The Therapeutic and Prognostic Implications of Tumor Immune Microenvironment in The Neoadjuvant Immunotherapy Combined With Chemoradiotherapy for Rectal Cancer
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Complete response rate (CR rate)
Study Overview
Brief 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 endpoint is the complete response rate, defined as the proportion of patients who achieve pathological complete response (pCR) or clinical complete response (cCR) without evidence of distant metastasis on post-treatment or preoperative assessment. The long-term prognosis and adverse effects will also be evaluated and analyzed.
Detailed Description
Objectives:
- 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.
- To clarify the effect of nCRT on TIME for rectal cancer, and the further effect of adding Immunotherapy.
- 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.
- To clarify the potential mechanism of immune response or immune escape to neoadjuvant immunotherapy for LARC patients.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age ≥ 18 years and ≤75 years on the day of signing informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Histologically proven rectal adenocarcinoma.
- •<12 cm from anal verge.
- •Clinical stage of T3/T4 or N positive and M0
- •No previous chemotherapy, radiotherapy, immunotherapy or surgical treatment
- •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.
- •Adequate hepatic and renal function to chemoradiotherapy, immunotherapy and surgery.
- •Willing and able to provide written informed consent.
Exclusion Criteria
- •Allergic to any component of chemotherapy or immunotherapy;
- •Patients with multiple primary colorectal cancer;
- •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;
- •Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, or other conditions requiring emergency surgical resection;
- •Prior or planed organ/bone marrow transplant
- •Patients who receive systemic steroid therapy or immunosuppressive agents within 30 days before enrollment in the study;
- •Pregnant or lactating women
- •Patients with a history of severe mental illness or being unable to comply with the research protocols.
- •Patients who have contraindications to chemoradiotherapy, immunotherapy or surgery.
- •Patients who have any other conditions that investigator judges unsuitable to participate.
Arms & Interventions
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).
If the investigator and the subject opt for a "watch-and-wait" strategy after completing neoadjuvant therapy, a one-year follow-up will be conducted. If no additional surgery is performed due to disease-related reasons by the end of the follow-up period, this outcome is recognized as a clinical complete response (cCR).
Intervention: PD-1 inhibitor (Drug)
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).
If the investigator and the subject opt for a "watch-and-wait" strategy after completing neoadjuvant therapy, a one-year follow-up will be conducted. If no additional surgery is performed due to disease-related reasons by the end of the follow-up period, this outcome is recognized as a clinical complete response (cCR).
Intervention: Long-course radiation therapy (Radiation)
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).
Intervention: Long-course radiation therapy (Radiation)
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).
If the investigator and the subject opt for a "watch-and-wait" strategy after completing neoadjuvant therapy, a one-year follow-up will be conducted. If no additional surgery is performed due to disease-related reasons by the end of the follow-up period, this outcome is recognized as a clinical complete response (cCR).
Intervention: Capecitabine (Drug)
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).
Intervention: Capecitabine (Drug)
Outcomes
Primary Outcomes
Complete response rate (CR rate)
Time Frame: 1-2 weeks after surgery or assessment after termination of neoadjuvant treatment
Proportion of patients who achieve pathological complete response (pCR) or clinical complete response (cCR) without evidence of distant metastasis on post-treatment or preoperative assessment.
Secondary Outcomes
- Pathological tumor regression grade (CAP)(1-2 weeks after surgery)
- Local recurrence (LR) rate(3, 5 years)
- Disease-related Treatment Failure (DrTF) rate(Baseline and months 3, 6, 12, 18, 24, 36, 48, 60)
- 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)(Baseline and months 3, 6, 12, 18, 24, 36, 48, 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)(Baseline and months 3, 6, 12, 18, 24, 36, 48, 60)
- Patient reported outcome: Functional outcome according to Wexner score(Baseline and months 3, 6, 12, 18, 24, 36, 48, 60)
- Rectal MRI defined tumor regression(Baseline and 1 week before surgery)
- Disease free survival (DFS)(3, 5 years)
- Rate of tumor down-staging(1-2 weeks after surgery)
- Lymphocytes infiltration changes after treatment(2 weeks before treatment and 1-2 weeks after surgery)
- Rectal MRI defined tumor down-staging(Baseline and 1 week before surgery)
- Rectal MRI defined tumor volume change(Baseline and 1 week before surgery)
- Overall survival (OS)(3, 5 years)
- R0 resection rate(Within two weeks after surgery)
- The expression of immune-related pathways(2 weeks before treatment and 1-2 weeks after surgery)
- Rate of adverse event(From date of randomization until the date of death from any cause, assessed up to 5 years)
- Surgical complications(The surgical complications are assessed up to 5 years from the surgery)
- Rate of sphincter-sparing surgery(Within two weeks after surgery)