Total Neoadjuvant Therapy With Short-course Radiation Followed by Envafolimab Plus CAPEOX for MSS Locally Advanced Ultra Low Rectal Adenocarcinoma (RECMULRA-TNT)

Total Neoadjuvant Therapy With Short-course Radiation Followed by Envafolimab Plus CAPEOX for MSS Locally Advanced Ultra Low Rectal Adenocarcinoma: An Prospective, Single Center, Single Arm Study

Short-course radiotherapy combined with immunotherapy may bring revolutionary changes to the total neoadjuvant therapy mode for locally advanced ultra low rectal cancer to preserve the organs. In view of the shortcomings of the current otal neoadjuvant therapy model for locally advanced ultra low rectal cancer, we will explore the feasibility of a new model of short-course radiotherapy combined with immunotherapy, and develop a possible optimal plan based on the existing theoretical basis, namely "short-course radiotherapy + PD-L1 monoclonal antibody combined with CAPEOX chemotherapy for 8 cycles", and explore the efficacy and adverse effects of this model. The study will also attempt to explore the characteristics of the treatment beneficiary population, explore the characteristics of the treatment beneficiary population by multi-dimensional tumor and microenvironmental information through multi-omics sequencing analysis, attempt to build an efficacy prediction model, early screening of the treatment beneficiary population for precise treatment, and thus explore a new model of radiotherapy combined with immunotherapy for the poplation who can be achieved organ preservation.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Envafolimab

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: sheng dai, MD&PhD; Phone Number: 13575472669; Email: daimd@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Recruiting
      • Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
      • Contact: Xiujun Cai

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients who are willing to receive neoadjuvant therapy.
2. ≧18 years old.
3. Diagnosed by digital rectal examination, colonoscopy, and high-resolution MRI of the pelvis, the tumor is less than or equal to 5 cm from the anus.
4. Histologically diagnosed as rectal adenocarcinoma.
5. The clinical staging by pelvic contrast-enhanced CT and pelvic high-resolution MRI were stage I, II and III.
6. MMR protein detection or MSI gene detection of rectal cancer specimens confirmed pMMR or MSS before treatment .
7. The patient is difficult cured by anal reserve procedure based on the primary physician's practice.
8. The patient has good compliance and can come to the hospital for re-examination as required.
9. ECOG Scale of Performance Status score 0-1 point.
10. Have not received anti-tumor and immunotherapy before enrollment.
11. Laboratory inspections must meet the following standards:

1) White blood cell count>3.5×109/L, absolute value of neutrophils>1.8×109/L, platelet count ≥75×109/L, hemoglobin ≥100g/L; 2) INR≤1.5, and APTT≤1.5 times the upper limit of normal or partial prothrombin time (PT) ≤1.5 times the upper limit of normal; 3) Total bilirubin ≤ 1.25 times the upper limit of normal; ALT and AST < 5 times the upper limit of normal; 4) 24h creatinine clearance >50mL/min or serum creatinine <1.5 times the upper limit of normal.

12. Voluntarily participate in this study and sign the informed consent.

Exclusion Criteria:

1. History of other malignant diseases in the past 5 years.
2. Patients with metastases from other sites (stage IV patients).
3. Patients with positive lateral lymph nodes by pelvic contrast-enhanced CT and pelvic high-resolution MRI.
4. Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, etc. requiring emergency surgery.
5. Known allergic to oxaliplatin, capecitabine, PD-L1 monoclonal antibody and other drugs.
6. Pathologically suggested signet ring cell carcinoma and mucinous adenocarcinoma.
7. dMMR or MSI-H patients.
8. The patient is accompanied by any unstable systemic disease, including but not limited to: severe infection, uncontrolled diabetes, hypertension uncontrolled by medication, unstable angina, cerebrovascular accident or transient cerebral ischemia, myocardial Infarction, congestive heart failure, severe cardiac arrhythmia requiring medication, hepatic, renal or metabolic disease; disease affecting the patient's life.
9. The disease (such as mental illness, etc.) or condition (such as alcoholism or drug abuse, etc.) associated with the patient will increase the risk of the patient receiving the trial drug treatment or affect the patient's compliance with the trial requirements, or may confuse the research results.
10. Active autoimmune disease that may worsen while receiving immunostimulants.
11. Known history of positive HIV test or known acquired immunodeficiency syndrome.
12. Patients who are using immunosuppressive agents, except for the following conditions:

1) Intranasal, inhaled, topical steroids, or topical steroid injections (eg, intra-articular injections); 2) Physiological doses of systemic corticosteroids ≤10 mg/day prednisone or equivalent; 3) Steroids used to prevent allergic reactions (eg, before CT scan). 13. Received any other experimental drug treatment or participated in another interventional clinical trial within 30 days before screening 14. Women who are pregnant or breastfeeding or who plan to become pregnant or breastfeeding during the study period; men or women who are unwilling to take effective contraceptive measures.

