Combination of AK104 and Neoadjuvant Chemoradiotherapy in pMMR/MSS Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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This is an open-label, single-arm study to investigate the efficacy and safety of AK104 (an Anti-PD1 and Anti-CTLA4 Bispecific Antibody) and neoadjuvant chemoradiotherapy in patients with pMMR/MSS locally advanced rectal cancer.

Detailed Description
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The study evaluates the addition of AK104(an Anti-PD1 and Anti-CTLA4 Bispecific Antibody) in neoadjuvant chemoradiotherapy in proficient Mismatch Repair (pMMR) /Microsatellite Stable (MSS) locally advanced rectal cancer (LARC). A total of 33 pMMR/MSS LARC patients will receive long-course chemoradiotherapy plus 2 cycles of AK104, followed by another 3 cycles of AK104, finally received clinical routine manage. The tumor response to treatment, adverse effects and long-term prognosis will be analyzed.

Official Title
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A Phase II Trial of AK104 Combined With Neoadjuvant Chemoradiotherapy in Proficient Mismatch Repair/Microsatellite Stable Locally Advanced Rectal Cancer

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: AK104
* Drug: Capecitabine
* Radiation: Neoadjuvant Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 ECOG 0-1 Rectal adenocarcinoma cT3-4aNany or cT1-4aN+ No distant metastasis Location ≤15 cm from the anal verge the MSI status is MSS and pMMR Sufficient bone marrow, kidney and liver function No previous surgery of the rectum, no previous chemotherapy, no previous pelvic radiation, no previous biotherapy, no immunotherapy Exclusion Criteria: bowel obstruction Distant metastasis Severe arrhythmia, cardiac dysfunction (NYHA grade III or IV ) Uncontrollable severe hypertesion Active severe infection Cachexia, organ dysfunction Previous pelvic radiotherapy or chemotherapy Multiple primary cancers Epileptic seizures Malignant history within 5 years, except cervical carcinoma in situ or cutaneous basal cell carcinoma Persons deprived of liberty or under guardianship Impossibility for compliance to follow-up Certain or suspicious allergy to research drug Pregnant or breast-feeding woman

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: Treatment Arm<br>A total of 33 pMMR/MSS LARC patients will receive long-course chemoradiotherapy plus 2 cycles of AK104, followed by another 3 cycles of AK104, finally received clinical routine manage. | Drug: AK104<br>* During neo-CRT: 2 cycles of AK104, 10mg/kg d1 q3w. After neo-CRT: 3 cycles of AK104, 10mg/kg d1 q3w.<br>* Other names: Cadonilimab;Drug: Capecitabine<br>* During neo-CRT: 825mg/m2 bid Monday-Friday per week<br>Radiation: Neoadjuvant Radiotherapy<br>* IMRT DT: 50Gy/25Fx<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 pathologic complete response (pCR) and clinical complete response (cCR). | an average of 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects | Adverse effects according to CTCAE 5.0 | From date of randomization until the date of death from any cause, assessed up to 5 years | 
| Rate of Major pathologic response and tumor regression grade distribution | Rate of Major pathologic response and tumor regression grade distribution | an average of 1 year. | 
| 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 1 year from the surgery. | 
| Disease free survival | 3 year disease free survival rate | 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. | 
| Local recurrence free survival | 3 year local recurrence free survival rate | From date of randomization until the date of first documented pelvic failure, assessed up to 36 months. | 
| Overall survival | 5 year overall survival rate | From date of randomization until the date of death from any cause, assessed up to 60 months. | 
| Long-term anal function | Long-term anal function was evaluated using the Wexner Continence Grading Scale ,the score being calculated after the patients' completion of a daily defecatory questionnaire. Range is from 0 (normal continence) to 20 (maximum incontinence with maximum disturbance of lifestyle) | 1.5 year after diagnosis |