125I Seed Brachytherapy Combined With Immunotherapy for Primary, Recurrent, or Metastatic Malignant Tumors

A Prospective, Randomized, Open-Label, Parallel-Group Clinical Trial Evaluating the Efficacy and Safety of 125I Seed Interstitial Brachytherapy Combined With Immune Checkpoint Inhibitor Therapy in Patients With Primary, Recurrent, or Metastatic Malignant Tumors Compared With Immune Checkpoint Inhibitor Therapy Alone

This prospective randomized trial evaluates the efficacy and safety of combining 125I seed interstitial brachytherapy with immune checkpoint inhibitor therapy in patients with primary, recurrent, or metastatic malignant tumors. Immunotherapy has become an important systemic treatment option, yet many patients experience limited benefit due to low tumor immunogenicity, insufficient T-cell infiltration, and an immunosuppressive tumor microenvironment.

125I seed brachytherapy provides continuous low-dose-rate radiation to the tumor, promoting antigen release, enhancing dendritic cell activation, and potentially converting immunologically "cold" tumors into more responsive "hot" lesions. Integrating localized radiation with systemic immunotherapy may improve tumor response, prolong progression-free survival, and reduce recurrence.

Patients will be randomized 1:1 to receive 125I seed implantation plus immunotherapy or immunotherapy alone. The primary endpoints are objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints include failure-free survival (FFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), local control, recurrence rate, adverse events, and quality of life. Exploratory analyses will assess radiomics features, subgroup responses, and different patterns of recurrence. This study aims to determine whether adding 125I seed brachytherapy enhances the clinical benefits of immunotherapy across diverse malignant tumors.

Study Overview

• Status: Not yet recruiting
• Conditions: Malignant Tumors
• Intervention / Treatment: Drug: Immune Checkpoint Inhibitors; Other: 125I Seed Implantation; Drug: Immune Checkpoint Inhibitors

Detailed Description

Patients with malignant tumors-including primary, recurrent, and metastatic disease-often exhibit heterogeneous responses to immune checkpoint inhibitors (ICIs). Limited tumor antigen exposure, poor immune infiltration, and an immunosuppressive tumor microenvironment frequently restrict the efficacy of immunotherapy. Strategies capable of enhancing local tumor immunogenicity and promoting systemic immune activation may improve clinical outcomes.

125I seed interstitial brachytherapy delivers continuous low-dose-rate radiation precisely to the tumor, offering both durable local control and immunomodulatory effects. Low-dose-rate irradiation can induce immunogenic tumor cell death, increase tumor antigen presentation, enhance dendritic cell activation, and promote T-cell recruitment. This process may convert immunologically inactive ("cold") tumors into immunologically active ("hot") lesions, thereby synergizing with ICIs to enhance anti-tumor immunity. Combining these modalities may improve objective response, delay treatment failure, reduce recurrence, and prolong survival.

This prospective, randomized, open-label, parallel-group trial will compare 125I seed brachytherapy plus immunotherapy with immunotherapy alone. Eligible patients will be randomized 1:1. The combination arm will receive CT-guided seed implantation followed by ICI therapy; the control arm will receive ICI monotherapy. All patients will undergo standardized imaging and clinical evaluations at pre-defined intervals.

The primary endpoints are objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints include failure-free survival (FFS), overall survival, disease control rate, duration of response, local control rate, tumor recurrence rate, treatment-related and immune-related adverse events, and patient-reported quality of life. Exploratory analyses will investigate radiomics features associated with response, patterns of recurrence (local, regional, or distant), and subgroup differences across tumor types, disease stages, biomarker profiles, and treatment characteristics. These analyses may help identify imaging or clinical predictors of benefit, refine patient selection, and support biomarker-driven optimization of 125I seed brachytherapy combined with immunotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Min Li, Dr.; Phone Number: 0531-51665482; Email: liminyingxiang.@163.com
• Study Contact Backup: Name: Min Li, Dr.; Email: 924787237@qq.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250031
      • The 960th Hospital of People's Liberation Army (PLA)
      • Contact: Min Li, Dr.; Phone Number: 0531-51665482; Email: 924787237@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 80 years.
• Histologically or clinically confirmed primary, recurrent, or metastatic malignant tumor.
• At least one measurable lesion according to RECIST 1.1 or iRECIST.
• Tumor site suitable for 125I seed implantation under CT or PET/CT guidance.
• Planned to receive or eligible to receive an immune checkpoint inhibitor (ICI).
• ECOG performance status 0-2.
• Adequate organ function:

ANC ≥ 1.5 × 10⁹/L Platelets ≥ 80 × 10⁹/L Hemoglobin ≥ 90 g/L AST/ALT ≤ 3 × ULN (≤ 5 × ULN for liver metastasis) Creatinine clearance ≥ 50 mL/min

• Life expectancy ≥ 3 months.
• Ability to understand and sign informed consent.

