Neoadjuvant Short-course Radiotherapy Followed by the Combination of Immunotherapy and Chemotherapy in Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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This is a single arm, open-label, prospective phase II clinical trial to evaluate the combination of neoadjuvant short-course radiotherapy and immunotherapy (PD-1 antibody) for patients with locally advanced rectal cancer (LARC). A total of 40 patients will be enrolled in this trial to receive 5*5Gy short-course radiotherapy, followed by 4 cycles of CAPOX chemotherapy and PD-1 antibody. Then they will receive the TME surgery and another 4 cycles of CAPOX chemotherapy. There are two cohorts according to the microsatellite instability status: (1) the micro-satellite stable (MSS) cohort（n=32), (2) the MSI-high cohort (n=8). The primary end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.

Official Title
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The Combination of Neoadjuvant Short-course Radiotherapy and Immunotherapy in Locally Advanced Rectal Cancer：A Open-label Single-arm Phase II Trial.

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: PD-1 antibody
* Drug: Capecitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Pathological confirmed rectal adenocarcinoma and the distance from anal verge less than 12 cm; 2. Clinical stage T3-4 and/or N+ (AJCC 8th); 3. No distant metastases; 4. Age 18-70 years old, female and male; 5. ECOG 0-1; 6. No previous chemotherapy, radiotherapy, immunotherapy or other anti-tumor treatment; 7. Adequate organ function defined at baseline as: ANC ≥1.5×109 /L，PLt ≥75×109 /L，Hb ≥90 g/L; TBIL ≤1.5×ULN, ALT ≤2.5ULN, AST ≤2.5ULN, BUN and Cr ≤1×ULN or Ccr ≥50ml/min (Cockcroft-Gault formula); INR ≤1.5×ULN or PT ≤1.5×ULN (If the patient is receiving anticoagulant therapy, PT should be within the intended use range of the anticoagulant drug); 8. With good compliance and no serious comorbidity; 9. Women of childbearing age must have taken reliable contraceptive measures or have a pregnancy test (serum or urine) within 7 days prior to enrollment and the results are negative; 10. Subject volunteers to join the study, sign the informed consent. Exclusion Criteria: 1. History of other uncured malignancies within 5 years. Cured tumor with good prognosis, such as skin basal cell carcinoma, cervical cancer and superficial bladder cancer, will be excluded; 2. Have received surgery within 4 weeks before the enrollment; 3. History of obstruction within 6 months before the enrollment; 4. History of active autoimmune disease, interstitial lung disease, epilepsy and dysphrenia; 5. With uncontrolled cardiovascular disease: active coronary heart disease; grade III-IV cardiac insufficiency according to the NYHA criteria; and myocardial infarction within 1 year; 6. With active infection or fever of >38.5 ℃ with unknown cause (tumor-induced fever judged could be enrolled); 7. DPD deficiency; 8. Allergic to any component of chemotherapy or immunotherapy; 9. With congenital or acquired immunodeficiency (such as those with HIV infection), active hepatitis B or hepatitis C; 10. Usage of corticosteroids (prednison dose of > 10 mg/day) or other immunosuppressors for systemic treatment within the first 14 days of research; 11. Receive attenuated live vaccine within 4 weeks before the research; 12. Pregnant women or breast-feeding women; 13. With other factors that would force to terminate the clinical trial ahead of time, such as the development of other severe comorbidity that required combined treatment, and family or social factors affecting the safety of patients or experimental data collection, as judged by the researchers.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant short-course radiotherapy+immunotherapy+chemotherapy<br>A total of 40 patients receive 5*5Gy short-course radiotherapy, followed by 4 cycles of CAPOX chemotherapy and PD-1 antibody, finally receive the TME surgery and another 4 cycles of CAPOX chemotherapy. Interventions: Shor-course radiotherapy: 25Gy/5Fx; Induction immunotherapy: Sintilimab 200mg ivgtt d1 q3w x 4 cycles; Concurrent Chemotherapy: Oxaliplatin: 130mg/m2 d1 q3w + Capecitabine: 1000mg/m2 d1-14 q3w x 4 cycles; | Drug: PD-1 antibody<br>* Sintilimab is a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor. Usage: 200mg ivgtt d1 q3w.<br>* Other names: Sintilimab;Drug: Capecitabine<br>* Usage: 1000mg/m2 d1-14 q3w<br>Drug: Oxaliplatin<br>* Usage: 130mg/m2 d1 q3w<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rate | Pathologic complete response rate | The TME surgery will be recommended at 1 week after the neoadjuvant therapy. The pCR rate is evaluated after surgery. Assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year DFS | 3-year disease free survival rate | Assessed up to 3 years | 
| 3-year local recurrence rate | 3-year local recurrence rate | Assessed up to 3 years | 
| 3-year OS | 3-year overall survival rate | Assessed up to 3 years | 
| Grade 3-4 adverse effects rate | Radiotherapy, immunotherapy and chemotherapy related grade 3-4 adverse events rate | Assessed up to 3 years | 
| Surgical complications | Type and Rate of surgical complications | Assessed up to 3 years from the TME surgery | 
| Quality of Life Scale | The Quality of Life Scale (QoLS, range 0-60) will be used to evaluate the quality of life. Higher scores mean the better quality of life | Assessed up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant short-course radiotherapy, Immunotherapy, Locally advanced rectal cancer, Pathological complete response