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

Primary Purpose

Locally Advanced Rectal Cancer

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
PD-1 inhibitor
Capecitabine
Long-course radiation therapy
Sponsored by
Peking Union Medical College Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Cancer focused on measuring Rectal Cancer, Immunotherapy, neoadjuvant therapy, Tumor Immune Microenvironment

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Neoadjuvant chemoradiotherapy plus PD-1 inhibitor

    Neoadjuvant chemoradiotherapy

    Arm Description

    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).

    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).

    Outcomes

    Primary Outcome Measures

    Pathological complete response (pCR) rates
    Proportion of patients who achieve a pathological complete response following treatment

    Secondary Outcome Measures

    Major pathological response (MPR) rates
    The proportion of patients experiencing a major pathological response to neoadjuvant treatment.
    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.
    Rate of tumor down-staging
    The proportion of patients experiencing tumor down-staging will be assessed by pathology.
    Lymphocytes infiltration changes after treatment
    The categories, number and distribution of lymphocytes infiltrated in tumor and tumor stroma are measured by Multiplex immunofluorescence assay.
    The expression of immune-related pathways
    The expression of immune-related pathways is measured by RNAseq.
    Rectal MRI defined tumor regression
    Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.
    Rectal MRI defined tumor down-staging
    Proportion of patients achieving rectal MRI-confirmed down-staging.
    Rectal MRI defined tumor volume change
    The change of patients' tumor volume will be confirmed by rectal MRI.
    Local recurrence(LR) rate
    Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology
    Disease free survival (DFS)
    The three-year and five-year disease-free survival of patients.
    Overall survival (OS)
    The three-year and five-year overall survival of patients.
    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".
    R0 resection rate
    Rate of complete tumor removal with negative microscopically resection margin.
    Rate of sphincter-sparing surgery
    Rate of sphincter-sparing surgery if surgery is performed.
    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.
    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.
    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.
    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.

    Full Information

    First Posted
    July 17, 2022
    Last Updated
    September 16, 2022
    Sponsor
    Peking Union Medical College Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05507112
    Brief Title
    TIME in Immunotherapy Combined With nCRT for Rectal Cancer
    Acronym
    TIMENT-R
    Official Title
    The Therapeutic and Prognostic Implications of Tumor Immune Microenvironment in The Neoadjuvant Immunotherapy Combined With Chemoradiotherapy for Rectal Cancer
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 20, 2022 (Anticipated)
    Primary Completion Date
    July 1, 2024 (Anticipated)
    Study Completion Date
    December 1, 2029 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Peking Union Medical College Hospital

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No

    5. 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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Locally Advanced Rectal Cancer
    Keywords
    Rectal Cancer, Immunotherapy, neoadjuvant therapy, Tumor Immune Microenvironment

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    100 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Neoadjuvant chemoradiotherapy plus PD-1 inhibitor
    Arm Type
    Experimental
    Arm Description
    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).
    Arm Title
    Neoadjuvant chemoradiotherapy
    Arm Type
    Active Comparator
    Arm Description
    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 Type
    Drug
    Intervention Name(s)
    PD-1 inhibitor
    Other Intervention Name(s)
    Tislelizumab
    Intervention Description
    Tislelizumab (3 cycles): 200mg i.v. q3w on day 1 of each cycle, and starting from the second week after the start of radiotherapy
    Intervention Type
    Drug
    Intervention Name(s)
    Capecitabine
    Other Intervention Name(s)
    Xeloda
    Intervention Description
    Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks.
    Intervention Type
    Radiation
    Intervention Name(s)
    Long-course radiation therapy
    Intervention Description
    45-50 Gy/day, 5 days a week for a total of 5 weeks.
    Primary Outcome Measure Information:
    Title
    Pathological complete response (pCR) rates
    Description
    Proportion of patients who achieve a pathological complete response following treatment
    Time Frame
    1-2 weeks after surgery
    Secondary Outcome Measure Information:
    Title
    Major pathological response (MPR) rates
    Description
    The proportion of patients experiencing a major pathological response to neoadjuvant treatment.
    Time Frame
    1-2 weeks after surgery
    Title
    Pathological tumor regression grade (TRG)
    Description
    TRG is evaluated according to the AJCC system. TRG0-1 is defined as good response, TRG2 as moderate response, and TRG3 as poor response.
    Time Frame
    1-2 weeks after surgery
    Title
    Rate of tumor down-staging
    Description
    The proportion of patients experiencing tumor down-staging will be assessed by pathology.
    Time Frame
    1-2 weeks after surgery
    Title
    Lymphocytes infiltration changes after treatment
    Description
    The categories, number and distribution of lymphocytes infiltrated in tumor and tumor stroma are measured by Multiplex immunofluorescence assay.
    Time Frame
    2 weeks before treatment and 1-2 weeks after surgery
    Title
    The expression of immune-related pathways
    Description
    The expression of immune-related pathways is measured by RNAseq.
    Time Frame
    2 weeks before treatment and 1-2 weeks after surgery
    Title
    Rectal MRI defined tumor regression
    Description
    Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.
    Time Frame
    Baseline and 1 week before surgery
    Title
    Rectal MRI defined tumor down-staging
    Description
    Proportion of patients achieving rectal MRI-confirmed down-staging.
    Time Frame
    Baseline and 1 week before surgery
    Title
    Rectal MRI defined tumor volume change
    Description
    The change of patients' tumor volume will be confirmed by rectal MRI.
    Time Frame
    Baseline and 1 week before surgery
    Title
    Local recurrence(LR) rate
    Description
    Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology
    Time Frame
    3, 5 years
    Title
    Disease free survival (DFS)
    Description
    The three-year and five-year disease-free survival of patients.
    Time Frame
    3, 5 years
    Title
    Overall survival (OS)
    Description
    The three-year and five-year overall survival of patients.
    Time Frame
    3, 5 years
    Title
    Surgical complications
    Description
    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".
    Time Frame
    The surgical complications are assessed up to 5 years from the surgery
    Title
    R0 resection rate
    Description
    Rate of complete tumor removal with negative microscopically resection margin.
    Time Frame
    Within two weeks after surgery
    Title
    Rate of sphincter-sparing surgery
    Description
    Rate of sphincter-sparing surgery if surgery is performed.
    Time Frame
    Within two weeks after surgery
    Title
    Rate of adverse event
    Description
    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.
    Time Frame
    From date of randomization until the date of death from any cause, assessed up to 5 years
    Title
    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)
    Description
    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.
    Time Frame
    Baseline and months 3, 6, 12, 24, 36, 60
    Title
    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)
    Description
    Score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.
    Time Frame
    Baseline and months 3, 6, 12, 24, 36, 60
    Title
    Patient reported outcome: Functional outcome according to Wexner score
    Description
    Five score values from "never" to "1 per day or more often". The more often the worse outcome.
    Time Frame
    Baseline and months 3, 6, 12, 24, 36, 60

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age ≥ 18 years and ≤75 years on the day of signing informed consent. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 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.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Jiaolin Zhou, Ph.D
    Phone
    +86-13910136704
    Email
    conniezhjl@163.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jiaolin Zhou, Ph.D
    Organizational Affiliation
    Peking Union Medical College Hospital
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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