Anti-PCSK9 Antibody Tafolecimab and Anti-PD-1 Antibody Sintilimab Combined With Neoadjuvant Chemoradiotherapy for pMMR/ MSS Locally Advanced Rectal Cancer : A Prospective, Multicenter, Randomized, Open-Label, Parallel-Controlled Trial

This is a randomized, controlled clinical trial based on prior exploratory findings, designed to evaluate the efficacy and safety of neoadjuvant chemoradiotherapy combined with tafolecimab(an anti-PCSK9 inhibitor) and sintilimab (an anti-PD-1 inhibitor) versus neoadjuvant chemoradiotherapy combined with sintilimab alone in patients with pMMR/MSS locally advanced rectal cancer. The primary endpoint is the complete response (CR) rate, including the pathological complete response (pCR) rate in patients who undergo surgery after neoadjuvant therapy, and the clinical complete response (cCR) rate in patients managed with a watch-and-wait strategy. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), downstaging rate, R0 resection rate, tumor regression grade, sphincter preservation rate, disease-free survival (DFS), overall survival (OS), and safety.

Study Overview

• Status: Not yet recruiting
• Conditions: Capecitabine; Radiotherapy; PD-1 Inhibitor; Oxaliplatin; Local Advanced Rectal Cancer; PCSK9 Inhibitor; RCT
• Intervention / Treatment: Radiation: Short-course radiotherapy; Drug: CAPOX (oxaliplatin/capecitabine); Drug: Sintilimab; Drug: Tafolecimab

• Study Type: Interventional
• Enrollment (Estimated): 148
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yong Li; Phone Number: 13822177479; Email: liyong@gdph.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial People's Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18 to 75 years, any sex.
2. Histologically confirmed rectal adenocarcinoma, determined to be pMMR (proficient mismatch repair) or MSS (microsatellite stable) by immunohistochemistry and/or genetic testing; clinical stage cT3/T4 or cN+; distal tumor margin ≤ 12 cm from the anal verge; and eligible for surgical resection.
3. No evidence of distant metastases.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Adequate hematologic and biochemical function: absolute neutrophil count ≥ 1.5 × 10⁹/L, hemoglobin ≥ 90 g/L, platelets ≥ 100 × 10⁹/L, ALT/AST ≤ 2.5 times the upper limit of normal (ULN), creatinine ≤ 3.0 × ULN.
6. Anticipated good compliance and provision of written informed consent.

Exclusion Criteria:

1. Known allergy or severe adverse reaction to any study drug, including tafolecimab, PD-1 inhibitor (sintilimab), capecitabine, oxaliplatin, or any excipients.
2. Rectal cancer confirmed as dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high).
3. Pregnant or breastfeeding women, or patients of childbearing potential who refuse to use effective contraception during the study.
4. Other malignancies within the past 5 years, except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, papillary thyroid carcinoma, or other malignancies considered cured after adequate treatment.
5. Prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, or local surgical excision.
6. Previous treatment with a PCSK9 inhibitor for any indication.
7. Severe or uncontrolled neurological disease, psychiatric disorder, or cognitive impairment that, in the investigator's judgment, would affect informed consent or protocol adherence.
8. Severe cardiovascular or cerebrovascular disease, including but not limited to: unstable angina, myocardial infarction, coronary revascularization, or stroke within 6 months before enrollment; clinically significant arrhythmia requiring treatment or left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) class III or IV heart failure.
9. Active infection requiring long-term systemic therapy (e.g., antibiotics, antivirals, or antifungals).
10. Active autoimmune disease, or requirement for long-term systemic immunosuppressive therapy or corticosteroids (at a dose equivalent to prednisone > 10 mg/day).
11. Known history of human immunodeficiency virus (HIV) infection, or active syphilis, or active pulmonary tuberculosis.
12. Active hepatitis B (HBsAg positive and HBV DNA > 200 IU/mL or > 1000 copies/mL) or active hepatitis C (HCV RNA positive).
13. Any other clinical condition that, in the investigator's opinion, could interfere with study assessments, increase treatment risk, or lead to premature study discontinuation (including but not limited to severe alcohol or drug abuse).

