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The Combination of Hypofractionated Radiotherapy and Immunotherapy in Locally Recurrent Rectal Cancer (TORCH-R)

Primary Purpose

Recurrent Rectal Cancer

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
PD-1 antibody
Capecitabine
5FU
folinic acid
Oxaliplatin
Irinotecan
Raltitrexed
Radiation
Sponsored by
Fudan University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Rectal Cancer

Eligibility Criteria

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

Inclusion Criteria: Patient is 18-75 years old at the time of signing the informed consent form. ECOG performance status 0-1. MRI/enhanced CT confirmed pelvic recurrence. According to RECIST 1.1, there is at least one measurable pelvic lesion. Distant metastasis lesions are no more than 5 and metastatic organ are no more than 3. No prior radiotherapy within 6 month. Previous system therapy. Patients Group Cohort A: participants with pelvic recurrence who have not previously been treated with first-line chemotherapy. Cohort B: Patients with disease progression or new lesions after first-line chemotherapy. Has an investigator determined life expectancy of at least 24 weeks. Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors. Non pregnant or lactating patients. Effective contraceptive methods should be used during the study and within 6 months of the last administration. Fully informed and willing to provide written informed consent for the trial. Exclusion Criteria: Neutrophil < 1.5×10^9/L, PLT < 100×10^9/L (PLT < 80×10^9/L in patients with liver metastasis), or Hb < 90g/L; blood transfusion within 2 weeks before enrollment is not allowed to meet the enrollment criteria. TBIL > 1.5 ULN, or TBIL > 2.5 ULN in patients with liver metastasis. AST or ALT > 2.5 ULN, or ALT and / or AST > 5 ULN in patients with liver metastasis. Cr > 1.5 ULN, or creatinine clearance < 50ml / min (calculated according to Cockcroft Gault formula). APTT > 1.5 ULN, PT > 1.5 ULN (subject to the normal value of the clinical trial research center). Serious electrolyte abnormalities. Urinary protein ≥ 2+, or 24-hour urine protein ≥1.0g/24h. Uncontrolled hypertension: SBP >140mmHg or DBP > 90mmHg. The presence of gastrointestinal diseases such as gastric or duodenal active ulcers, ulcerative colitis or unresected tumours with active bleeding; or other conditions likely to cause gastrointestinal bleeding or perforation; or unhealed gastrointestinal perforation or gastrointestinal fistula after surgical treatment. A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months. A history of heart disease within 6 months (including congestive heart failure, acute myocardial infarction, severe/unstable angina, coronary artery bypass grafting, cardiac insufficiency ≥ NYHA grade 2 and LVEF<50%). Uncontrolled malignant pleural effusion, ascites, or pericardial effusion. History of anti-PD-1, PD-L1, PD-L2, CTLA-4 or any other specific T cell co-stimulation or checkpoint pathway targeted therapy. The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years excluding adequately treated non-melanoma skin cancer, carcinoma in situ of cervix and superficial bladder tumour (non-invasive tumour, or carcinoma in situ, or T1). A history of liver disease including, but not limited to HBV infection or HBV DNA positive(≥1×10^4/ml), HCV infection or HCV DNA positive(≥1×10^3/ml) and liver cirrhosis. Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication; Or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period. The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems. Serious mental abnormalities. The diameter of brain metastasis is greater than 3cm or the total volume is greater than 30cc. Clinical or radiological evidence of spinal cord compression, or tumours within 3 mm of the spinal cord on MRI.

Sites / Locations

  • Fudan University Shanghai Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

The enrolled patients will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history) for pelvic recurrence. Patients (cohort A) will receive CAPOX, FOLFIRI or mFOLFOX6 chemotherapy based on previous adverse reactions to chemotherapy agents and at the discretion of the oncologist. Patients (cohort B) will receive CAPOX, FOLFIRI, mFOLFOX6, mXELIRI, irinotecan and raltitrexed, or oxaliplatin and raltitrexed chemotherapy based on the first-line chemotherapy and previous adverse reactions to chemotherapy agents and at the discretion of the oncologist. All metastasis sites will receive stereotactic ablative radiotherapy (SABR). SABR would be delivered between chemoimmunotherapy cycles. Five-fraction regimens (25-50Gy/5Fx) are delivered daily. Dose Constraints are based on SABR-COMET 10 trial.

Outcomes

Primary Outcome Measures

Local objective response rate
the proportion of patients with the best pelvic response of confirmed complete or partial response according to RECIST 1.1, as assessed by the investigator.

