Short-course Radiotherapy Based TNT Combined With PD-1 Inhibitor for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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TORCH is a prospective, multicentre, randomized phase II trial. 130 LARC (T3-4/N+M0, distance from anal verge ≤12cm) patients will be treated with total neoadjuvant therapy (TNT) and assigned to Group A and Group B. Group A receives SCRT (25Gy/5Fx) followed by 6 cycles of Toripalimab combined with CAPOX (ToriCAPOX). Group B receives 2 cycles of ToriCAPOX followed by SCRT and 4 cycles of ToriCAPOX. TME surgery is scheduled after TNT while a watch and wait (W&W) option can be applied to patients achieving clinical complete response (cCR). The primary endpoint is complete response (CR, pathological complete response [pCR] plus cCR) rate. The secondary endpoints include the grade 3-4 acute adverse effects (AE) rate, 3-year DFS rate, etc.

Official Title
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A Prospective Phase II Trial of Short-course Radiotherapy Based Total Neoadjuvant Therapy Combined With PD-1 Inhibitor for Locally Advanced Rectal Cancer (TORCH）

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: PD-1 antibody
* Drug: Capecitabine
* Drug: Oxaliplatin
* Radiation: Short-course radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological confrmed adenocarcinoma Clinical stage T3-4 and/or N+ The distance from anal verge ≤12 cm Without distance metastases Age 18-70 years old, female and male KPS > =70 Baseline blood and biochemical indicators meet the following criteria: neutrophils≥1.5×10^9/L, Hb≥90 g/L, PLT≥100×10^9/L, ALT/AST≤2.5 ULN, Cr≤1 ULN With good compliance and signed the consent form Exclusion Criteria: Pregnancy or breast-feeding women Known history of other malignancies within 5 years Known history of previous anti-tumor treatment, including radiotherapy, chemotherapy, immune checkpoint inhibitors, T cell-related therapy, etc Known history of severe neurological or mental illness (such as schizophrenia, dementia or epilepsy) Current severe cardiac disease (cardiac dysfunction and arrhythmia), renal dysfunction and liver dysfunction Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment Uncontrolled infection which needs systemic therapy Active autoimmune disease or immunodefciencies, known history of organ transplantation or systematic use of immunosuppressive agents Known history of human immunodefciency virus (HIV) infection (i.e., HIV 1 to 2 antibody positive), active syphilis infection, active pulmonary tuberculosis infection Active Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (i.e., HBsAg positive or HBV DNA positive, HCV RNA positive if anti-HCV antibody testing positive) Allergic to any component of the therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Group A<br>The patients will receive short-course radiotherapy (25Gy/5Fx), followed by 6 cycles of CAPOX and PD-1 antibody. TME surgery is scheduled after TNT while a W&W option can be applied to patients achieving cCR. | Drug: PD-1 antibody<br>* PD-1 antibody (Toripalimab): 240mg d1 q3w<br>* Other names: Toripalimab;Drug: Capecitabine<br>* Capecitabine: 1000mg/m2 bid d1-14 q3w<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* Oxaliplatin: 130mg/m2 d1 q3w<br>Radiation: Short-course radiotherapy<br>* Shor-course radiotherapy: 25Gy/5Fx<br>|
| Experimental: Group B<br>The patients will firstly receive 2 cycles of CAPOX and PD-1 antibody, then receive short-course radiotherapy (25Gy/5Fx), followed by 4 cycles of CAPOX and PD-1 antibody. TME surgery is scheduled after TNT while a W&W option can be applied to patients achieving cCR. | Drug: PD-1 antibody<br>* PD-1 antibody (Toripalimab): 240mg d1 q3w<br>* Other names: Toripalimab;Drug: Capecitabine<br>* Capecitabine: 1000mg/m2 bid d1-14 q3w<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* Oxaliplatin: 130mg/m2 d1 q3w<br>Radiation: Short-course radiotherapy<br>* Shor-course radiotherapy: 25Gy/5Fx<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | Rate of complete response (CR), including the rate of pathologic complete response (pCR) after surgery and the rate of cCR with W&W strategy. | The status of cCR will be evaluated after the completion of neoadjuvant therapy. The pCR rate will be evaluated after surgery. The cCR patients who adopted W&W strategy will be included into the CR rate caluculation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3-4 adverse effects rate | Rate of chemotherapy, radiotherapy and immunotherapy related adverse events | From date of randomization until the date of death from any cause, assessed up to 5 years | 
| 3 year disease free survival rate | Rate of 3 year disease free survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 
| 3 year local recurrence free survival rate | Rate of 3 year local recurrence free survival | From date of randomization until the date of first documented pelvic failure, assessed up to 36 months. | 
| 3 year overall survival rate | Rate of 3 year overall survival | From date of randomization until the date of death from any cause, assessed up to 36 months. | 
| Rate of Surgical complications | Rate of surgical complications, such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc. | The surgery was scheduled 2-4 weeks after the end of neoadjuvant therapy. And the surgical complications were assessed up to 5 years from the surgery. | 
| Scores of Quality of Life | Quality of life will be evaluated using EORTC QLQ-C30, EORTC QLQ-CR29, LARS score and Wexner score. | From date of randomization until the date of death from any cause, assessed up to 10 years |