A Phase ll Study of Neoadjuvant Short-course Radiotherapy Followed by Ivonescimab and Chemotherapy in pMMR/MSS Locally Advanced Rectal Cancer

Phase 2

Not yet recruiting

• Conditions: Rectal Adenocarcinoma
• Interventions: Drug: lvonescimab; Drug: CAPOX (oxaliplatin/capecitabine); Radiation: radiotherapy; Procedure: Surgery or watch&wait

• Registration Number: NCT06919510
• Lead Sponsor: Sun Yat-sen University

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of short-course radiotherapy followed by ivonescimab and chemotherapy in participants with pMMR/MSS locally advanced rectal cancer. Patients were randomly assigned to experimental group A or control group B according to a 1:1 ratio. In group A, patients will receive neoadjuvant short-course radiotherapy followed by ivonescimab and chemotherapy. In group B, patients will receive neoadjuvant short-course radiotherapy followed by chemotherapy. After neoadjuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator, (2) Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy).

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-04
• Study Start: 2025-04-01
• Study First Submitted: 2025-04-02
• Study First Submitted QC: 2025-04-02
• Last Update Submitted: 2025-04-02
• Study First Posted: 2025-04-09
• Last Update Posted: 2025-04-09
• Primary Completion: 2026-06-01
• Study Completion: 2028-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. Age between 18 and 75 years;
2. ECOG perfommance status of 0 or 1;
3. Life expectancy: more than 2 years;
4. Histologically proven rectal adenocarcinoma;
5. Tumor biopsy immunohistochemistry proven pMMR, positive for four proteins, MLH1, MSH2, MSH6 and PMS2, or MSS determined by gene testing;
6. According to the 8th Edition of the AJCC Staging Manual, clinical stage cT3-4NanyM0 or cTxN+M0 of II-III rectal cancer was determined by Magnetic resonance imaging (MRI)±transrectal ultrasonography/ ultrasound endoscopy. Lower edge of the tumor was ≤ 12 cm from the anal verge;
7. Eligible for R0 surgery;
8. No prior anti-tumor treatment for rectal cancer,including radiotherapy,chemotherapy, immunotherapy, biologics, small molecule targeted therapy, etc;
9. Adequate organ function;
10. Males or females with reproductive ability who are willing to use contraception in the trial;

Exclusion Criteria

1. Any distant metastasis or inoperable disease, regardless clinical stage;
2. Previous (within 5 years) or concurrent other malignant tumors, excluding those that have been cured;
3. Current presence of gastric intestine obstruction, bleeding or perforation which need emergency surgery;
4. Multiple primary rectal cancers;
5. Previous pelvic or abdominal radiotherapy;
6. Difficulty swallowing;
7. Current presence of uncontrolled combined disease;
8. Active clinical infections;
9. History of severe bleeding tendency or coagulation dysfunction;
10. Presence or history of immunodeficiency; positive for HIV antibodies, current long-term use of systemic corticosteroids or other immunosuppressants;
11. Subjects with known active tuberculosis (TB); suspected active TB should be excluded by clinical examination, known active syphilis infection;
12. Received a live vaccine within 30 days prior to the study, or plan to receive a live vaccine during the study;
13. Local or systemic disease caused by non-malignancy, or disease or symptom secondary to tumor, that can lead to higher medical risk and/or uncertainty in survival;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A (Short-course radiotherapy followed by ivonescimab and chemotherapy)	lvonescimab	Subjects will receive short-course radiotherapy of 25Gy/5 fractions, followed by neoadjuvant chemotherapy of CAPOX and ivonescimab. After neoadjuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator: (2) Watch and Wait(only for patients with clinical complete response after neoadjuvant therapy).
Group A (Short-course radiotherapy followed by ivonescimab and chemotherapy)	CAPOX (oxaliplatin/capecitabine)	Subjects will receive short-course radiotherapy of 25Gy/5 fractions, followed by neoadjuvant chemotherapy of CAPOX and ivonescimab. After neoadjuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator: (2) Watch and Wait(only for patients with clinical complete response after neoadjuvant therapy).
Group A (Short-course radiotherapy followed by ivonescimab and chemotherapy)	radiotherapy	Subjects will receive short-course radiotherapy of 25Gy/5 fractions, followed by neoadjuvant chemotherapy of CAPOX and ivonescimab. After neoadjuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator: (2) Watch and Wait(only for patients with clinical complete response after neoadjuvant therapy).
Group A (Short-course radiotherapy followed by ivonescimab and chemotherapy)	Surgery or watch&wait	Subjects will receive short-course radiotherapy of 25Gy/5 fractions, followed by neoadjuvant chemotherapy of CAPOX and ivonescimab. After neoadjuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator: (2) Watch and Wait(only for patients with clinical complete response after neoadjuvant therapy).
Group B (Short-course radiotherapy followed by chemotherapy)	CAPOX (oxaliplatin/capecitabine)	Subjects will receive short-course radiotherapy of 25Gy/5 Fraction, followed by neoadjuvant chemotherapy of CAPOX .After neoadiuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator; (2) Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy).
Group B (Short-course radiotherapy followed by chemotherapy)	radiotherapy	Subjects will receive short-course radiotherapy of 25Gy/5 Fraction, followed by neoadjuvant chemotherapy of CAPOX .After neoadiuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator; (2) Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy).
Group B (Short-course radiotherapy followed by chemotherapy)	Surgery or watch&wait	Subjects will receive short-course radiotherapy of 25Gy/5 Fraction, followed by neoadjuvant chemotherapy of CAPOX .After neoadiuvant treatment, the patients and investigator could choose one of the following treatments:(1) Surgery. The patients will receive surgery within 4-8 weeks after the last dose of capecitabine, and the surgical method is selected by the investigator; (2) Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy).

Primary Outcome Measures

Name	Time	Method
Adverse events	Through study completion, an average of 6 month	Adverse events and surgical safety
Clinical complete response rate	2-4 weeks after the completion of neoadjuvant therapy (last dose of capecitabine)	The proportion of clinical complete response cases.
Complete response rate	4 weeks after curative surgery for pCR; 2-4 weeks after the completion of neoadjuvant therapy (last dose of capecitabine) for cCR	The proportion of CR cases (pCR for those who underwent surgery and cCR for those who didn't receive surgery)

Secondary Outcome Measures

Name	Time	Method
Pathologic complete response	4 weeks after surgery	The proportion of pathologic complete response cases for those who underwent surgery
OS	3 years after Randomization	Overall survial
TRG	4 weeks after surgery	Tumor regression grade according to AJCC TRG grading system
R0 resection rate	4 weeks after surgery	R0 resection rate
Local recurrence	3 years after Randomization	Local recurrence
Distant metastasis	3 years after Randomization	Distant metastasis
EFS	3 years after Randomization	Event free of survival