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

NCT07686796 | Not Yet Recruiting Phase 3

• 1 other identifier: PIONEER-02
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Local Advanced Rectal Cancer; PD-1 Inhibitor; PCSK9 Inhibitor; RCT; Radiotherapy; Capecitabine; Oxaliplatin

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• 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;

Study Arms (2)

Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab

EXPERIMENTAL

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; Drug: CAPOX (oxaliplatin/capecitabine); Drug: Sintilimab; Drug: Tafolecimab

Neoadjuvant Chemoradiotherapy plus Sintilimab

ACTIVE COMPARATOR

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; Drug: CAPOX (oxaliplatin/capecitabine); Drug: Sintilimab

Interventions

Short-course radiotherapy RADIATION

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.

Neoadjuvant Chemoradiotherapy plus Sintilimab; Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab

CAPOX (oxaliplatin/capecitabine) DRUG

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.)

Neoadjuvant Chemoradiotherapy plus Sintilimab; Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab

Sintilimab DRUG

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.

Neoadjuvant Chemoradiotherapy plus Sintilimab; Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab

Tafolecimab DRUG

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.)

Neoadjuvant Chemoradiotherapy plus Sintilimab and Tafolecimab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 75 years, any sex.
• 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.
• No evidence of distant metastases.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• 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.
• Anticipated good compliance and provision of written informed consent.

You may not qualify if:

• Known allergy or severe adverse reaction to any study drug, including tafolecimab, PD-1 inhibitor (sintilimab), capecitabine, oxaliplatin, or any excipients.
• Rectal cancer confirmed as dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high).
• Pregnant or breastfeeding women, or patients of childbearing potential who refuse to use effective contraception during the study.
• 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.
• Prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, or local surgical excision.
• Previous treatment with a PCSK9 inhibitor for any indication.
• Severe or uncontrolled neurological disease, psychiatric disorder, or cognitive impairment that, in the investigator's judgment, would affect informed consent or protocol adherence.
• 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.
• Active infection requiring long-term systemic therapy (e.g., antibiotics, antivirals, or antifungals).
• Active autoimmune disease, or requirement for long-term systemic immunosuppressive therapy or corticosteroids (at a dose equivalent to prednisone \> 10 mg/day).
• Known history of human immunodeficiency virus (HIV) infection, or active syphilis, or active pulmonary tuberculosis.
• Active hepatitis B (HBsAg positive and HBV DNA \> 200 IU/mL or \> 1000 copies/mL) or active hepatitis C (HCV RNA positive).
• 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).

Sponsors & Collaborators

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

Study Sites (1)

Guangdong Provincial People's Hospital

Guangzhou, Guangdong, 510080, China

Location

MeSH Terms

Interventions

Oxaliplatin; Capecitabine; sintilimab

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Central Study Contacts

Yong Li

CONTACT

13822177479; liyong@gdph.org.cn

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study. Masking is not feasible because tafolecimab is administered via subcutaneous injection as part of the experimental regimen, while the control group does not receive any subcutaneous injection.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2026
• First Posted: July 7, 2026
• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2035
• Last Updated: July 7, 2026

Record last verified: 2026-07

Locations

CN (1)