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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.
Objectives:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Neoadjuvant chemoradiotherapy plus PD-1 inhibitor | Experimental | 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). |
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| Neoadjuvant chemoradiotherapy | Active Comparator | 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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PD-1 inhibitor | Drug | Tislelizumab (3 cycles): 200mg i.v. q3w on day 1 of each cycle, and starting from the second week after the start of radiotherapy |
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| Measure | Description | Time Frame |
|---|---|---|
| Complete response rate (CR rate) | 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. | 1-2 weeks after surgery or assessment after termination of neoadjuvant treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Pathological tumor regression grade (CAP) | All tumor tissues will be analyzed by experienced pathologists. Determination of tumor regression will adopt College of American Pathologists (CAP) tumor regression grade, which are as follows: CAP0: No viable cancer cells (complete response); CAP1:Single cells or rare small groups of cancer cells (near complete response); CAP2: Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells (partial response); and CAP3: Extensive residual cancer with no evident tumor regression (poor or no response). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jiaolin Zhou, Ph.D | Peking Union Medical College Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Peking Union Medical College Hospital | Beijing | Beijing Municipality | 100730 | China |
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| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D000082082 | Immune Checkpoint Inhibitors |
| C000707970 | tislelizumab |
| D000069287 | Capecitabine |
| ID | Term |
|---|---|
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D000074322 | Antineoplastic Agents, Immunological |
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| Capecitabine | Drug | Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks. |
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| Long-course radiation therapy | Radiation | 45-50 Gy/day, 5 days a week for a total of 5 weeks. |
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| 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 |
| Disease-related Treatment Failure (DrTF) rate | DrTF was deļ¬ned as the time from the initiation of radiotherpay to the date of each of the following, whichever occurred first: disease progression during/after treatment, distant metastasis at any timepoint, or death from any cause. | Baseline and months 3, 6, 12, 18, 24, 36, 48, 60 |
| 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, 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) | Score values from 1 (not at all) to 4 (very much). Score outcome depends on score type. | Baseline and months 3, 6, 12, 18, 24, 36, 48, 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, 18, 24, 36, 48, 60 |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D000970 | Antineoplastic Agents |
| D045506 | Therapeutic Uses |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |