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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Rectal Neoplasms Malignant, Radiotherapy

Intervention / Treatment
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* Drug: Sintilimab
* Radiation: Short-course radiotherapy
* Combination Product: CAPOX/mFOLFOX


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iTNT group<br>The intervention of iTNT group is Short-course radiotherapy followed by neoadjuvant chemotherapy and PD-1 inhibitor, which consists of a short-course radiotherapy(SCRT, 5 Gy x 5 alone), then after 14 days of radiotherapy completed, four cycles of PD-1 inhibitor and four cycles of CAPOX or six cycles of mFOLFOX will be performed. The regimen of PD-1 inhibitor and CAPOX treatment includes Sintilimab 200 mg IV, day 1，Oxaliplatin 130 mg/m2 IV day 1，Capecitabine 1000 mg/m2 twice daily PO for 14 days(3 weeks per cycle). The regimen of PD-1 inhibitor and mFOLFOX treatment includes Sintilimab 200 mg IV day 1(3 weeks per cycle), Oxaliplatin 85 mg/m2 IV day 1, Leucovorin 400 mg/m2 IV day 1, 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) IV continuous infusion(2 weeks per cycle), then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients. | Drug: Sintilimab<br>* PD-1 inhibitor<br>* Other names: Immune checkpoint inhibitor;Radiation: Short-course radiotherapy<br>* Pelvic radiation<br>* Other names: hypofraction;Combination Product: CAPOX/mFOLFOX<br>* chemotherapy regimen<br>* Other names: neoadjuvant chemotherapy;|
| Active Comparator: TNT group<br>The intervention of TNT group is Short-course radiotherapy followed by neoadjuvant chemotherapy, which consists of a short-course radiotherapy(SCRT, 5 Gy x 5 alone), then after 14 days of radiotherapy completed, four cycles of CAPOX or six cycles of mFOLFOX will be performed. The regimen of CAPOX treatment includes Oxaliplatin 130 mg/m2 IV day 1，Capecitabine 1000 mg/m2 twice daily PO for 14 days(3 weeks per cycle). The regimen of mFOLFOX treatment includes, Oxaliplatin 85 mg/m2 IV day 1, Leucovorin 400 mg/m2 IV day 1, 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) IV continuous infusion(2 weeks per cycle), then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients. | Radiation: Short-course radiotherapy<br>* Pelvic radiation<br>* Other names: hypofraction;Combination Product: CAPOX/mFOLFOX<br>* chemotherapy regimen<br>* Other names: neoadjuvant chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete remission | The rate of pathological complete remission plus clinical complete remission | one year | 
| Disease-free survival rate |  | three year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute toxicities during radiation, chemotherapy ± immunotherapy |  | three months | 
| Incidence of surgical complications |  | 30 days | 
| Overall survival rate |  | three year | 
| Locoregional recurrence rate |  | three year | 
| Distance metastasis rate |  | three year | 
| Radical resection (R0) |  | one year | 
| Quality of life (QoL) | Quality of life will be evaluated using EORTC QLQ-C30 (range 0-100). It evaluates the quality of life from 30 aspects, including appetite, mental status, sleep quality, fatigue, etc. The higher scores mean a better quality of life. | From date of randomization until the date of death from any cause, assessed up to 10 years | 
| Quality of life (QoL) | Quality of life will be evaluated using EORTC QLQ-Cr29 (range 0-100). It evaluates the quality of life from 29 aspects, including defecation function, urine function，pain, sex function, etc. The higher scores mean a better quality of life. | From date of randomization until the date of death from any cause, assessed up to 10 years | 
| Quality of life (QoL) | Quality of life will be evaluated using Wexner score(range 0-20). It evaluates the defecation function. The lower scores mean a better quality of life. | From date of randomization until the date of death from any cause, assessed up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, short-course radiotherapy, total neoadjuvant therapy, PD-1 inhibitor