This is an investigator-initiated, Phase I clinical trial. It aims to evaluate the safety, tolerability, dosimetry, and preliminary anti-tumor activity of a novel radiopharmaceutical, [177Lu]Lu-DOTA-EB-RGD2, in patients with recurrent high-grade gliomas. Participants will receive the drug either via intravenous infusion or directly into the tumor cavity through a pre-implanted Ommaya reservoir (a subcutaneously placed device that allows direct access to the tumor cavity). The study employs a "3+3" dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events, biodistribution, and tumor response (by MRI) will be assessed. Approximately 24 patients will be enrolled across two major Chinese medical centers: Beijing Tiantan Hospital and Peking Union Medical College Hospital.

This is a multicenter, open-label, Phase I dose-escalation study with two parallel routes of administration: intravenous (IV) and locoregional (via Ommaya reservoir into the tumor cavity). The primary objective is to determine the maximum tolerated dose (MTD) of [177Lu]Lu-DOTA-EB-RGD2 for each route using a standard "3+3" design. Three dose levels per cycle are planned for each route (IV and locoregional). Treatment is given every 3 weeks for up to 2 cycles, with possible additional cycles based on clinical benefit as judged by the investigator.

Primary endpoint: Dose-limiting toxicity (DLT) incidence during the first 6 weeks (2 cycles), graded by CTCAE v5.0.

Secondary endpoints: Adverse events (type, frequency, severity); time-activity curves and absorbed radiation doses in organs and tumors (based on whole-body planar imaging and SPECT/CT at multiple time points); pharmacokinetic parameters (AUC, Cmax, Tmax, clearance [CL], volume of distribution [Vz], terminal half-life) from blood and urine sampling; objective response rate (ORR) per RANO 2.0 (by contrast-enhanced MRI); overall survival.

Exploratory endpoints: Change in tumor αvβ3 integrin expression by NOTA-PRGD2 PET/CT; correlation between baseline NOTA-PRGD2 PET uptake and treatment response.

Sample size: Approximately 24 patients (up to 3+3 per dose level per route) using the 3+3 rule. No formal hypothesis testing is planned; descriptive statistics will be used.

Study duration: 36 months (recruitment approximately 12 months, treatment and follow-up approximately 24 months). The trial is conducted at Beijing Tiantan Hospital and Peking Union Medical College Hospital, China.

Inclusion Criteria:

1. The participant must sign the informed consent form before participation.

2. Age ≥ 18 years.

3. Histologically confirmed glioblastoma (WHO classification) after surgical resection or biopsy.

4. Participants receiving corticosteroids (e.g., dexamethasone) must be on a stable or decreasing dose ≤ 4 mg/day (or equivalent) for at least 7 days before start of study treatment.

5. Adequate bone marrow and organ function confirmed by laboratory tests performed ≤ 14 days before first study treatment:

   Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count ≥ 100 × 10⁹/L; Hemoglobin ≥ 10.0 g/dL; Serum creatinine ≤ 1.5 × upper limit of normal (ULN); Total bilirubin ≤ 1.5 × ULN; albumin ≥ 30 g/L; ALT and AST < 3 × ULN in absence of liver metastases, or < 5 × ULN if liver metastases present; Coagulation: activated partial thromboplastin time (APTT) ≤ 2 × ULN, international normalized ratio (INR) ≤ 1.5 (if not receiving anticoagulation therapy);

6. Evidence of disease progression (PD) by RANO 2.0 criteria confirming recurrence: ≥ 25% increase in product of perpendicular diameters or > 40% increase in tumor volume compared to baseline after initial treatment or best response, while on stable or increasing corticosteroid dose. Clinical deterioration or increased corticosteroid dose alone is insufficient. MRI contrast enhancement, MRS, and/or metabolic PET should help differentiate true progression from radiation necrosis/pseudoprogression. Also, at least one bi-dimensionally measurable contrast-enhancing lesion with shortest diameter ≥ 10 mm must be present on MRI.

7. For participants receiving Ommaya reservoir implantation for locoregional administration, surgery must be completed at least 2 weeks before first radionuclide therapy, with no postoperative complications. Baseline MRI for efficacy assessment must be performed at least 2 weeks after implantation and before first radionuclide therapy.

