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

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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Adenocarcinoma
• Intervention / Treatment: Drug: lvonescimab; Drug: CAPOX (oxaliplatin/capecitabine); Radiation: radiotherapy; Procedure: Surgery or watch&wait

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (Short-course radiotherapy followed by ivonescimab and chemotherapy); 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).	Drug: lvonescimab; lvonescimab, DS1, D1,q3w, intravenous infusion; Drug: CAPOX (oxaliplatin/capecitabine); Oxaliplatin 130 mg / m2, D1, intravenous infusion, q3w, Capecitabine 1000 mg / m2,twice a day, oral,1-14 days, then rest for 7 days, q3w.; Radiation: radiotherapy; 5* 5Gy, once a day, 5Gy each time, for 5 days; Procedure: Surgery or watch&wait; The surgical method is selected by the investigator. Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy)
Active Comparator: Group B (Short-course radiotherapy followed by chemotherapy); 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).	Drug: CAPOX (oxaliplatin/capecitabine); Oxaliplatin 130 mg / m2, D1, intravenous infusion, q3w, Capecitabine 1000 mg / m2,twice a day, oral,1-14 days, then rest for 7 days, q3w.; Radiation: radiotherapy; 5* 5Gy, once a day, 5Gy each time, for 5 days; Procedure: Surgery or watch&wait; The surgical method is selected by the investigator. Watch and Wait (only for patients with clinical complete response after neoadjuvant therapy)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Akeso

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 2, 2025
• First Submitted That Met QC Criteria: April 2, 2025
• First Posted (Actual): April 9, 2025

Study Record Updates

• Last Update Posted (Actual): April 9, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Rectal Neoplasms; Adenocarcinoma; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Capecitabine; Oxaliplatin
• Other Study ID Numbers: AK112-IIT-016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No