Circulating Tumor DNA and T Cell Repertoire Predict Radiotherapeutic Outcomes in NSCLC Patients With Brain Metastasis

Not yet recruiting

• Conditions: Carcinoma, Non-Small-Cell Lung; Brain Metastases
• Interventions: Radiation: Whole-brain radiotherapy

• Registration Number: NCT05737589
• Lead Sponsor: Xiaorong Dong

Brief Summary

Collection of ctDNA and TCR data to predict the efficacy and prognosis of brain radiotherapy in patients with brain metastases from non-small cell lung cancer (NSCLC) in a comprehensive manner

Detailed Description

The scarcity of biopsies or focal resections for brain metastases limits the discovery of biomarkers for diagnosing and prognosis of NSCLC patients with brain metastases. Circulating tumor DNA (ctDNA) is derived from the necrosis, apoptosis, and secretion of tumor cells and is widely distributed in various body fluids, including peripheral blood and cerebrospinal fluid (CSF). Genomic alterations in blood and CSF ctDNA are prognostic markers in NSCLC patients with brain metastases. Still, they have limited predictive power. T cell-mediated immune responses are essential to suppress carcinogenesis and metastasis in NSCLC. Targeted sequencing in the highly variable complementarity determining region 3 (CDR3) region of the T cell receptor (TCR) β-chain provides a powerful approach to quantifying the diversity of T cells. Radiotherapy causes antigen exposure through direct local destruction of cancer cells, which activates the local and systemic immune system. Radiotherapy can also cause intracellular DNA damage, and the ensuing mutations in DNA mismatch repair defects may increase neoantigen load, triggering an immune response. The TCR, closely related to immune system modifications, can also be altered by radiotherapy. However, no clinical studies have explored ctDNA and TCR to predict the efficacy and prognosis of brain radiotherapy in patients with NSCLC brain metastases. Therefore, we retrieved the visit data of 50 patients with advanced NSCLC brain metastases who received brain radiotherapy through the hospital electronic medical record system and recorded the ctDNA and TCR values of patients' blood and CSF at baseline (within 2 weeks before radiotherapy), T0 (within 24 hours after the completion of radiotherapy) and T28 (28 days after the completion of radiotherapy), disease progression recurrence and survival time by examining. The dynamic changes of ctDNA and TCR during brain radiotherapy were studied to comprehensively assess the ability of ctDNA and TCR to predict the efficacy and prognosis of brain radiotherapy in patients with NSCLC brain metastases.

Study Timeline

• Status Verified: 2023-02
• Study First Submitted: 2023-02-12
• Study First Submitted QC: 2023-02-12
• Last Update Submitted: 2023-02-12
• Study Start: 2023-02-13
• Study First Posted: 2023-02-21
• Last Update Posted: 2023-02-21
• Primary Completion: 2024-02-13
• Study Completion: 2024-10-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Age > 18 years

2. Patients must have histologically or cytologically confirmed NSCLC and imaging-confirmed primary non-small cell lung cancer with brain metastases

3. ECOG PS score of 0-2

4. At least 1 lesion meeting RECIST 1.1 target lesion (TL) criteria at baseline. Must have baseline assessment imaging of the tumor by CT or MRI scan within 28 days prior to treatment

5. No prior radiation therapy to the tumor, including but not limited to whole brain radiotherapy, prophylactic brain irradiation, stereotactic radiation therapy, etc.

6. Major organ function indicators meet the criteria for conventional radiation therapy Adequate organ and bone marrow function is defined as follows

   1. Hemoglobin ≥ 9.0 g/dL
   2. absolute neutrophil count ≥ 1.5 × 109 / L
   3. Platelet count ≥ 100 × 109 / L
   4. Serum bilirubin ≤ 1.5 × the upper limit of normal (ULN). The above criteria were not applied to patients diagnosed with Gilbert's syndrome, but these patients were allowed to be enrolled after consultation between the study physician and their primary care physician.
   5. Alanine aminotransferase ALT or aspartate aminotransferase AST ≤ 2.5 × ULN
   6. Creatinine clearance (CL) > 40 mL/min calculated or actually measured according to the Cockcroft-Gault method (based on actual body weight) Men. Creatinine CL = Body weight (kg) × (140 - age) (mL/min) 72 x serum creatinine (mg/dL) Females. Creatinine CL = Body weight (kg) × (140 - age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)

7. Female subjects of childbearing age must exclude pregnancy

8. Life expectancy >12 weeks

9. Body weight >30Kg

Exclusion Criteria

1. History of allogeneic organ transplantation
2. Active or previously documented autoimmune or inflammatory disease (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis (except diverticular disease), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener's syndrome [granulomatous vasculitis, Graves' disease, rheumatoid arthritis, pituitary inflammation, uveitis, etc.])
3. History of active primary immunodeficiency
4. Other malignancies within the last 3 years.
5. Presence of uncontrolled co-morbidities including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmias, active interstitial lung disease, a severe chronic gastrointestinal disease with diarrhea or mental illness that limits compliance with study requirements, significantly increases the risk of AE or affects the patient's life/ social conditions
6. Active infection at the time of treatment, including tuberculosis (clinical assessment includes history, physical examination, imaging findings, and tuberculosis screening consistent with local clinical practice), hepatitis B (known hepatitis B surface antigen positive [HBsAg] result), hepatitis C virus (HCV) or human immunodeficiency virus (HIV 1/2 antibody positive). Patients with previous hepatitis B virus (HBV) infection or cured HBV infection (defined as the presence of positive hepatitis B core antibodies and negative HBsAg) may participate in this study. patients with positive HCV antibodies who are negative for HCV ribonucleic acid (RNA) by polymerase chain reaction only may participate in this study.
7. Stage IV NSCLC according to the 8th edition of the International Society for the Study of Lung Cancer Thoracic Oncology Staging Manual
8. Histological findings of NSCLC with mixed small cell component

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Observation group	Whole-brain radiotherapy	This is an observational study, no interventions will be applied to patients in the observation group, and only blood and cerebrospinal fluid ctDNA and TCR data of patients with brain metastases from non-small cell lung cancer treated with radiotherapy will be recorded to predict patient prognosis. Peripheral blood and CSF samples were collected at baseline, 24 h (T0), and 28 days (T28) after completion of radiotherapy and underwent deep sequencing of ctDNA and TCR. The 6-month response rates of brain metastases and systemic lesions were evaluated based on Response Evaluation Criteria in Solid Tumors version 1.1 for further study.

Primary Outcome Measures

Name	Time	Method
overall survival (OS)	February 13, 2023-February 13, 2024	OS is defined as the time elapsed between the initiation of radiotherapy and mortality from any cause.

Secondary Outcome Measures

Name	Time	Method
progression-free survival (PFS)	February 13, 2023-February 13, 2024	PFS is defined as the time elapsed between the start of radiotherapy and the first sign of disease progression or death from any cause.
intracranial PFS (iPFS)	February 13, 2023-February 13, 2024	The duration from the start of radiotherapy to the first intracranial lesion progression or death from any cause is referred to as iPFS.

Trial Locations

Locations (1)

Union hospital; 🇨🇳 Wuhan, Hubei, China