Neoadjuvant Long-course Chemoradiation Plus PD-1 Blockade for Mid-low Locally Advanced Rectal Cancer
- Conditions
- Locally Advanced Rectal Cancer
- Interventions
- Combination Product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)
- Registration Number
- NCT05245474
- Lead Sponsor
- Beijing Friendship Hospital
- Brief Summary
This is a phase II/III, multi-center, open-label, 3-arm, randomized controlled trial assessing the efficacy and safety of neoadjuvant long-course chemoradiation combined with Tislelizumab (PD-1 inhibitor) and subsequent TME surgery, by comparing assorted endpoints between two experiment groups (Experiment group 1: chemoradiation+concurrent PD-1 inhibitor; Experiment group 2: chemoradiation+sequential PD-1 inhibitor) with a control group (chemoradiation only).
- Detailed Description
This phase II, multi-center, open-label, 3-arm, randomized trial aims to recruit patients aged 18-75 years, diagnosed histologically as rectal adenocarcinoma, without metastasis (by CT), staged II/III (by MRI, T4b excluded), with distal margin within 10cm to anal verge. All patients should have no history of immune diseases, nor history of immunotherapy or radiotherapy. Sample size was thoroughly calculated to be 186. Eligible participants will be randomly assigned to Experiment Arm 1 (50.4Gy radiation, capecitabine, and anti-PD1 starting at Day 8 of radiation), Experiment Arm 2 (50.4Gy radiation, capecitabine, and anti-PD1 starting 2 weeks after completion of radiation), and Control Arm (50.4Gy radiation, capecitabine) in a 1:1:1 ratio. Randomization is stratified by different centers, with a block size of 6. For both experiment arms, Tislelizumab (anti-PD1) is scheduled to be administered at 200mg each time for 3 times, with 3-week intervals. The primary endpoint is pCR rate, and secondary endpoints include sphincter-preserving rate, adverse event rates, and DFS and OS rate at 2, 3 and 5 years post-operation. Data will be analyzed with an intention-to-treat or modified intention-to-treat approach.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 186
- aged 18~75
- ECOG score 0~2
- biopsy diagnosed rectal adenocarcinoma, distal margin within 10cm to anal verge
- no distant metastasis, staged II/III (T4b excluded) by MRI
- maximum diameter of rectal cancer lesion≥10mm according to baseline CT or MRI (i.e. a "measurable lesion" as per RECIST 1.1 criteria)
- willing and able to comply with study protocol
- consent to the use of blood and tissue specimens for study
- no history of previous anti-tumor treatment (e.g. radiation, chemo, immuno, bio, herbal, etc.)
- no disorders/diseases of immune system (e.g. systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, hyperthyroidism/hypothyroidism, ulcerative colitis, autoimmune hemolytic anemia, HIV infection, etc.)
- no significant dysfunction of major viscera (e.g. heart, lung, liver, kidney, etc.)
- no jaundice or gastrointestinal obstruction
- no acute/ongoing infection
- no significant irregularities in blood routine test and biochemical test results, particular requirements include: neutrophils≥1.5×109/L, HGB≥80g/L, platelet≥100×109/L, serum creatinine≤1.5×ULN, total bilirubin≤1.5×ULN, ALT、AST≤2.5×ULN
- no social or mental disorder
- for women of child-bearing age, a negative result of serological pregnancy test is required, and effective contraception measures from inclusion till 60 days after the last dose of study drug is required
- multiple cancers, or with concomitant malignant tumors besides rectal cancer
- having received any anti-cancer treatment (surgery, drugs, etc.) in the past 5 years
- history of recent major surgery
- with condition that affects the absorption of capecitabine via gastrointestinal tract (e.g. inability to swallow, nausea, vomiting, chronic diarrhea, etc.)
- with uncontrolled, severe, concomitant diseases of any sort
- allergic to any of the ingredients under study
- estimated survival ≤ 5 years due to any reason
- preparing for or having previously received organ or bone marrow transplant
- having received immunosuppressive or systemic hormone therapy for immunosuppressive purposes within 1 month prior to inclusion
- for patients with history of disorder of central nervous system, investigator discretion is required as to whether the clinical severity prevents the signing of informed consent or affects the patient's oral medication compliance
- with other conditions/issues that may affect the study results or cause the study treatment to be terminated halfway (e.g. alcoholism, drug abuse, etc.)
- pregnant or lactating women, or women intending on conception during treatment period
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CRT+concurrent PD-1 inhibition (Experiment Arm 1) Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor) Long-course chemoradiation plus PD-1 inhibition (Tislelizumab 200mg, 3 times, 3-week interval) starting on Day 8 of radiation therapy. TME surgery is scheduled in 8\~12 weeks after completion of radiation. CRT without PD-1 inhibition (Control Arm) Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor) Long-course chemoradiation plus PD-1 inhibition with no PD-1 inhibition. TME surgery is scheduled in 6\~12 weeks after completion of radiation. CRT+sequential PD-1 inhibition (Experiment Arm 2) Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor) Long-course chemoradiation plus PD-1 inhibition (Tislelizumab 200mg, 3 times, 3-week interval) starting on Day 15 after completion of radiation therapy. TME surgery is scheduled in 8\~12 weeks after completion of radiation.
- Primary Outcome Measures
Name Time Method pCR rate within 10 days after surgery pathological complete response rate
- Secondary Outcome Measures
Name Time Method 5-y DFS rate 5 year 5-year disease free survival rate
3-y OS rate 3 year 3-year overall survival rate
NAR score within 10 days after surgery neoadjuvant rectal score
2-y OS rate 2 year 2-year overall survival rate
2-y DFS rate 2 year 2-year disease free survival rate
3-y DFS rate 3 year 3-year disease free survival rate
5-y OS rate 5 year 5-year overall survival rate
median DFS time 0~60 months median length (in months) of disease free survival period
immune-related adverse event rate from commencing of PD-1 inhibition to the 30th day after surgery adverse event rate that is deemed to be associated with PD-1 inhibition
Grade 3+ immune-related adverse event rate from commencing of PD-1 inhibition to the 30th day after surgery adverse event (above Grade 3) rate that is deemed to be associated with PD-1 inhibition
treatment-related adverse event rate from commencing of treatment to the 30th day after surgery adverse event rate that is deemed to be associated with all treatments
median OS time 0~60 months median length (in months) of overall survival period
R0 resection rate within 10 days after surgery rate of R0 resection
sphincter preserving rate instantly after surgery proportion of patients with preserved anal sphincter
nearly pCR rate within 10 days after surgery nearly pathological complete response rate
ORR before surgery objective response rate
Grade 3+ treatment-related adverse event rate from commencing of treatment to the 30th day after surgery adverse event (above Grade 3) rate that is deemed to be associated with all treatments
incidence rate of surgical complications within 30 days after surgery incidence rate of surgical complications within 30 days after surgery
quality of life score during the 5 years after surgery quality of life score during the 5 years after surgery, multiple timepoint assessment
cCR rate before surgery clinical complete response rate
incidence rate of Grade 3+ surgical complications within 30 days after surgery incidence rate of Grade 3+ surgical complications within 30 days after surgery
Trial Locations
- Locations (8)
Xuanwu Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Beijing Cancer Hospital
🇨🇳Beijing, Beijing, China
Beijing Chaoyang Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Beijing Hospital
🇨🇳Beijing, Beijing, China
Peking University People's Hospital
🇨🇳Beijing, Beijing, China
Beijing Friendship Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Peking Union Medical College Hospital
🇨🇳Beijing, Beijing, China
Peking University First Hospital
🇨🇳Beijing, Beijing, China