Neoadjuvant Chemoradiotherapy Plus Sintilimab for Intermediate/High Immunoscore Locally Advanced Rectal Cancer

Official title

Neoadjuvant Chemoradiotherapy Plus Sintilimab for Intermediate/High Immunoscore Locally Advanced Rectal Cancer: A Single-Center, Open-Label, Single-Arm, Phase 2 Trial

Overview

Immunoscore has been reported to be superior to microsatellite instability staging in predicting the disease-specific recurrence and survival for patients with colorectal cancer. However, the relationship between Immunoscore and its impact on patient's response to PD-1 blockade remains to be elucidated. This phase II, prospective, open label study is designed to evaluate the efficacy and safety of combination neoadjuvant chemoradiotherapy (nCRT) with the anti-PD-1 antibody sintilimab for intermediate/high Immunoscore locally advanced rectal cancer.

Detailed description

This study investigates the safety, tolerability, and feasibility of sintilimab, an immunotherapy agent, in combination with nCRT for treatment of patients with intermediate/high Immunoscore locally advanced rectal cancer. Sintilimab is an anti-PD-1 inhibitor that works by enhancing the functional activity of the target immune cells to facilitate tumor regression and ultimately immune rejection.

Interventions

• Drug Sintilimab
  6 cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) followed by long course chemoradiotherapy (50 Gy in 25 fractions) followed by surgery. Patients will receive sintilimab 3mg/kg every 2 weeks during chemoradiotherapy (2nd-6th cycle).

Primary outcome measures

• Pathological complete response [Time frame: 1 month after surgery]

Secondary outcome measures (8)

• Margin-free (R0) resection rate [Time frame: Immediately after the surgery]
• 3-year event-free survival rate [Time frame: 3 years after the surgery]
• 3-year overall survival rate [Time frame: 3 years after the surgery]
• Local recurrence [Time frame: 3 years after the surgery]
• Tumor downstaging [Time frame: during the 3-year period of follow-up]
• Tumor regression grade [Time frame: during the 3-year period of follow-up]
• Number of participants with surgical complications [Time frame: 30 days after surgery]
• Correlation between minimal residual disease (MRD) and survival [Time frame: 3 years after the surgery]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years and ≤75 years.
• Willing and able to provide written informed consent for participation in this study.
• Treatment-naive patients with histological or cytological documentation of rectal adenocarcinoma (<12 cm from the anal verge).
• Clinical stage of T3/T4 or N positive and M0, before nCRT.
• Non complicated primary tumor (complete obstruction, perforation, bleeding).
• Subjects with an intermediate or high immunoscore (according to Immunoscore®).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Women of childbearing potential who consent to practicing contraception during the period from giving informed consent to at least 23 weeks after the last dose of therapy.
• Women of childbearing potential with a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.
• Subjects with normal organ and marrow function as defined below:

Leukocytes ≥ 3,000/k/uL; Absolute neutrophil count ≥ 1,500/k/uL; Platelet count ≥ 100,000/k/uL; Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); AST (SGOT) ≤ 2.5 x institutional upper limit of normal (ULN); ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN); Serum creatinine ≤ 1.5 x institute upper limit of normal (ULN).

Exclusion criteria

• Subjects with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer.
• Subjects with a history of any arterial thrombotic event within the past 6 months. This includes angina (stable or unstable), myocardial infarction (MI), Transient Ischemic Attacks (TIA), or cerebralvascular accident (CVA).
• Subjects with active lung disease (such as interstitial pneumonia, pneumonia, obstructive pulmonary disease, asthma) or active tuberculosis.
• Subjects with any uncontrollable clinical problems, including but not limited to: active autoimmune disease, uncontrolled diabetes, uncontrolled hypertension, heart failure grade III/IV (NYHA-classification), or persistent or severe infection.
• Subjects with a history of anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy.
• Subjects with known allergy to the study drugs or to any of its excipients.
• Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
• Breast- feeding or pregnant women.
• Subjects with significant unstable mental diseases or other medical diseases that may interfere with the safety of the subjects, obtaining informed consent, or compliance with the procedures for the clinical 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

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Department of colorectal surgery, the Sixth Affiliated Hospital, Sun Yat-Sen University — Guangzhou

Identifiers

NCT: NCT05450029 · GIHSYSU-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