Assess the Efficacy of Radiotherapy and Sequential Chemotherapy and AK104 Before TME Surgery for Local CRC（AK104-IIT-13）

Study Overview
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Brief Summary
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This study is a single-arm, open-label, multicenter clinical study to evaluate the efficacy and safety of preoperative short-course radiotherapy combined with AK104 and chemotherapy + TME surgery in patients with advanced rectal cancer.

Detailed Description
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Studies included a screening period (no more than 28 days after participants signed informed consent form to 28 days before first dose), treatment (receiving appropriate treatment until disease progression, intolerable toxicity, withdrawal of informed consent, death or study end, whichever occurs first), and follow-up (including safety follow-up and survival follow-up). Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed). Patients are not recommended to enter the organ preservation observation; If the efficacy after preoperative chemoradiotherapy is evaluated as clinical complete remission (cCR) and the patient strongly refuses surgery, the patient should be informed of the risk of recurrence and ask the patient to sign a rejection of surgery. Medication safety is assessed and, depending on the severity of adverse events (AEs) and drug relevance, investigators will take steps to ensure subject safety. After surgery (or patients who strongly refuse surgery) there is a 30- and 90-day safety follow-up, and survival assessments are performed every 3 months to obtain survival information and collect new tumor treatment information until the death of the participant, withdrawal of informed consent, or the end of the study, whichever occurs first.

Official Title
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A Single-arm, Multicenter, Phase II Study Evaluating the Efficacy and Safety of Preoperative Short-course Radiotherapy Followed by Sequential Chemotherapy and AK104 for Locally Advanced Rectal Cancer

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: AK104 injection
* Procedure: TME surgery
* Drug: Capecitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age 18-75 years old, gender is not limited; 2. Stage II/III under MRI or endoscopic ultrasound ; 3. Fiber colonoscopy or diagnosis examination, the lower boundary of the lesion is 15m ≤ from the margin; 4. Rectal adenocarcinoma confirmed or revisited by pathology; 5. Karl Fischer score ≥ 80 points or ECOG score of 0-1; 6. Meet the following laboratory diagnostic indicators: hemoglobin ≥ 100g/L, white blood cell ≥ 3.5×109/L; neutrophils≥ 1.5×109/L, platelet ≥ 100×109/L; creatinine ≤ 1.0× upper limit of normal (UNL), urea nitrogen (BUN) ≤ 1.0× upper limit of normal (UNL); Alanine aminotransferase (ALT) ≤1.5× upper limit of normal (UNL); Aspartate aminotransferase (AST) ≤1.5× upper limit of normal (UNL); Alkaline phosphatase (ALP) ≤1.5× upper limit of normal (UNL); Total bilirubin (TBIL) ≤ 1.5× upper limit of normal (UNL); urine protein (-); Clotting time is normal. 7. No history of allergy to 5-Fu drugs, no history of allergy to platinum drugs; 8. With primary rectal cancer required to undergo surgery (except palliative ostomy), chemotherapy or other anti-tumor therapy before diagnosis to enrollment; 9. Not received radiation before; 10. Sign the informed consent form. Exclusion Criteria: 1. Previous anti-PD-1/L1 and anti-CTLA-4 immune drugs or other immunoassay drugs; 2. With severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener's granulomatosis), etc.; 3. Symptomatic interstitial lung disease or active infection/non-infectious pneumonia; 4. Patients have risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer or other known risk factors for intestinal perforation; 5. History of other malignant tumors, excluding curable non-melanogenic skin cancer and carcinoma in situ of the cervix; 6. Active infection, heart failure, myocardial infarction, unstable angina or unstable arrhythmia within 6 months; 7. Physical examination or clinical laboratory findings that the investigator believes may interfere with the results or increase the patient's risk of treatment complications, or other uncontrollable diseases; 8. Breastfeeding or pregnant women; 9. Congenital or acquired immunodeficiency diseases including human immunodeficiency virus (HIV), or organ transplantation, allogeneic stem cell transplantation; 10. Known active hepatitis B virus (HBV), hepatitis C virus (HCV), active tuberculosis infection; 11. Vaccinated against tumors, or received other vaccines within 4 weeks before starting treatment (Note: Because the seasonal influenza vaccine for injection is mostly an inactivated vaccine, it is allowed to be vaccinated, while intranasal preparations are usually live attenuated vaccines, so it is not allowed) 12. Use other immunological agents, chemotherapy drugs, drugs in other clinical studies, and long-term cortisol therapy are not enrolled 13. With mental illness, substance abuse, and social problems that affect compliance will not be enrolled after a doctor's review 14. Allergic or contraindicated to the treatment of drugs.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK104 injection++chemotherapy<br>Local CRC with short-course radiotherapy followed by sequential chemotherapy and AK104 | Drug: AK104 injection<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Immunotherapy;Procedure: TME surgery<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Surgery;Drug: Capecitabine<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;Drug: Oxaliplatin<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;|
| Experimental: TME surgery<br>Local CRC with short-course radiotherapy followed by sequential chemotherapy and AK104 | Drug: AK104 injection<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Immunotherapy;Procedure: TME surgery<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Surgery;Drug: Capecitabine<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;Drug: Oxaliplatin<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;|
| Experimental: chemotherapy<br>Local CRC with short-course radiotherapy followed by sequential chemotherapy and AK104 | Drug: AK104 injection<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Immunotherapy;Procedure: TME surgery<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Surgery;Drug: Capecitabine<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;Drug: Oxaliplatin<br>* Eligible subjects will receive short-course radiotherapy (SCRT), IMRT/VMAT, pelvic 25Gy/5f/1 week. Two weeks after the end of treatment, subjects continued to receive neoadjuvant chemotherapy combined with immunotherapy regimen for 4 cycles: AK104 10 mg/kg, intravenous infusion every 3 weeks (Q3W), plus CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14, oxaliplatin: 130mg/m2, ivgtt, d1), Q3W. Neoadjuvant therapy was assessed 2 weeks after the end of neoadjuvant therapy, and TME surgery was performed 4 weeks after the end of neoadjuvant therapy (R0 surgery was performed).<br>* Other names: Chemotherapy drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response rate (pCR) | To assess the result from pathology report | From date of randomization until the date of end of treatment,about 18 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathologic response rate (MPR) | To assess the result from pathology report | From date of randomization until the date of end of treatment,about 18 weeks. | 
| 3-years DFS rate | To compute the length between end of treatment and relapse | From date of randomization until the date of first documented disease relapse or date of death from any cause, whichever came first about 3years.. | 
| 3-years OS rate | To compute the length between end of treatment and death | From date of randomization until date of death from any cause,about 3 years. | 
| Incidence and severity of adverse events (AEs) and clinically meaningful abnormal laboratory test results | To assess the result from inspection paper during the trail | From date of randomization until the date of end of treatment,about 18 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AK104, colorectal cancer, Pelvic short-course radiotherapy, TME surgery, pCR