TIME in Immunotherapy Combined With nCRT for Rectal Cancer

Locally Advanced Rectal Cancer Clinical Trial

— TIMENT-R  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05507112
• Other study ID #: PUMCH_TIMENT-R
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: September 20, 2022
• Est. completion date: December 1, 2029

Study information

• Verified date: July 2022
• Source: Peking Union Medical College Hospital
• Contact: Jiaolin Zhou, Ph.D
• Phone: +86-13910136704
• Email: conniezhjl[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: December 1, 2029
• Est. primary completion date: July 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Locally Advanced Rectal Cancer
• Rectal Neoplasms

Intervention

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
• Capecitabine
Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks.

Radiation:
• Long-course radiation therapy
45-50 Gy/day, 5 days a week for a total of 5 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete response (pCR) rates	Proportion of patients who achieve a pathological complete response following treatment	1-2 weeks after surgery
Secondary	Major pathological response (MPR) rates	The proportion of patients experiencing a major pathological response to neoadjuvant treatment.	1-2 weeks after surgery
Secondary	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
Secondary	Rate of tumor down-staging	The proportion of patients experiencing tumor down-staging will be assessed by pathology.	1-2 weeks after surgery
Secondary	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
Secondary	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
Secondary	Rectal MRI defined tumor regression	Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.	Baseline and 1 week before surgery
Secondary	Rectal MRI defined tumor down-staging	Proportion of patients achieving rectal MRI-confirmed down-staging.	Baseline and 1 week before surgery
Secondary	Rectal MRI defined tumor volume change	The change of patients' tumor volume will be confirmed by rectal MRI.	Baseline and 1 week before surgery
Secondary	Local recurrence(LR) rate	Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology	3, 5 years
Secondary	Disease free survival (DFS)	The three-year and five-year disease-free survival of patients.	3, 5 years
Secondary	Overall survival (OS)	The three-year and five-year overall survival of patients.	3, 5 years
Secondary	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
Secondary	R0 resection rate	Rate of complete tumor removal with negative microscopically resection margin.	Within two weeks after surgery
Secondary	Rate of sphincter-sparing surgery	Rate of sphincter-sparing surgery if surgery is performed.	Within two weeks after surgery
Secondary	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
Secondary	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
Secondary	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
Secondary	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