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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Hypofractionated Radiotherapy Combined With Chemotherapy and Toripalimab for Locally Recurrent Rectal Cancer: a Single-arm, Two-cohort, Phase II Trial (TORCH-R)

Conditions
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Recurrent Rectal Cancer

Intervention / Treatment
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* Drug: PD-1 antibody
* Drug: Capecitabine
* Drug: 5FU
* Drug: folinic acid
* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Raltitrexed
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>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. | Drug: PD-1 antibody<br>* PD-1 antibody (Toripalimab): 240mg q3w or 160mg q2w<br>* Other names: Toripalimab;Drug: Capecitabine<br>* Capecitabine: 1000mg/m2 d1-14 q3w<br>* Other names: Xeloda;Drug: 5FU<br>* 400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr)<br>Drug: folinic acid<br>* 400 mg/m2 q2w<br>Drug: Oxaliplatin<br>* 130 mg/m² q3w or 85 mg/m² q2w<br>Drug: Irinotecan<br>* 180 mg/m² q2w and 200 mg/m² q3w<br>Drug: Raltitrexed<br>* 2 mg/m² q2w and 3 mg/m² q3w<br>Radiation: Radiation<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extrapelvic objective response rate | proportion of patients with confirmed extrapelvic complete or partial response per RECIST 1.1. | up to 1 year | 
| R0 resection rate | the proportion of patients who achieve R0 resection of pelvic recurrent tumour after therapy. | up to 1 year | 
| Duration of response (DOR) | time from the first documented pelvic objective response to pelvic or extrapelvic disease progression in patients with confirmed response. | up to 1 year | 
| Progression-Free Survival | time from the date of start treatment until disease progression or censored at last follow-up or death. | up to 3 year | 
| Overall Survival | from the date of start treatment until the date of death from any cause or censored at last follow-up. | up to 3 year | 
| 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. | up to 1 year |