Dosimetry, Safety, and Efficacy Study of [177Lu]Lu-XT771 in Patients With Recurrent Glioblastoma

Early Phase 1RecruitingNCT07648823

Beijing Tiantan Hospital5 enrolled

Overview

The primary objective of this study is to evaluate the dosimetry, safety, and tolerability of the investigational radiopharmaceutical \[177Lu\]Lu-XT771 in patients with recurrent glioblastoma, an aggressive form of brain cancer. \[177Lu\]Lu-XT771 is designed to specifically target and deliver beta radiation directly to tumor cells that overexpress carbonic anhydrase IX and XII (CA IX and CA XII). This early-phase, investigator-initiated trial will enroll a small group of approximately 3-5 patients, each receiving a single dose of \[177Lu\]Lu-XT771. The drug will be administered locoregionally via an implanted Ommaya reservoir, directly into the tumor cavity. Following administration, patients will be closely monitored using single-photon emission computed tomography/computed tomography (SPECT/CT) to assess the biodistribution of the drug and to quantify the absorbed radiation dose to both the tumor and normal organs. The study will also document all adverse events to characterize the safety profile of the treatment and will provide a preliminary assessment of its anti-tumor activity, as measured by progression-free survival. The information gathered from this exploratory study will be used to determine the recommended safe starting dose for future Phase I clinical trials.

Background and Rationale: Glioblastoma (GBM) is a highly aggressive brain tumor associated with poor prognosis, particularly upon recurrence. Standard therapeutic options for recurrent GBM are limited, representing an urgent unmet medical need. Carbonic anhydrase IX (CA IX) and XII (CA XII) are transmembrane proteins specifically overexpressed in the hypoxic microenvironment of glioblastoma. They play critical roles in tumor progression and treatment resistance, yet they exhibit scarce expression in normal tissues. This differential expression makes them ideal targets for targeted radioligand therapy. Investigational Drug: \[177Lu\]Lu-XT771 is an investigational, first-in-human (FIH) targeted radiopharmaceutical. It is designed to specifically bind to CA IX and CA XII receptors on the tumor cell surface. Upon binding, the Lutetium-177 isotope delivers localized beta radiation directly to the tumor cells, aiming to destroy the tumor while minimizing radiation exposure to surrounding healthy brain tissue. Preclinical in vivo models have demonstrated that local administration of \[177Lu\]Lu-XT771 results in prolonged tumor retention, high cumulative radiation absorbed doses, and significant inhibition of tumor proliferation. Study Procedures: In this exploratory, early-phase dosimetric study, eligible patients with recurrence of glioblastoma will undergo surgical placement of an Ommaya reservoir. Prior to the therapeutic injection, a leakage test using a \[68Ga\]Ga-XT771 tracer will be performed to ensure there is no leakage into the subcutaneous or subarachnoid spaces. Once safety is confirmed, a single locoregional dose of 3-5 mCi of \[177Lu\]Lu-XT771 will be directly injected into the tumor cavity via the Ommaya reservoir. Patients will be isolated post-injection until their systemic radioactivity levels fall below the required safety discharge standards. Monitoring and Dosimetry Assessments: To precisely evaluate the radiation dosimetry and biodistribution, patients will undergo a series of whole-body planar scintigraphy and head/abdomen SPECT/CT scans at multiple pre-defined time points post-injection (e.g., 30 minutes, 2 hours, 24 hours, 48 hours, 72 hours, and 5-7 days). These scans will quantify the drug's distribution and the radiation dose absorbed by both the tumor lesions and normal organs (such as the kidneys). Patients will be continuously monitored for safety and adverse events. Efficacy will be assessed preliminarily using contrast-enhanced head MRI based on RANO 2.0 criteria. The dosimetry, safety, and pharmacokinetic data gathered from this trial will be crucial for calculating and determining the recommended safe starting dose for a subsequent, larger-scale Phase I clinical trial.