Exclusion Criteria:

• Prior I-125 seed implantation at the planned treatment site.
• Active uncontrolled infection or systemic inflammatory disease.
• Known history of autoimmune disease requiring systemic immunosuppression.
• Prior treatment with immune checkpoint inhibitors within the last 4 weeks.
• Uncontrolled coagulopathy or contraindication to interventional seed implantation:

INR > 1.5 Platelets < 50 × 10⁹/L

• Tumor location that poses unacceptable procedural risk, including inability to obtain a safe puncture path.
• Severe cardiopulmonary dysfunction (e.g., heart failure, unstable arrhythmia, severe COPD).
• Pregnancy or breastfeeding.
• Known allergy or contraindication to radiopharmaceuticals, contrast agents, or anesthesia agents used during implantation.
• Any condition that, in the investigator's judgment, makes the participant unsuitable for the study (e.g., poor compliance, severe psychiatric disorder).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 125I Seed Brachytherapy + Immunotherapy; Participants in this arm will receive CT-guided 125I seed interstitial brachytherapy, followed by systemic immune checkpoint inhibitor (ICI) therapy administered according to the approved dosing schedule for the selected agent. Seed implantation will be planned and delivered using standardized TPS-based dosimetric protocols, and immunotherapy will continue until progression, unacceptable toxicity, or study completion.	Drug: Immune Checkpoint Inhibitors; Examples include PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, camrelizumab, sintilimab) Administered per standard dosing schedule (e.g., every 2-3 weeks); Other: 125I Seed Implantation; PET/CT-guided implantation or CT-guided implantation Dose planning: D90 typically 90-140 Gy (adjusted per tumor type and size) Post-implant dosimetry: D90, V100, V150 recorded; Drug: Immune Checkpoint Inhibitors; Same agent class and dosing schedule as the experimental arm Administered until disease progression, unacceptable toxicity, or study completion
Active Comparator: Immunotherapy Alone; Participants in this arm will receive systemic immune checkpoint inhibitor (ICI) therapy alone, following the same agent, schedule, and supportive care standards used in the experimental arm. No local radiotherapy or seed implantation will be performed. Treatment will continue until disease progression, unacceptable toxicity, or study completion.	Drug: Immune Checkpoint Inhibitors; Examples include PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, camrelizumab, sintilimab) Administered per standard dosing schedule (e.g., every 2-3 weeks); Drug: Immune Checkpoint Inhibitors; Same agent class and dosing schedule as the experimental arm Administered until disease progression, unacceptable toxicity, or study completion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Proportion of patients achieving complete response (CR) or partial response (PR) as defined by RECIST 1.1 or iRECIST, assessed via CT/MRI/PET-CT.	Every 6-12 weeks, up to 24 months
Progression-Free Survival (PFS)	Time from randomization to radiographic disease progression or death from any cause.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure-Free Survival (FFS)	Time from randomization to the first occurrence of treatment failure, including disease progression, local recurrence, distant metastasis, discontinuation due to adverse events, or death.	Up to 24 months
Overall Survival (OS)	Time from randomization to death from any cause.	Up to 36 months
Disease Control Rate (DCR)	Percentage of patients achieving CR, PR, or stable disease (SD), according to RECIST 1.1/iRECIST.	Every 6-12 weeks, up to 24 months
Duration of Response (DoR)	Time from first documentation of CR/PR until radiographic progression or death.	Up to 24 months
Local Control Rate (LCR)	Proportion of treated lesions without local progression, based on imaging (CT/MRI/PET-CT) and dosimetric correlation of the implanted region.	Up to 24 months
Tumor Recurrence Rate	Rate of local or regional tumor recurrence, defined by new lesions or regrowth within the same anatomical region as confirmed by imaging.	Up to 24 months
Treatment-Related Adverse Events (TRAEs)	Incidence, severity, and type of adverse events associated with treatment, graded according to CTCAE v5.0.	From baseline until 90 days after last treatment
Immune-Related Adverse Events (irAEs)	Incidence and grade of immunotherapy-related toxicities such as pneumonitis, colitis, dermatitis, endocrinopathies.	Up to 24 months
Quality of Life (QoL)	Assessed using validated patient-reported instruments (e.g., EORTC QLQ-C30).	Baseline, Week 12, Week 24, and every 6 months up to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiomics Features and Predictive Modeling	Extraction of radiomic features from PET/CT or CT images to explore associations with ORR, PFS, recurrence pattern, and treatment response.	Up to 24 months
Subgroup Analyses	Assessment of treatment effect by clinical subgroups (primary vs recurrent vs metastatic disease, tumor type, PD-L1 expression, inflammatory markers).	Up to 24 months
Patterns of Failure / Recurrence Patterns	Classification of failure patterns (local, regional, distant) and correlation with dosimetry (D90, V100) and imaging biomarkers.	Up to 24 months

Collaborators and Investigators

• Sponsor: Li Min
• Investigators: Study Director: Min Li, Dr.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: November 30, 2025
• First Submitted That Met QC Criteria: November 30, 2025
• First Posted (Estimated): December 11, 2025

Study Record Updates

• Last Update Posted (Actual): January 6, 2026
• Last Update Submitted That Met QC Criteria: January 2, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Immune Checkpoint Inhibitors; lodine-125 Seed Brachytherapy; Local-Systemic Synergy; Recurrent or Refractory Tumors
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Neoplasms; Recurrence; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: 960HP20251119

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) will be made available to qualified researchers upon reasonable request after completion of the study and publication of the primary results. Data to be shared may include demographic information, treatment assignment, key efficacy outcomes, adverse events, and imaging-derived parameters. A data-sharing agreement will be required to ensure appropriate use of the dataset.
• IPD Sharing Time Frame: Individual participant data (IPD) will be available beginning 6 months after publication of the primary study results and will remain available for 5 years following publication, or until the main study database is closed, whichever occurs first.

IPD Sharing Access Criteria

Qualified researchers affiliated with academic institutions or recognized research organizations may request access to de-identified individual participant data (IPD), including imaging-derived parameters, dosimetric results, and clinical outcome data.

Requests must include a brief research proposal describing the scientific rationale, objectives, and planned analyses. Approval will be granted by the study's principal investigator and institutional ethics committee. Data will be shared through secure institutional data transfer systems after execution of a formal data sharing agreement that ensures patient confidentiality and compliance with applicable privacy regulations.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No