8. Tumor uptake confirmed by NOTA-PRGD2 PET/CT after diagnosis of recurrence and before radionuclide therapy. For participants with Ommaya reservoir, PET/CT must be performed at least 2 weeks after implantation and before first radionuclide therapy.

9. Life expectancy > 6 months.

10. Karnofsky Performance Status (KPS) score ≥ 50.

Exclusion Criteria:

1. Receiving any other concurrent treatment for glioblastoma outside this study.
2. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed from the start of [177Lu]Lu-DOTA-EB-RGD2 treatment until 6 months after treatment.
3. Refusal to use effective contraception during sexual intercourse from informed consent until 6 months after the last dose of study drug.
4. Inability to tolerate imaging procedures, repeated blood sampling, or poor venous access.
5. Cardiac dysfunction, clinically significant cardiac disease history, or ECG abnormalities indicating a major safety risk, including:

(1) Documented myocardial infarction, angina pectoris, cardiomyopathy, symptomatic pericarditis, or coronary artery bypass grafting within 6 months before enrollment.

(2) Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: (a) risk factors for torsade de pointes (TdP) including uncorrected hypocalcemia, hypokalemia, hypomagnesemia, history of heart failure, or clinically significant/symptomatic bradycardia; (b) use of medications known to prolong the QT interval and/or cause TdP that cannot be discontinued or replaced with a safer alternative (e.g., within 5 half-lives or 7 days before study drug); (c) inability to determine the Fridericia-corrected QT interval (QTcF).

(3) Clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular block (e.g., bifascicular block, Mobitz type II, third-degree AV block).

(4) Resting QTcF ≥ 450 ms (male) or ≥ 460 ms (female). (5) Left ventricular ejection fraction (LVEF) < 50% by echocardiography. (6) Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg, regardless of antihypertensive use.

6. Other malignancy within 5 years before study drug administration, except adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer after curative surgery, carcinoma in situ after curative surgery, or papillary thyroid cancer after curative surgery (hormonal therapy for non-metastatic prostate or breast cancer allowed).

7. Abnormal serum virology (HBsAg, T. pallidum antibody, HIV antibody, HCV antibody). Patients with untreated active hepatitis B who are willing to receive anti-HBV therapy during study treatment are allowed; patients with inactive hepatitis B are allowed; patients with inactive hepatitis C (HCV antibody positive but HCV RNA below lower limit of detection) are allowed.

8. Use of bevacizumab for glioblastoma or supportive care (e.g., edema reduction) within 60 days before start of study treatment.

9. Patients with disease progression within the first 12 weeks after completion of radiotherapy are excluded from recurrent disease trials.

10. Prior intracranial locoregional drug therapy before [177Lu]Lu-DOTA-EB-RGD2 treatment.

11. Active intracranial or intratumoral hemorrhage detected by CT/MRI. 12. Seizure within 14 days before start of study treatment; epilepsy or increased intracranial pressure uncontrolled by medication.

13. Grade 4 myelosuppression from prior anticancer therapy that has not recovered within 2 weeks, or grade 3 myelosuppression requiring >6 weeks to recover.

14. Blood transfusion within 4 weeks before screening to meet eligibility criteria.

15. Known hypersensitivity or delayed allergic reaction to any component of [177Lu]Lu-DOTA-EB-RGD2 or similar drugs.

16. Severe disease of the cardiac, respiratory, central nervous system, renal, hepatic, or other organ systems that, in the investigator's opinion, may increase participant safety risk.

17. Active infection requiring intravenous antibiotics (bacterial, fungal, or viral) within 4 weeks before first dose, or any other uncontrolled active infection deemed clinically significant by the investigator.

18. History of drug or alcohol abuse within one year before screening, long-term drug use, or psychiatric illness that may affect compliance.

19. Participation in another investigational drug or device trial within 4 weeks before first dose.

The decision on whether to share individual participant data (IPD) has not yet been finalized. This is a Phase I investigator-initiated trial with a small sample size (approximately 24 participants). Data sharing will be considered in accordance with institutional policies, patient consent, and Chinese regulatory requirements. Any future sharing would require additional ethical approval and a data transfer agreement.