Secondary Outcome Measures

Extrapelvic objective response rate
proportion of patients with confirmed extrapelvic complete or partial response per RECIST 1.1.
R0 resection rate
the proportion of patients who achieve R0 resection of pelvic recurrent tumour after therapy.
Duration of response (DOR)
time from the first documented pelvic objective response to pelvic or extrapelvic disease progression in patients with confirmed response.
Progression-Free Survival
time from the date of start treatment until disease progression or censored at last follow-up or death.
Overall Survival
from the date of start treatment until the date of death from any cause or censored at last follow-up.
Safety and tolerability of the treatment
proportion of patients with treatment-related acute toxicities as assessed by NCI CTCAE v5.0, from treatment initiation until 90 days upon completion of immunotherapy.

Full Information

First Posted
November 17, 2022
Last Updated
October 4, 2023
Sponsor
Fudan University
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1. Study Identification

Unique Protocol Identification Number
NCT05628038
Brief Title
The Combination of Hypofractionated Radiotherapy and Immunotherapy in Locally Recurrent Rectal Cancer
Acronym
TORCH-R
Official Title
Hypofractionated Radiotherapy Combined With Chemotherapy and Toripalimab for Locally Recurrent Rectal Cancer: a Single-arm, Two-cohort, Phase II Trial (TORCH-R)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 18, 2022 (Actual)
Primary Completion Date
December 1, 2024 (Anticipated)
Study Completion Date
December 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fudan University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The study is a prospective, single-center, single-arm, two-cohort, phase II clinical trial. Patients aged 18 years or older who had pelvic recurrence rectal cancer with or without resectable distant metastasis, with treatment naive disease (cohort A) or progressive disease after first-line chemotherapy (cohort B), Eastern Cooperative Oncology Group performance status of 0-1, will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history), 18 weeks toripalimab and investigator's choice of chemotherapy, and stereotactic ablative radiotherapy (SABR) for all metastatic lesions between chemoimmunotherapy cycles, followed by multidisciplinary team (MDT) for decision:follow-up of complete response (CR), radical surgery, sustained treatment of non resection, or exit. The primary endpoint was local objective response rate. Secondary endpoints were extrapelvic objective response rate, R0 resection rate, duration of response, progression-free survival, overall survival, and safety and tolerability of the treatment. Shanghai Junshi Biomedical Technology Co., Ltd. Provides the first three cycles of toripalimab for free and has purchased liability insurance for clinical trial subjects.
Detailed Description
For patients with locally recurrent rectal cancer (LRRC), response rate of chemoradiotherapy is 40-50% and only approximately 40-50% of patients with recurrent rectal cancer can undergo R0 resection. Recent studies have shown promising synergistic effects of the combination of immunotherapy (PD-1/PD-L1 antibodies) and neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). Thus, for LRRC patients, addition of immunotherapy to CRT is likely to further improve the response rate and prognosis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Rectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
93 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
The enrolled patients will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history) for pelvic recurrence. Patients (cohort A) will receive CAPOX, FOLFIRI or mFOLFOX6 chemotherapy based on previous adverse reactions to chemotherapy agents and at the discretion of the oncologist. Patients (cohort B) will receive CAPOX, FOLFIRI, mFOLFOX6, mXELIRI, irinotecan and raltitrexed, or oxaliplatin and raltitrexed chemotherapy based on the first-line chemotherapy and previous adverse reactions to chemotherapy agents and at the discretion of the oncologist. All metastasis sites will receive stereotactic ablative radiotherapy (SABR). SABR would be delivered between chemoimmunotherapy cycles. Five-fraction regimens (25-50Gy/5Fx) are delivered daily. Dose Constraints are based on SABR-COMET 10 trial.
Intervention Type
Drug
Intervention Name(s)
PD-1 antibody
Other Intervention Name(s)
Toripalimab
Intervention Description
PD-1 antibody (Toripalimab): 240mg q3w or 160mg q2w
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Other Intervention Name(s)
Xeloda
Intervention Description
Capecitabine: 1000mg/m2 d1-14 q3w
Intervention Type
Drug
Intervention Name(s)
5FU
Intervention Description
400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr)
Intervention Type
Drug
Intervention Name(s)
folinic acid
Intervention Description
400 mg/m2 q2w
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Intervention Description
130 mg/m² q3w or 85 mg/m² q2w
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Intervention Description
180 mg/m² q2w and 200 mg/m² q3w
Intervention Type
Drug
Intervention Name(s)
Raltitrexed
Intervention Description
2 mg/m² q2w and 3 mg/m² q3w
Intervention Type
Radiation
Intervention Name(s)
Radiation
Intervention Description
25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history) for pelvic recurrence tumor. 35-60Gy/5-8Fx irradiation for distance metastasis tumor.
Primary Outcome Measure Information:
Title
Local objective response rate
Description
the proportion of patients with the best pelvic response of confirmed complete or partial response according to RECIST 1.1, as assessed by the investigator.
Time Frame
up to 1 year
Secondary Outcome Measure Information:
Title
Extrapelvic objective response rate
Description
proportion of patients with confirmed extrapelvic complete or partial response per RECIST 1.1.
Time Frame
up to 1 year
Title
R0 resection rate
Description
the proportion of patients who achieve R0 resection of pelvic recurrent tumour after therapy.
Time Frame
up to 1 year
Title
Duration of response (DOR)
Description
time from the first documented pelvic objective response to pelvic or extrapelvic disease progression in patients with confirmed response.
Time Frame
up to 1 year
Title
Progression-Free Survival
Description
time from the date of start treatment until disease progression or censored at last follow-up or death.
Time Frame
up to 3 year
Title
Overall Survival
Description
from the date of start treatment until the date of death from any cause or censored at last follow-up.
Time Frame
up to 3 year
Title
Safety and tolerability of the treatment
Description
proportion of patients with treatment-related acute toxicities as assessed by NCI CTCAE v5.0, from treatment initiation until 90 days upon completion of immunotherapy.
Time Frame
up to 1 year

