PCSK9 Inhibitor and PD-1 Inhibitor Combined With Neoadjuvant Chemoradiotherapy for pMMR/MSS Locally Advanced Rectal Cancer

Clinical Study of PCSK9 Inhibitor and PD-1 Inhibitor Combined With Neoadjuvant Chemoradiotherapy in the Treatment of pMMR/MSS Locally Advanced Rectal Cancer

This is a single-center, open-label, single-arm clinical study aimed at conducting a preliminary evaluation of the efficacy and safety of combining PCSK9 inhibitors and PD-1 inhibitors (dual inhibitors) with neoadjuvant chemoradiotherapy in patients with pMMR/MSS locally advanced rectal cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Locally Advanced Rectal Cancer (LARC)
• Intervention / Treatment: Drug: Neoadjuvant Chemoradiotherapy Combined with PD-1 inhibitor Immunotherapy and PCSK9 Inhibitor Therapy

Detailed Description

This study aims to evaluate the complete response (CR) rate of PCSK9 inhibitor and PD-1 inhibitor combination therapy (dual inhibitors) in conjunction with neoadjuvant chemoradiotherapy for patients with pMMR/MSS locally advanced rectal cancer. Specifically, the study will assess the pathological complete response (pCR) rate two weeks after neoadjuvant therapy, the clinical complete response (cCR) rate under the "watch-and-wait" strategy, objective response rate (ORR), R0 resection rate, tumor regression grade (TRG), and sphincter preservation rate. Additionally, the study will evaluate the 2-year disease-free survival (DFS) and overall survival (OS) following dual-inhibitor combined neoadjuvant chemoradiotherapy. The safety and tolerability of this combination therapy will also be comprehensively assessed based on NCI-CTCAE 4.03 criteria.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial People's Hospital
    • Guangzhou, Guangdong, China
      • No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age between 18 and 75 years, regardless of gender;
2. Histologically confirmed pMMR/MSS rectal adenocarcinoma, with clinical staging of cT3/T4 or cN+, and tumor located ≤12 cm from the anal verge;
3. No distant metastasis;
4. ECOG performance status of 0-1;
5. Baseline hematological and biochemical parameters meet the following criteria: neutrophils ≥1.5×10^9/L, hemoglobin ≥90 g/L, platelets ≥100×10^9/L, ALT/AST ≤2.5 ULN, creatinine ≤1 ULN;
6. Good compliance and willingness to sign an informed consent form.

Exclusion Criteria:

1. History of allergies to PCSK9 monoclonal antibody, PD-1 monoclonal antibody, capecitabine, or oxaliplatin;
2. Preoperative pathological diagnosis of non-pMMR/MSS rectal adenocarcinoma;
3. Use of other long-term lipid-lowering drugs leading to conditions such as hypolipidemia;
4. Pregnant or breastfeeding women;
5. History of other malignancies within the past 5 years;
6. Previous history of anti-tumor treatments, including radiotherapy, chemotherapy, immune checkpoint inhibitors, T-cell related therapies, etc.;
7. History of severe neurological or psychiatric disorders (e.g., schizophrenia, dementia, or epilepsy);
8. Current severe cardiovascular disease (heart failure or arrhythmia), renal insufficiency, or liver dysfunction; Note: Whether the patient can tolerate the specific treatment or measures should be assessed by a cardiologist based on the patient's condition.
9. Acute myocardial infarction or ischemic stroke within 6 months prior to enrollment;
10. Presence of uncontrolled infections requiring systemic treatment;
11. Active autoimmune diseases or immunodeficiencies, a history of organ transplantation, or systemic use of immunosuppressive agents;
12. Known history of HIV infection (e.g., HIV 1-2 antibody positive), active syphilis, or active pulmonary tuberculosis;
13. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection during screening (e.g., HBsAg positive, HBV DNA positive, HCV RNA positive, or anti-HCV antibody positive);
14. Known allergy to any component of the treatment;
15. Investigator's judgment that other factors exist which may cause early termination of the trial, such as severe disease (including psychiatric disorders), alcohol abuse, drug use, or social or familial factors affecting patient safety or compliance;
16. History of hypocholesterolemia (total cholesterol [TC] <3.6 mmol/L or <140 mg/dL, low-density lipoprotein cholesterol [LDL-C] <1.8 mmol/L or <70 mg/dL, high-density lipoprotein cholesterol [HDL-C] <1.0 mmol/L [male] or <1.3 mmol/L [female]), hypolipidemia (triglycerides [TG] <0.5 mmol/L or <45 mg/dL), or a family history of these conditions.

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: Neoadjuvant Chemoradiotherapy Combined with Immunotherapy and PCSK9 inhibitor Treatment; Building on short-term radiotherapy combined with chemotherapy, the treatment integrates PD-1 inhibitor immunotherapy and PCSK9 inhibitor therapy.

Drug: Neoadjuvant Chemoradiotherapy Combined with PD-1 inhibitor Immunotherapy and PCSK9 Inhibitor Therapy; Neoadjuvant Treatment 1.1 Short-Course Radiotherapy (SCRT) Total Dose: 25 Gy in 5 fractions over 5 days. Interval: 1-week rest before the next stage. 1.2 Chemotherapy and Immunotherapy Regimen: Start 1 week after SCRT with 6 cycles of CAPOX chemotherapy combined with PD-1 inhibitor immunotherapy (3 weeks per cycle).1.3 PCSK9 Inhibitor Administration: Subcutaneous injection every 4 weeks during neoadjuvant therapy (6 cycles total).; Multidisciplinary Team (MDT) Discussion Timing: 2 weeks after completing neoadjuvant therapy. Approach: Patients achieving clinical complete response (cCR): "Watch-and-wait" strategy. Others: Surgery based on MDT evaluation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR	complete response rate=(number of pathological complete responses + number of clinical complete responses)/total number of patients	pCR :within 2 weeks after surgery; cCR :2 weeks after radiotherapy ends
AE rate	Adverse event rate	During neoadjuvant chemoradiotherapy combined with immunotherapy, an average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OPR	organ preservation rate	immediately after surgery
DFS	Disease-free survival	5 years
OS	Overall survival time	5 years
ORR	objective response rate	within 2 weeks after surgery
TRG	Tumor regression grade	At the time of postoperative pathological assessment (within 1 week after surgery)

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital

Publications and helpful links

General Publications

• Liu X, Bao X, Hu M, Chang H, Jiao M, Cheng J, Xie L, Huang Q, Li F, Li CY. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020 Dec;588(7839):693-698. doi: 10.1038/s41586-020-2911-7. Epub 2020 Nov 11.
• Yuan J, Cai T, Zheng X, Ren Y, Qi J, Lu X, Chen H, Lin H, Chen Z, Liu M, He S, Chen Q, Feng S, Wu Y, Zhang Z, Ding Y, Yang W. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell. 2021 Apr;12(4):240-260. doi: 10.1007/s13238-021-00821-2. Epub 2021 Feb 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2025
• Primary Completion (Estimated): February 28, 2030
• Study Completion (Estimated): February 28, 2030

Study Registration Dates

• First Submitted: March 6, 2025
• First Submitted That Met QC Criteria: April 11, 2025
• First Posted (Actual): April 18, 2025

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: PD-1 inhibitor; neoadjuvant chemoradiotherapy; PCSK9 inhibitor; pMMR/MSS
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Antimetabolites; Serine Proteinase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Immune Checkpoint Inhibitors; PCSK9 Inhibitors
• Other Study ID Numbers: lron-Man 03

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