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.

Study Overview

• Status: Not yet recruiting
• Conditions: Radiotherapy; Rectal Neoplasms Malignant
• Intervention / Treatment: Drug: Sintilimab; Radiation: Short-course radiotherapy; Combination product: CAPOX/mFOLFOX

• Study Type: Interventional
• Enrollment (Anticipated): 588
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Wenjue Zhang; Phone Number: +86-13620986880; Email: wenjuezhang@163.com

Study Locations

• China
  • Shenzhen, China
    • National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Beijing
    • Beijing, Beijing, China
      • Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: iTNT group; 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; PD-1 inhibitor; Other Names: Immune checkpoint inhibitor; Radiation: Short-course radiotherapy; Pelvic radiation; Other Names: hypofraction; Combination product: CAPOX/mFOLFOX; chemotherapy regimen; Other Names: neoadjuvant chemotherapy
ACTIVE_COMPARATOR: TNT group; 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; Pelvic radiation; Other Names: hypofraction; Combination product: CAPOX/mFOLFOX; chemotherapy regimen; Other Names: neoadjuvant chemotherapy

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rate		three year
Incidence of acute toxicities during radiation, chemotherapy ± immunotherapy		three months
Incidence of surgical complications		30 days
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

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): August 6, 2022
• Primary Completion (ANTICIPATED): July 31, 2028
• Study Completion (ANTICIPATED): July 31, 2030

Study Registration Dates

• First Submitted: July 21, 2022
• First Submitted That Met QC Criteria: July 29, 2022
• First Posted (ACTUAL): August 2, 2022

Study Record Updates

• Last Update Posted (ACTUAL): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 29, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: rectal cancer; PD-1 inhibitor; short-course radiotherapy; total neoadjuvant therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immune Checkpoint Inhibitors
• Other Study ID Numbers: NCC22/206-3408

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