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: Patient is 18-75 years old at the time of signing the informed consent form. ECOG performance status 0-1. MRI/enhanced CT confirmed pelvic recurrence. According to RECIST 1.1, there is at least one measurable pelvic lesion. Distant metastasis lesions are no more than 5 and metastatic organ are no more than 3. No prior radiotherapy within 6 month. Previous system therapy. Patients Group Cohort A: participants with pelvic recurrence who have not previously been treated with first-line chemotherapy. Cohort B: Patients with disease progression or new lesions after first-line chemotherapy. Has an investigator determined life expectancy of at least 24 weeks. Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors. Non pregnant or lactating patients. Effective contraceptive methods should be used during the study and within 6 months of the last administration. Fully informed and willing to provide written informed consent for the trial. Exclusion Criteria: Neutrophil < 1.5×10^9/L, PLT < 100×10^9/L (PLT < 80×10^9/L in patients with liver metastasis), or Hb < 90g/L; blood transfusion within 2 weeks before enrollment is not allowed to meet the enrollment criteria. TBIL > 1.5 ULN, or TBIL > 2.5 ULN in patients with liver metastasis. AST or ALT > 2.5 ULN, or ALT and / or AST > 5 ULN in patients with liver metastasis. Cr > 1.5 ULN, or creatinine clearance < 50ml / min (calculated according to Cockcroft Gault formula). APTT > 1.5 ULN, PT > 1.5 ULN (subject to the normal value of the clinical trial research center). Serious electrolyte abnormalities. Urinary protein ≥ 2+, or 24-hour urine protein ≥1.0g/24h. Uncontrolled hypertension: SBP >140mmHg or DBP > 90mmHg. The presence of gastrointestinal diseases such as gastric or duodenal active ulcers, ulcerative colitis or unresected tumours with active bleeding; or other conditions likely to cause gastrointestinal bleeding or perforation; or unhealed gastrointestinal perforation or gastrointestinal fistula after surgical treatment. A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months. A history of heart disease within 6 months (including congestive heart failure, acute myocardial infarction, severe/unstable angina, coronary artery bypass grafting, cardiac insufficiency ≥ NYHA grade 2 and LVEF<50%). Uncontrolled malignant pleural effusion, ascites, or pericardial effusion. History of anti-PD-1, PD-L1, PD-L2, CTLA-4 or any other specific T cell co-stimulation or checkpoint pathway targeted therapy. The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years excluding adequately treated non-melanoma skin cancer, carcinoma in situ of cervix and superficial bladder tumour (non-invasive tumour, or carcinoma in situ, or T1). A history of liver disease including, but not limited to HBV infection or HBV DNA positive(≥1×10^4/ml), HCV infection or HCV DNA positive(≥1×10^3/ml) and liver cirrhosis. Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication; Or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period. The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems. Serious mental abnormalities. The diameter of brain metastasis is greater than 3cm or the total volume is greater than 30cc. Clinical or radiological evidence of spinal cord compression, or tumours within 3 mm of the spinal cord on MRI.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhen Zhang, MD PhD
Phone
18801735029
Email
zhen_zhang@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhen Zhang, MD PhD
Organizational Affiliation
Fudan University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fudan University Shanghai Cancer Center
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200032
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhen Zhang, MD,PhD
Phone
18801735029
Email
zhen_zhang@fudan.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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The Combination of Hypofractionated Radiotherapy and Immunotherapy in Locally Recurrent Rectal Cancer

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