Interventions

[177Lu]Lu-XT771DRUG

\[177Lu\]Lu-XT771 is a novel, first-in-human radiopharmaceutical designed to specifically target Carbonic Anhydrase IX (CA IX) and XII (CA XII), which are overexpressed in the glioblastoma microenvironment. Unlike systemic intravenous therapies, this intervention utilizes a highly localized delivery method: a single dose of 3-5 mCi \[177Lu\]Lu-XT771 is injected directly into the tumor resection cavity via a surgically implanted Ommaya reservoir. To ensure precise safety, two specific steps are required: 1) A mandatory pre-treatment leakage test using a \[68Ga\]Ga-XT771 tracer (4-6 mCi) with PET/CT imaging to rule out any leakage into the subcutaneous or subarachnoid spaces; and 2) The extraction of an equivalent volume of cerebrospinal fluid immediately prior to the therapeutic injection. Furthermore, to mitigate radiation-induced cerebral edema, the intervention is paired with a prophylactic regimen of oral dexamethasone (4 mg, three times daily) for 4 days.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Subject has fully understood the study and voluntarily signed the informed consent form. 2. Age ≥ 18 and ≤ 80 years old. 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1. 4. Life expectancy of at least 3 months. 5. Histologically confirmed glioblastoma (based on the 2021 WHO Classification of Tumors of the Central Nervous System, 5th edition), and confirmed CA IX/CA XII positive by histology or \[68Ga\]Ga-XT771 PET/CT. 6. Histologically confirmed recurrence of glioblastoma following prior treatments. 7. Suitable for Ommaya reservoir placement and meets the conditions for drug administration, as judged by the investigator. 8. Tumor resection cavity volume between 2.5 and 25 cm\^3. 9. On a stable or decreasing dose of corticosteroids (≤5 mg/day of dexamethasone or equivalent) for at least 1 week prior to the first dose. 10. Toxicity from prior anti-tumor treatments (e.g., chemotherapy, radiotherapy, immunotherapy) recovered to ≤ Grade 1 (excluding alopecia). 11. Adequate organ and bone marrow function meeting the following criteria: * Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5 ×10\^9/L and white blood cell (WBC) count ≥ 3 ×10\^9 /L (without growth factor support within 28 days prior to dosing); Platelet count ≥ 75 ×10\^9/L; Hemoglobin ≥ 90 g/L. * Hepatic function: Total bilirubin ≤ 1.5 × ULN (≤ 2.0 × ULN for subjects with liver metastases; ≤ 3.0 × ULN for subjects with confirmed Gilbert's syndrome); ALT and AST ≤ 3 × ULN (\< 5 × ULN for subjects with liver metastases); Albumin \> 30 g/L. * Renal function: Serum creatinine ≤ 1.5 × ULN and creatinine clearance rate ≥ 50 mL/min. * Coagulation: INR ≤ 2.0, APTT ≤ 1.5 × ULN. (Exception: subjects receiving warfarin may have an INR between 2 and 3 inclusive). 12. Fertile subjects (and their partners) must agree to use highly effective contraceptive methods (e.g., condoms, oral or injectable contraceptives) during the treatment period and for 6 months after the last dose of the study drug. Exclusion Criteria: 1. Received anti-tumor treatments (including radiotherapy, chemotherapy, biological therapy, endocrine therapy, targeted therapy, etc.) within 4 weeks prior to dosing. Exceptions: (1) immunotherapy, nitrosoureas, or mitomycin C within 6 weeks prior to dosing; (2) oral fluorouracils and small molecule targeted drugs within 2 weeks or 5 half-lives (whichever is longer) prior to dosing; (3) Traditional Chinese Medicine with anti-tumor indication within 2 weeks prior to dosing; (4) cranial radiotherapy within 3 months prior to dosing. 2. Received any other unapproved investigational drug within 4 weeks prior to dosing. 3. Underwent major organ surgery (excluding needle biopsy) or experienced significant trauma within 4 weeks prior to dosing, or expected to require elective surgery during the study period. 4. Known or suspected allergy to the study drug or its analogue components. 5. Inability to undergo contrast-enhanced MRI scans (e.g., due to pacemakers, contrast agent allergy). 6. Presence of active or uncontrolled infections requiring systemic intravenous treatment, or unexplained fever \>38.5°C during the screening period or before dosing. 7. Presence of severe coagulation disorders or evidence of significant bleeding risk; history of gastrointestinal bleeding; any Grade ≥2 bleeding event (CTCAE v5.0) within the past 6 months. 8. Active Hepatitis B (HBsAg positive and HBV-DNA \> 500 IU/mL or above the lower limit of detection of the study center) or Active Hepatitis C (HCV antibody positive and HCV-RNA \> the lower limit of detection of the study center). 9. Uncontrolled hypertension as judged by the investigator (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg despite standard treatment). 10. History of severe cardiovascular disease, such as ventricular arrhythmias requiring clinical intervention; QTc interval \> 480 ms; acute coronary syndrome, congestive heart failure, stroke, or other ≥ Grade III cardiovascular events within 6 months prior to dosing; NYHA class II-IV or LVEF \< 50%. 11. History of other uncured malignancies within the past 3 years or concurrently, except for curable in situ cancers (e.g., carcinoma in situ of the cervix, basal cell carcinoma of the skin). 12. Presence of two or more intracranial lesions, extracranial metastases, or tumors located in the infratentorial compartment or basal ganglia. 13. Brain MRI indicating that the enhancing edge of the tumor invades the ventricular wall, or the surgical cavity communicates with the ventricle. 14. Psychiatric disorders or poor compliance. 15. Pregnant or lactating women. 16. The investigator considers the subject unsuitable for participation in this clinical study due to other severe systemic diseases or other reasons.

Outcomes

Primary Outcomes

Radiation Dosimetry

To evaluate the radiation dosimetry and biodistribution of a single locoregional injection of \[177Lu\]Lu-XT771. It will be quantified using serial whole-body planar scintigraphy and SPECT/CT imaging to measure drug distribution and calculate the cumulative radiation absorbed dose in the tumor cavity and critical normal organs (e.g., kidneys). These dosimetric data will be used to determine the recommended starting dose for future Phase I trials.

Time frame: 30 minutes, 2 hours, 24 hours, 48 hours, 72 hours, and 5-7 days post-injection

Incidence and severity of adverse events and incidence of serious adverse events

Safety and tolerability will be evaluated by monitoring the incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). All AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Assessments include patient complaints, vital signs, physical examinations, 12-lead ECGs, and clinical laboratory abnormalities.

Time frame: From the time of informed consent up to 30 days after the last dose

Secondary Outcomes

Progression-Free Survival (PFS)

PFS is defined as the time from the date of \[177Lu\]Lu-XT771 administration until the first date of objectively documented radiographic disease progression or death from any cause. Tumor response and progression will be assessed using contrast-enhanced head MRI based on the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria.

Time frame: Every 8 weeks from the date of injection until disease progression or completion of 1 year of follow-up, whichever occurs first.