Neoadjuvant Long-course Chemoradiation Plus PD-1 Blockade for Mid-low Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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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
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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 approach.

Official Title
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Efficacy and Safety of Neoadjuvant Long-course Chemoradiation Plus Tislelizumab in Mid-low Locally Advanced Rectal Cancer: a Phase II, Multi-center, Open-label, Randomized Controlled Trial (POLARSTAR Trial)

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Combination Product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

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: CRT+concurrent PD-1 inhibition (Experiment Arm 1)<br>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. | Combination Product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)<br>* Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3<br>|
| Experimental: CRT+sequential PD-1 inhibition (Experiment Arm 2)<br>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. | Combination Product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)<br>* Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3<br>|
| Active Comparator: CRT without PD-1 inhibition (Control Arm)<br>Long-course chemoradiation plus PD-1 inhibition with no PD-1 inhibition. TME surgery is scheduled in 6 12 weeks after completion of radiation. | Combination Product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)<br>* Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rate | pathological complete response rate | within 10 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAR score | neoadjuvant rectal score | within 10 days after surgery | 
| 2-y OS rate | 2-year overall survival rate | 2 year | 
| 2-y DFS rate | 2-year disease free survival rate | 2 year | 
| 3-y OS rate | 3-year overall survival rate | 3 year | 
| 3-y DFS rate | 3-year disease free survival rate | 3 year | 
| 5-y OS rate | 5-year overall survival rate | 5 year | 
| 5-y DFS rate | 5-year disease free survival rate | 5 year | 
| median OS time | median length (in months) of overall survival period | 0 60 months | 
| median DFS time | median length (in months) of disease free survival period | 0 60 months | 
| R0 resection rate | rate of R0 resection | within 10 days after surgery | 
| sphincter preserving rate | proportion of patients with preserved anal sphincter | instantly after surgery | 
| nearly pCR rate | nearly pathological complete response rate | within 10 days after surgery | 
| ORR | objective response rate | before surgery | 
| immune-related adverse event rate | adverse event rate that is deemed to be associated with PD-1 inhibition | from commencing of PD-1 inhibition to the 30th day after surgery | 
| Grade 3+ immune-related adverse event rate | adverse event (above Grade 3) rate that is deemed to be associated with PD-1 inhibition | from commencing of PD-1 inhibition to the 30th day after surgery | 
| treatment-related adverse event rate | adverse event rate that is deemed to be associated with all treatments | from commencing of treatment to the 30th day after surgery | 
| Grade 3+ treatment-related adverse event rate | adverse event (above Grade 3) rate that is deemed to be associated with all treatments | from commencing of treatment to the 30th day after surgery | 
| cCR rate | clinical complete response rate | before surgery | 
| incidence rate of surgical complications | incidence rate of surgical complications within 30 days after surgery | within 30 days after surgery | 
| incidence rate of Grade 3+ surgical complications | incidence rate of Grade 3+ surgical complications within 30 days after surgery | within 30 days after surgery | 
| quality of life score | quality of life score during the 5 years after surgery, multiple timepoint assessment | during the 5 years after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LARC, radiation, chemoradiation, PD-1, Tislelizumab, neoadjuvant, randomized, controlled