Neoadjuvant Therapy for Locally Advanced Low Rectal Cancer (SMARTi-RC01)

Official title

Neoadjuvant Chemoradiotherapy Combined With Serplulimab With or Without Bevacizumab for Locally Advanced Rectal Cancer: A Single-Center, Open-Label, Phase II Randomized Trial

Overview

The goal of this clinical trial is to learn if combining serplulimab (PD-1 inhibitor) with bevacizumab and short-course total neoadjuvant therapy (TNT) works to treat locally advanced mid-to-low rectal cancer in adults. It will also learn about the safety of this combination. The main questions it aims to answer are: Does adding bevacizumab to serplulimab and TNT increase the complete remission rate (cCR + pCR) compared with serplulimab and TNT alone? What medical problems do participants have when receiving these treatments? Researchers will compare: Experimental group: serplulimab + bevacizumab + chemotherapy + short-course radiotherapy Control group: serplulimab + chemotherapy + short-course radiotherapy Participants will: Receive either the experimental or control regimen for about 4-5 months before surgery or a watch-and-wait approach if complete response is achieved Undergo treatment in cycles that include chemotherapy, immunotherapy (and bevacizumab if in the experimental group), and short-course radiotherapy Visit the clinic regularly for check-ups, blood tests, imaging, endoscopy, and to monitor side effects Be followed for up to 5 years after treatment to assess cancer control, organ preservation, and survival outcomes

Interventions

• Drug Serplulimab
  Serplulimab 300 mg IV on Day 1
• Drug Bevacizumab
  Bevacizumab 5 mg/kg IV on Day 1
• Radiation Short-Course Radioterapy
  25 Gy in 5 fractions over 1 week
• Drug Chemotherapy (CAPOX or capecitabine)
  Capecitabine: 800 mg/m² orally, twice daily (BID), on Days 1-14 of each cycle Oxaliplatin: 130 mg/m² intravenous infusion, on Day 1 of each cycle

Primary outcome measures

• Complete Remission (CR) Rate assessed by pathology, MRI, endoscopy, and clinical examination [Time frame: At the time of surgery for pCR, and at 1 year after achieving cCR for sustained cCR]

Secondary outcome measures (7)

• Organ Preservation Rate (OPR) assessed by MRI, endoscopy, and clinical examination [Time frame: From the end of neoadjuvant therapy through 3 years of follow-up.]
• R0 Resection Rate confirmed by histopathology [Time frame: At the time of surgery.]
• Disease-Free Survival (DFS) measured by imaging and clinical follow-up [Time frame: Up to 5 years after randomization.]
• Overall Survival (OS) assessed by survival follow-up [Time frame: Time Frame: Up to 5 years after randomization.]
• Objective Response Rate (ORR) assessed by RECIST v1.1 [Time frame: During neoadjuvant therapy (baseline to pre-surgery evaluation).]
• Disease Control Rate (DCR) assessed by RECIST v1.1 [Time frame: During neoadjuvant therapy (baseline to pre-surgery evaluation).]
• Safety Outcomes assessed by NCI-CTCAE v5.0 [Time frame: From first dose to 90 days after last dose of study treatment.]

Eligibility criteria

Inclusion criteria

Participants must meet all of the following criteria to be eligible for the study:

• Age: 18 to 75 years old.
• Diagnosis: Pathologically confirmed rectal adenocarcinoma with proficient mismatch repair (pMMR) / microsatellite stable (MSS) status, based on biopsy of the primary tumor.
• Disease Stage: Untreated, preoperative clinical stage cT2-T4 and/or N+, M0 (AJCC 8th edition), unsuitable for initial local excision to achieve radical cure.
• Tumor Location: Tumor within 8 cm from the anal verge, or assessed by surgeons as not suitable for immediate sphincter-preserving surgery.
• Organ Preservation Intent: Strong desire for sphincter preservation and willingness to accept close surveillance for at least 2 years after chemoradiotherapy.
• Surgical Candidacy: Agrees to undergo radical surgery and judged by surgeon to have no contraindication to surgery.
• Cancer History: No concurrent multiple primary malignancies.
• Measurable Lesions: At least one measurable or evaluable lesion according to RECIST v1.1 criteria.
• Life Expectancy: ≥ 3 months.
• Performance Status: ECOG performance status score of 0-1.
• Compliance: Good compliance and willingness to sign written informed consent.

Exclusion criteria

Participants will be excluded if any of the following conditions apply:

• Molecular Subtype: Rectal cancer with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) status.
• Autoimmune Disease: Active, known, or suspected autoimmune disease.
• Immunodeficiency: Known history of primary immunodeficiency.
• Transplant History: History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Pregnancy or Lactation: Pregnant or breastfeeding women.
• Urgent Surgical Indications: Intestinal perforation, gastrointestinal bleeding, or other conditions requiring emergency surgery.
• Uncontrolled Comorbidities, including but not limited to:

HIV infection (HIV antibody positive) Active or poorly controlled severe infection Active hepatitis Severe or uncontrolled systemic diseases (e.g., severe psychiatric or neurological disorders, epilepsy, dementia, unstable or decompensated respiratory, cardiovascular, hepatic, or renal disease, uncontrolled hypertension ≥ CTCAE Grade 2 despite medication) Active bleeding or recent thrombotic disease requiring therapeutic anticoagulation, or bleeding tendency, or coagulation abnormalities (INR > 1.5 × ULN, APTT > 1.5 × ULN)

• Laboratory Abnormalities at Baseline:

Hemoglobin < 80 g/L Absolute neutrophil count (ANC) < 1.5 × 10⁹/L Platelets < 80 × 10⁹/L ALT or AST > 2.5 × ULN ALP > 2.5 × ULN Total bilirubin ≥ 1.5 × ULN Serum creatinine ≥ 1 × ULN

• Allergy: Known hypersensitivity to any component of the investigational drugs.
• Other Clinical Trial Participation: Currently enrolled in another interventional drug clinical trial.
• Other Conditions: Any other condition judged by the investigator to make the patient unsuitable for the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07134101 · 2025-SR-610

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