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

NCT ID: NCT05628038

Last Updated: 2024-10-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 93 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-30
• Study Completion Date: 2025-12-01

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 +/- 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.

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.

Conditions

Recurrent Rectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

PD-1 antibody

Intervention Type: DRUG

PD-1 antibody (Toripalimab): 240mg q3w or 160mg q2w

Capecitabine

Intervention Type: DRUG

Capecitabine: 1000mg/m2 d1-14 q3w

5FU

Intervention Type: DRUG

400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr)

folinic acid

Intervention Type: DRUG

400 mg/m2 q2w

Oxaliplatin

Intervention Type: DRUG

130 mg/m² q3w or 85 mg/m² q2w

Irinotecan

Intervention Type: DRUG

180 mg/m² q2w and 200 mg/m² q3w

Raltitrexed

Intervention Type: DRUG

2 mg/m² q2w and 3 mg/m² q3w

Cetuximab

Intervention Type: DRUG

400 mg/m² q2w

Bevacizumab

Intervention Type: DRUG

5 mg/kg q2w or 7.5mg/kg q3w

Radiation

Intervention Type: 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.

Interventions

PD-1 antibody

PD-1 antibody (Toripalimab): 240mg q3w or 160mg q2w

Intervention Type: DRUG

Capecitabine

Capecitabine: 1000mg/m2 d1-14 q3w

Intervention Type: DRUG

5FU

400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr)

Intervention Type: DRUG

folinic acid

400 mg/m2 q2w

Intervention Type: DRUG

Oxaliplatin

130 mg/m² q3w or 85 mg/m² q2w

Intervention Type: DRUG

Irinotecan

180 mg/m² q2w and 200 mg/m² q3w

Intervention Type: DRUG

Raltitrexed

2 mg/m² q2w and 3 mg/m² q3w

Intervention Type: DRUG

Cetuximab

400 mg/m² q2w

Intervention Type: DRUG

Bevacizumab

5 mg/kg q2w or 7.5mg/kg q3w

Intervention Type: DRUG

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.

Intervention Type: RADIATION

Other Intervention Names

Toripalimab; Xeloda

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Zhen Zhang

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhen Zhang, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhen Zhang, MD PhD

Role: CONTACT

zhen_zhang@fudan.edu.cn

18801735029

Facility Contacts

Zhen Zhang, MD,PhD

Role: primary

zhen_zhang@fudan.edu.cn

18801735029

References

Wan J, Wu R, Fu M, Shen L, Zhang H, Wang Y, Wang Y, Zhou S, Chen Y, Xia F, Zhang Z. TORCH-R trial protocol: hypofractionated radiotherapy combined with chemotherapy and toripalimab for locally recurrent rectal cancer: a prospective, single-arm, two-cohort, phase II trial. Front Oncol. 2023 Nov 20;13:1304767. doi: 10.3389/fonc.2023.1304767. eCollection 2023.

Reference Type: DERIVED

PMID: 38053659 (View on PubMed)

Other Identifiers

FDRT-2022-289-3006

Identifier Type: -

Identifier Source: org_study_id