TIME in Immunotherapy Combined With nCRT for Rectal Cancer (TIMENT-R)

The Therapeutic and Prognostic Implications of Tumor Immune Microenvironment in The Neoadjuvant Immunotherapy Combined With Chemoradiotherapy for Rectal Cancer

This is an open-label, prospective phase II clinical trial to evaluate the therapeutic and prognostic implications of tumor immune microenvironment in the neoadjuvant immunotherapy combined with chemoradiotherapy for patients with rectal cancer. A total of 100 patients will be enrolled in this trial. The primary end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Drug: PD-1 inhibitor; Drug: Capecitabine; Radiation: Long-course radiation therapy

Detailed Description

Objectives:

1. To clarify the efficacy and safety of combined therapy for locally advanced rectal cancer (LARC) patients and verify the efficacy and safety of neoadjuvant immunotherapy for dMMR/MSI-H LARC patients.
2. To clarify the effect of nCRT on TIME for rectal cancer, and the further effect of adding Immunotherapy.
3. To verify the feasibility of predicting the efficacy of combined therapy by the infiltration level of CD8+ PD1+ TILs in tumor tissue before treatment in pMMR/MSS LARC patients and explore the comprehensive prediction index of the efficacy of combined therapy for LARC patients.
4. To clarify the potential mechanism of immune response or immune escape to neoadjuvant immunotherapy for LARC patients.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jiaolin Zhou, Ph.D; Phone Number: +86-13910136704; Email: conniezhjl@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years and ≤75 years on the day of signing informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
3. Histologically proven rectal adenocarcinoma.
4. <12 cm from anal verge.
5. Clinical stage of T3/T4 or N positive and M0
6. No previous chemotherapy, radiotherapy, immunotherapy or surgical treatment
7. No immune system disease (e. g. systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic vasculitis, scleroderma, mixed connective tissue disease, dermatomyositis (DM), hyperthyroidism, hypothyroidism, ulcerative colitis (UC), autoimmune hemolytic anemia (AIHA) or human immunodeficiency virus (HIV) infection.
8. Adequate hepatic and renal function to chemoradiotherapy, immunotherapy and surgery.
9. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Allergic to any component of chemotherapy or immunotherapy;
2. Patients with multiple primary colorectal cancer;
3. Other malignant tumors within 5 years, except for adequately treated cervical carcinoma in situ or cutaneous basal cell carcinoma, or basically controlled localized prostate cancer or surgically excised ductal carcinoma in situ of breast;
4. Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, or other conditions requiring emergency surgical resection;
5. Prior or planed organ/bone marrow transplant
6. Patients who receive systemic steroid therapy or immunosuppressive agents within 30 days before enrollment in the study;
7. Pregnant or lactating women
8. Patients with a history of severe mental illness or being unable to comply with the research protocols.
9. Patients who have contraindications to chemoradiotherapy, immunotherapy or surgery.
10. Patients who have any other conditions that investigator judges unsuitable to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Neoadjuvant chemoradiotherapy plus PD-1 inhibitor; Capecitabine 1650mg/m2 is given 5 days a week in parallel with radiotherapy 45 to 50 Gy during 5 consecutive weeks. Tislelizumab is given on day 1 of week 2, 5 and 8 at 200 mg i.v. 8-12 weeks after completion of radiation therapy, patients undergo total mesorectal excision (TME).	Drug: PD-1 inhibitor; Tislelizumab (3 cycles): 200mg i.v. q3w on day 1 of each cycle, and starting from the second week after the start of radiotherapy; Other Names: Tislelizumab; Drug: Capecitabine; Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks.; Other Names: Xeloda; Radiation: Long-course radiation therapy; 45-50 Gy/day, 5 days a week for a total of 5 weeks.
ACTIVE_COMPARATOR: Neoadjuvant chemoradiotherapy; Capecitabine 1650mg/m2 is given 5 days a week in parallel with radiotherapy 45 to 50 Gy during 5 consecutive weeks. 8-12 weeks after completion of radiation therapy, patients undergo total mesorectal excision (TME).	Drug: Capecitabine; Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks.; Other Names: Xeloda; Radiation: Long-course radiation therapy; 45-50 Gy/day, 5 days a week for a total of 5 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response (pCR) rates	Proportion of patients who achieve a pathological complete response following treatment	1-2 weeks after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response (MPR) rates	The proportion of patients experiencing a major pathological response to neoadjuvant treatment.	1-2 weeks after surgery
Pathological tumor regression grade (TRG)	TRG is evaluated according to the AJCC system. TRG0-1 is defined as good response, TRG2 as moderate response, and TRG3 as poor response.	1-2 weeks after surgery
Rate of tumor down-staging	The proportion of patients experiencing tumor down-staging will be assessed by pathology.	1-2 weeks after surgery
Lymphocytes infiltration changes after treatment	The categories, number and distribution of lymphocytes infiltrated in tumor and tumor stroma are measured by Multiplex immunofluorescence assay.	2 weeks before treatment and 1-2 weeks after surgery
The expression of immune-related pathways	The expression of immune-related pathways is measured by RNAseq.	2 weeks before treatment and 1-2 weeks after surgery
Rectal MRI defined tumor regression	Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.	Baseline and 1 week before surgery
Rectal MRI defined tumor down-staging	Proportion of patients achieving rectal MRI-confirmed down-staging.	Baseline and 1 week before surgery
Rectal MRI defined tumor volume change	The change of patients' tumor volume will be confirmed by rectal MRI.	Baseline and 1 week before surgery
Local recurrence(LR) rate	Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology	3, 5 years
Disease free survival (DFS)	The three-year and five-year disease-free survival of patients.	3, 5 years
Overall survival (OS)	The three-year and five-year overall survival of patients.	3, 5 years
Surgical complications	Rate of surgical complications, such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc, which will also be assessed according to "Clavien-Dindo Classification of surgical complications".	The surgical complications are assessed up to 5 years from the surgery
R0 resection rate	Rate of complete tumor removal with negative microscopically resection margin.	Within two weeks after surgery
Rate of sphincter-sparing surgery	Rate of sphincter-sparing surgery if surgery is performed.	Within two weeks after surgery
Rate of adverse event	Rate of adverse events will be assessed according to National Cancer Institution Common Terminology Criteria of Adverse Events (NCI-CTCAE) v.4.02. Adverse events of this trial will include immune-related adverse events, chemo- and radiotherapy related adverse events, and combined treatment-related adverse events.	From date of randomization until the date of death from any cause, assessed up to 5 years
Patient reported outcome: Quality of life according to questionnaire European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) (v 3.0)	Score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.	Baseline and months 3, 6, 12, 24, 36, 60
Patient reported outcome: Quality of life according to questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29)	Score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.	Baseline and months 3, 6, 12, 24, 36, 60
Patient reported outcome: Functional outcome according to Wexner score	Five score values from "never" to "1 per day or more often". The more often the worse outcome.	Baseline and months 3, 6, 12, 24, 36, 60

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Investigators: Study Chair: Jiaolin Zhou, Ph.D, Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 20, 2022
• Primary Completion (ANTICIPATED): July 1, 2024
• Study Completion (ANTICIPATED): December 1, 2029

Study Registration Dates

• First Submitted: July 17, 2022
• First Submitted That Met QC Criteria: August 16, 2022
• First Posted (ACTUAL): August 18, 2022

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Immunotherapy; neoadjuvant therapy; Rectal Cancer; Tumor Immune Microenvironment
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Immune Checkpoint Inhibitors
• Other Study ID Numbers: PUMCH_TIMENT-R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No