SBRT + PD-1 Antibody in Unresectable Locally Recurrent Rectal Cancer（SPARKLE）

Summary

This is a prospective study to delve into the therapeutic benefits of combining stereotactic body radiation therapy (SBRT) with PD-1 monoclonal antibody treatment for patients with unresectable locally recurrent rectal cancer (ULRRC). Our aim is to ascertain the safety of this approach and to offer robust, evidence-based medical guidance for the management of ULRRC using this innovative combination therapy. Researchers will combine SBRT with PD-1 for ULRRC to see if this treatment can provide a benefit of survival. Participants will: 1. Receive chemotherapy combined with PD-1 therapy for 1 cycle → SBRT treatment → Chemotherapy combined with PD-1 therapy for 3-6 cycles (assessment 6 weeks after SBRT treatment) → Surgery/Maintenance therapy. 2. Visit the clinic once every 3 months for checkups and tests

Eligibility

Inclusion Criteria:

1. Before implementing procedures related to the research protocol rather than routine care, informed consent forms with the subject's voluntary signature and dated must be obtained in accordance with regulations and institutional guidelines;
2. Patients with pMMR/MSS colorectal cancer;
3. Age between 18 and 75 years;
4. Tumor recurrence confirmed by histology, cytology, or imaging, and the multidisciplinary team (MDT) including surgeons assesses that the recurrent lesion cannot achieve a one-stage R0 resection (unresectable is defined as: 1. Pelvic MRI showing sacral infiltration at or above S2, 2. And/or lateral pelvic wall invasion, 3. And/or obturator vascular nerve infiltration, 4. After MDT discussion, there are no indications for a one-stage R0 resection, 5. The patient refuses total pelvic exenteration or debulking surgery);
5. Locally recurrent rectal adenocarcinoma without clear distant metastasis at diagnosis/MDT team assesses oligometastases as resectable/controllable (UICC 8th edition);
6. No prior radiotherapy, or a gap of more than 6 months between the completion of initial radiotherapy and the start of retreatment, with a previous radiotherapy dose of less than 50.4Gy, and no late toxicity in the small bowel or bladder;
7. ECOG performance status 0-1;
8. Peripheral blood counts and liver and kidney functions within the following allowed ranges (tested within 15 days before treatment start):

   * White blood cells (WBC) ≥ 3.0×10\^9/L or Absolute Neutrophil Count (ANC) ≥ 1.5×10\^9/L;

     * Hemoglobin (HGB) ≥ 80 g/L;

       * Platelets (PLT) ≥ 100×10\^9/L;

         * Liver transaminases (AST/ALT) \< 3.0 times the upper limit of the normal range;

           * Total bilirubin (TBIL) \< 1.5 times the upper limit of the normal range;

             * Creatinine (CREAT) \< 1.5 times the upper limit of the normal range;
9. No history of other malignancies, not pregnant or breastfeeding, and should use effective contraception during the study period and for 6 months after the last administration;
10. Expected survival ≥ 12 months.

Exclusion Criteria:

1. Patients with a history of severe drug allergies (including allergies to platinum-based agents, 5-FU, LV, and 5-HT3 receptor antagonists);
2. Patients who have participated in or are currently participating in other clinical trials within 4 weeks of enrollment;
3. History of receiving anti-PD-1, PD-L1, PD-L2, CTLA-4, or any other specific T-cell co-stimulation or checkpoint pathway targeted therapies;
4. Severe electrolyte abnormalities;
5. Presence of gastrointestinal diseases, such as active ulcers of the stomach or duodenum, ulcerative colitis, or unresected tumors with active bleeding; or other conditions that may lead to gastrointestinal bleeding or perforation; or gastrointestinal perforations that have not healed after surgical treatment;
6. History of arterial thrombosis or deep vein thrombosis within 6 months; history of bleeding or evidence of bleeding tendency within 2 months;
7. Pregnant or breastfeeding women or women who may become pregnant with a positive pregnancy test before the first dose; or female participants who are unwilling to strictly use contraception during the study period and their partners;
8. Brain metastases with a diameter greater than 3cm or a total volume greater than 30cc;
9. Clinical or radiological evidence of spinal cord compression, or tumors within 3 millimeters of the spinal cord on MRI;
10. History or concurrent presence of other active malignant tumors (except for malignant tumors that have been treated curatively and have not recurred for more than 3 years or carcinoma in situ that can be cured with adequate treatment);
11. Combined with severe electrocardiogram abnormalities or active coronary artery disease within 12 months before participating in the study, severe/unstable angina or newly diagnosed angina or myocardial infarction, New York Heart Association (NYHA) Class II or higher congestive heart failure;
12. Patients with active infections (infections causing fever above 38°C);
13. Patients with poorly controlled hypercalcemia, hypertension, diabetes;
14. Patients with severe pulmonary diseases (interstitial pneumonia, pulmonary fibrosis, severe emphysema, etc.);
15. Patients with mental disorders affecting clinical treatment or a history of central nervous system diseases;
16. Patients with severe complications (intestinal obstruction, renal insufficiency, liver dysfunction, cerebrovascular disorders, etc.);
17. Any toxicity of grade 2 or above from previous treatments that has not yet resolved (except for anemia, alopecia, and skin pigmentation);
18. Any medical condition that is unstable or would affect patient safety and compliance with the study;
19. Patients deemed unsuitable for participation in this clinical trial by the investigator.

Conditions2

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