Short-course Radiotherapy Followed by Chemotherapy and PD-1 Inhibitor for Locally Advanced Rectal Cancer

Preoperative Short-course Radiotherapy Followed by Chemotherapy With or Without PD-1 Inhibitor for Locally Advanced Rectal Cancer: a Prospective, Multicenter, Randomized Controlled, Phase II/III Study (STELLAR II Study)

This phase II/III trial studies how well neoadjuvant short-course radiotherapy and chemotherapy with or without PD-1 inhibitors works in treating patients with locally advanced rectal adenocarcinoma. Neoadjuvant short-course radiation therapy followed by two-drug regimen chemotherapy, such as CAPOX, were shown to be non-inferior to standard long-course chemoradiotherapy in our previous STELLAR study. Immune checkpoint inhibitors (ICIs) using monoclonal antibodies, such as PD-1 or PD-L1 inhibitor, show promising efficiency and reliable security in some limited sample prospective or retrospective studies. When treating patients with locally advanced rectal cancer, giving sequential neoadjuvant short-course radiotherapy and chemotherapy with PD-1 inhibitor may work better.

Inclusion Criteria:

• Biopsy proven rectal adenocarcinoma;

• Distance between tumour and anal verge≤ 10cm;

• Locally advanced tumour;(8th edition AJCC/UICC staging :cT3-T4N0/cT2-4N+，M0) Cancer Staging must be based on pelvic MRI or Endoscopic ultrasound;

• Eastern Cooperative Oncology Group(ECOG) performance score ≤ 1;

• Mentally and physically fit for chemotherapy; Adequate blood counts: White blood cell count ≥3.5 x 109/L Haemoglobin levels ≥100g/L Platelet count ≥100 x 109/L Creatinine levels ≤1.0× upper normal limit（UNL） Urea nitrogen levels ≤1.0× upper normal limit（UNL） Alanine aminotransferase(ALT) ≤1.5× upper normal limit（UNL） Aspartate aminotransferase(AST) ≤1.5× upper normal limit（UNL） Alkaline phosphatase(ALP) ≤1.5× upper normal limit（UNL） Total bilirubin(TBIL)

  ≤1.5× upper normal limit（UNL）

• No excision of tumor, chemotherapy or other anti-tumor treatment after the diagnosis.

• No previous pelvic radiation history；

• Written informed consent;

Exclusion Criteria:

• Previous treatment with anti-PD-1/L1 and anti-CTLA-4 or other immune experimental drugs.
• Severe autoimmune disease: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener's granulomatosis)
• Symptomatic interstitial lung disease or active infectious/non-infectious pneumonia.
• At risk for bowel perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer or other known risk factors for bowel perforation.
• history of other malignancies, excluding curable non-melanotic skin cancer and cervix carcinoma in situ；
• Active infection, heart failure, heart attack within 6 months, unstable angina or unstable arrhythmia.
• Any condition investigator considered may interfere with the results or place the patient at increased risk of treatment complications, or other uncontrollable disease.
• Pregnancy or breast feeding
• Immunodeficiency disorders including human immunodeficiency virus (HIV), or history of organ transplantation, allogeneic stem cell transplantation
• Active hepatitis B virus (HBV) hepatitis (HBV-DNA ≥ 2000 U/mL), hepatitis C virus (HCV) hepatitis, active tuberculosis infection.
• Oncology vaccination history or any vaccination within 4 weeks prior to the start of treatment.(Note: influenza vaccines are mostly inactivated and therefore allowed, intranasal preparations are usually live attenuated vaccines and therefore not allowed)
• Concomitant other immune agents, chemotherapeutic agents, other drugs in clinical studies, and long term cortisol application