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

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

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 +/- target therapy, 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.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Rectal Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: PD-1 antibody; Drug: folinic acid; Drug: Oxaliplatin; Drug: Irinotecan; Drug: Raltitrexed; Radiation: Radiation; Drug: 5FU; Drug: Cetuximab; Drug: Bevacizumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 93
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhen Zhang, MD PhD; Phone Number: 18801735029; Email: zhen_zhang@fudan.edu.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Zhen Zhang, MD,PhD; Phone Number: 18801735029; Email: zhen_zhang@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment arm; The enrolled patients will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history) for pelvic recurrence. Cohort A patients will receive CAPOX, FOLFIRI or mFOLFOX6 chemotherapy andcohort B patients will receive CAPOX, FOLFIRI, mFOLFOX6, mXELIRI, irinotecan and raltitrexed, or oxaliplatin and raltitrexed chemotherapy, based on previous chemotherapy and adverse reactions to chemotherapy agents or at the discretion of the oncologist. All metastasis sites will receive stereotactic ablative radiotherapy (SABR) between chemoimmunotherapy cycles. Five-fraction regimens (25-50Gy/5Fx) are delivered daily. Dose Constraints are based on SABR-COMET 10 trial. Besides, according to the medical oncologist recommendation, patients with unresectable pelvic recurrence or distant metastasis will receive target therapy based on the KRAS/NRAS/BRAF mutation station.

Drug: Capecitabine; Capecitabine: 1000mg/m2 d1-14 q3w; Other Names: Xeloda; Drug: PD-1 antibody; PD-1 antibody (Toripalimab): 240mg q3w or 160mg q2w; Other Names: Toripalimab; Drug: folinic acid; 400 mg/m2 q2w; Drug: Oxaliplatin; 130 mg/m² q3w or 85 mg/m² q2w; Drug: Irinotecan; 180 mg/m² q2w and 200 mg/m² q3w; Drug: Raltitrexed; 2 mg/m² q2w and 3 mg/m² q3w; Radiation: Radiation; 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.; Drug: 5FU; 400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr); Drug: Cetuximab; 400 mg/m² q2w; Drug: Bevacizumab; 5 mg/kg q2w or 7.5mg/kg q3w

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Zhen Zhang, MD PhD, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 17, 2022
• First Submitted That Met QC Criteria: November 17, 2022
• First Posted (Actual): November 28, 2022

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 28, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Folic Acid Antagonists; Antibodies; Capecitabine; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid; Cetuximab; Raltitrexed
• Other Study ID Numbers: FDRT-2022-289-3006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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