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab; Short-course radiotherapy (SCRT): total dose 25 Gy in 5 daily fractions, followed by a 1-week rest. One week after SCRT, 6 cycles of CAPOX chemotherapy plus sintilimab are given (each cycle = 21 days). CAPOX consists of oxaliplatin 130 mg/m² IV on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14. Sintilimab is administered at 3 mg/kg IV (body weight <60 kg) or 200 mg IV (body weight ≥60 kg) on Day 1 of each cycle. Throughout the neoadjuvant period, tafolecimab 450 mg is administered subcutaneously once every 4 weeks for 6 doses, starting on the first day of SCRT.	Radiation: Short-course radiotherapy; Total dose: 25 Gy, to be completed in 5 sessions (once a day for 5 days). After the short-course radiotherapy, a 1-week rest is required before moving on to the next stage of treatment.; Drug: CAPOX (oxaliplatin/capecitabine); One week after short-course radiotherapy, 6 cycles of CAPOX chemotherapy combined with PD-1 inhibitor immunotherapy were administered. Each cycle lasted for 3 weeks, for a total of 6 cycles. (One cycle is defined as: Oxaliplatin, 130 mg/m², intravenous infusion, on day 1. Capecitabine, 1000 mg/m², orally, twice a day (morning and evening), from day 1 to day 14.); Drug: Sintilimab; For patients with a body weight of less than 60 kg, the dose is 3 mg/kg, administered by intravenous infusion on the first day; for patients with a body weight of 60 kg or more, the dose is 200 mg, also administered by intravenous infusion on the first day.; Drug: Tafolecimab; The entire course of treatment with PCSK9 inhibitor (Tafolecimab) was administered, with 450 mg of Tafolecimab administered subcutaneously. (The treatment involved neoadjuvant radiotherapy and chemotherapy combined with immunotherapy and Tafolecimab. The treatment was carried out from the time the patient began receiving short-course radiotherapy. Each cycle consisted of 4 weeks, with injection on the first day of each cycle, for a total of 6 times.)
Active Comparator: Neoadjuvant Chemoradiotherapy plus Sintilimab; Short-course radiotherapy (SCRT): total dose 25 Gy in 5 daily fractions, followed by a 1-week rest. One week after SCRT, 6 cycles of CAPOX chemotherapy plus sintilimab are given (each cycle = 21 days). CAPOX consists of oxaliplatin 130 mg/m² IV on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14. Sintilimab is administered at 3 mg/kg IV (body weight <60 kg) or 200 mg IV (body weight ≥60 kg) on Day 1 of each cycle.	Radiation: Short-course radiotherapy; Total dose: 25 Gy, to be completed in 5 sessions (once a day for 5 days). After the short-course radiotherapy, a 1-week rest is required before moving on to the next stage of treatment.; Drug: CAPOX (oxaliplatin/capecitabine); One week after short-course radiotherapy, 6 cycles of CAPOX chemotherapy combined with PD-1 inhibitor immunotherapy were administered. Each cycle lasted for 3 weeks, for a total of 6 cycles. (One cycle is defined as: Oxaliplatin, 130 mg/m², intravenous infusion, on day 1. Capecitabine, 1000 mg/m², orally, twice a day (morning and evening), from day 1 to day 14.); Drug: Sintilimab; For patients with a body weight of less than 60 kg, the dose is 3 mg/kg, administered by intravenous infusion on the first day; for patients with a body weight of 60 kg or more, the dose is 200 mg, also administered by intravenous infusion on the first day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate	Defined as the Proportion of Participants Achieving Pathological Complete Response (pCR) After Surgery or Clinical Complete Response (cCR) Under Watch-and-Wait Strategy Following Neoadjuvant Therapy	Within 4 weeks after completion of neoadjuvant therapy for cCR and within 2 weeks after the time of surgery for pCR
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0		From the first dose of neoadjuvant treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Major Pathological Response (MPR) Rate	within 2 weeks after the time of surgery
Objective Response Rate (ORR)	Within 4 weeks after completion of neoadjuvant therapy or within 2 weeks after surgery;
Downstaging Rate	Within 4 weeks after completion of neoadjuvant therapy or within 2 weeks after surgery;
Tumor Regression Grade (TRG)	Within 2 weeks after surgery;
R0 Resection Rate	Within 2 weeks after surgery;
Disease-Free Survival (DFS)	approximately 5 years after completion of neoadjuvant chemotherapy
Overall Survival (OS)	approximately 5 years after completion of neoadjuvant chemotherapy

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Collaborators: Fudan University; Beijing Friendship Hospital; Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Peking University Cancer Hospital & Institute; Ruijin Hospital; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; The First Hospital of Jilin University; Third Affiliated Hospital, Sun Yat-Sen University; Sixth Affiliated Hospital, Sun Yat-sen University; The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine; Affiliated Hospital of Qinghai University; The First Affiliated Hospital of Xiamen University; Meizhou People's Hospital; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Sun Yat-Sen University Cancer Center; Zhangzhou Hospital, Fujian Province; Nanchang University Second Affiliated Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2035

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 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; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; Oxaliplatin; sintilimab
• Other Study ID Numbers: PIONEER-02

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