TIMENT-R: TIME in Immunotherapy Combined With nCRT for Rectal Cancer
Study Details
Study Description
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 end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Objectives:
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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.
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To clarify the effect of nCRT on TIME for rectal cancer, and the further effect of adding Immunotherapy.
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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.
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To clarify the potential mechanism of immune response or escape to neoadjuvant immunotherapy for LARC patients.
Study Design
Arms and Interventions
| 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 in the week posterior to day 1 of radiotherapy
Other Names:
Drug: Capecitabine
Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks, given with radiation therapy.
Other Names:
Radiation: Long-course radiation therapy
45-50 Gy/day, 5 days a week for a total of 5 weeks, given with Capecitabine
|
| 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, given with radiation therapy.
Other Names:
Radiation: Long-course radiation therapy
45-50 Gy/day, 5 days a week for a total of 5 weeks, given with Capecitabine
|
Outcome Measures
Primary Outcome Measures
- Pathological complete response (pCR) rates [1-2 weeks after surgery]
Proportion of patients who achieve a pathological complete response following treatment
Secondary Outcome Measures
- Major pathological response (MPR) rates [1-2 weeks after surgery]
The proportion of patients experiencing a major pathological response to neoadjuvant treatment.
- Pathological tumor regression grade (pTRG) [1-2 weeks after surgery]
pTRG is evaluated according to the AJCC system. pTRG0-1 is defined as good response, pTRG2 as moderate response, and pTRG3 as poor response.
- Rate of tumor down-staging [1-2 weeks after surgery]
The proportion of patients experiencing tumor down-staging will be assessed by pathology.
- Lymphocytes infiltration changes after treatment [2 weeks before treatment and 1-2 weeks after surgery]
The categories, number and distribution of lymphocytes infiltrated in tumor and tumor stroma are measured by Multiplex immunofluorescence.
- The expression of immune-related pathways [2 weeks before treatment and 1-2 weeks after surgery]
The expression of immune-related pathways is measured by RNAseq.
- Rectal MRI defined tumor regression [Baseline and 1 week before surgery]
Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.
- Rectal MRI defined tumor down-staging [Baseline and 1 week before surgery]
Proportion of patients achieving rectal MRI-confirmed down-staging.
- Rectal MRI defined tumor volume change [Baseline and 1 week before surgery]
The change of patients' tumor volume will be confirmed by rectal MRI.
- Local recurrence(LR) rate [3, 5 years]
Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology
- Disease free survival (DFS) [3, 5 years]
The three-year and five-year disease-free survival of patients.
- Overall survival (OS) [3, 5 years]
The three-year and five-year overall survival of patients.
- Surgical complications [The surgical complications are assessed up to 5 years from the surgery]
Rate of surgical complications, such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc. Incidence of adverse events will also be assessed according to "Clavien-Dindo Classification of surgical complications".
- R0 resection rate [Within two weeks after surgery]
defined as microscopically margin negative resection with no tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the pathologist.
- Rate of sphincter-sparing surgery [Within two weeks after surgery]
Rate of sphincter-sparing surgery if surgery is performed.
- Rate of adverse drug event [From date of randomization until the date of death from any cause, assessed up to 5 years]
Rate of adverse drug events will be assessed according to National Cancer Institution Common Terminology Criteria of Adverse Events (NCI-CTCAE) v.4.02. Adverse drug events include immune-related adverse events, combined treatment-related adverse events and other adverse events.
- 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, 24, 36, 60]
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.
- 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, 24, 36, 60]
Score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.
- Patient reported outcome: Functional outcome according to Wexner score [Baseline and months 3, 6, 12, 24, 36, 60]
Five score values from "never" to "1 per day or more often". The more often the worse outcome.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥ 18 years and ≤75 years on the day of signing informed consent.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
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Histologically proven rectal adenocarcinoma.
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<12 cm from anal verge.
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Clinical stage of T3/T4 or N positive and M0
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No previous chemotherapy, radiotherapy, immunotherapy or surgical treatment
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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.
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Adequate hepatic and renal function to chemoradiotherapy, immunotherapy and surgery.
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Willing and able to provide written informed consent.
Exclusion Criteria:
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Allergic to any component of chemotherapy or immunotherapy;
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Patients with multiple primary colorectal cancer;
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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;
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Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, and other conditions requiring emergency surgical resection;
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Prior or planed organ/bone marrow transplant
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Patients who receive systemic steroid therapy or immunosuppressive agents within 30 days before enrollment in the study;
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Pregnant or lactating women
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Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
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Patients who have contradictions to chemoradiotherapy, immunotherapy and surgery.
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The investigator judges that the patient is not suitable to participate in other situations.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Peking Union Medical College Hospital
Investigators
- Study Chair: Jiaolin Zhou, Ph.D, Peking Union Medical College Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PUMCH_TIMENT-R