15. Vulnerable groups, including mentally ill, cognitively impaired, critically ill patients, minors, etc.

16. Other conditions that the investigator judges that the patient is not suitable to participate in the clinical study, etc.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Total Neoadjuvant Therapy with Short-course Radiation followed by Envafolimab plus CAPEOX; The enrolled patients with MSS-type advanced ultra low rectal cancer will receive a combined regimen of neoadjuvant chemoradiotherapy combined with immunotherapy and biopsy or local excision.; Radiotherapy uses a short-range mode, irradiating the primary tumor and high-risk areas with dose of 25 Gy.; After radiotherapy, PD-L1 antibody (150mg/week, subcutaneous injection × 24 weeks) immunotherapy combined with 8 courses of CAPEOX chemotherapy was performed.; Two weeks after the end of the combined treatment plan in step 2), biopsy or local excision of the lesion is performed.

Drug: Envafolimab; Drug: Envafolimab This product is administered by subcutaneous injection. The recommended dose of subcutaneous injection is 150 mg, administered weekly (QW). Other Names: KN053 Drug: Oxaliplatin 130mg/m2，ivgtt，d1 Drug: Capecitabine 1000mg/m2，po，bid，d1-14 Radiation: Short-course Radiation Short-course radiotherapy, using three-dimensional conformal or intensity-modulated radiotherapy, the dose is divided into 5Gy/f, the total dose is 25Gy/5f, 1f/d, and the irradiation is completed within 7 days. Procedure/Surgery: Biopsy, local excision or TME surgery (total mesorectal excision) Biopsy can choose endoscopic or needle biopsy, colcal excision refers to excison of the local lession after total neoadjuvant therapy The total mesorectal excision can choose open, laparoscopic or robotic according to the specific condition of the patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Organ reservation rate	population who achieve complete clinical response after total neoadjuvant therapy	After 2 weeks (once biopsy or local excision is done)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TRAEs	Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v5.0	Up to 3 years
Total mesorectal excision rate	population who not achieve complete clinical response after total neoadjuvant therapy	After 2 weeks (once biopsy or local excision is done)
Total mesorectal excision rate after recurrence	population who recurrent and have Salvage total mesorectal excision after achieving complete clinical response after total neoadjuvant therapy	from primary evaluation at 2 weeks after total neoadjuvant therapy finished
Tumor regression grade f	Tumor regression grade following short-course radiation then Envafolimab Plus CAPEOX as assessed by AJCC/CAP TRG system	After 2 weeks (once biopsy or local excision is done)
Overall survival	The proportion of participants who remain survival at 3 years	Up to 3 years
Progression free survival	The proportion of participants who remain progression free at 3 years	Up to 3 years
Surgical Complications	Surgical Complications of biopsy, local excision or total mesorectal resection procedure for patients after short-course radiation then Envafolimab Plus CAPEOX as assessed by Clavien-Dindo classification	Up to 3 years
QoL	Quality of life of the patients in total neoadjuvant settings of short-course radiation followed with Envafolimab Plus CAPEOX as assessed by Functional Assessment of Cancer Therapy - Colorectal (FACT-C) questionnaire liscenced from The Functional Assessment of Chronic Illness Therapy System ("FACIT System"). By using the Manual scoring template, some items are reverse scored. Subscale scores, total scores and TOI scores. The higher the score, the better the QOL.	Up to 3 years

Collaborators and Investigators

• Sponsor: Sir Run Run Shaw Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): May 11, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): June 30, 2025

Study Registration Dates

• First Submitted: May 4, 2023
• First Submitted That Met QC Criteria: May 4, 2023
• First Posted (Actual): May 15, 2023

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma
• Other Study ID Numbers: SRRSHLS-2023-R0097

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