabine; Oxaliplatin
• Other Study ID Numbers: HLX10IIT462

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No