This is a single-arm, window-of-opportunity clinical study evaluating tarlatamab administered before and after surgery in adult participants with surgically resectable recurrent DLL3-positive high-grade glioma. The study is designed to assess the feasibility and safety of neoadjuvant tarlatamab treatment prior to planned tumor resection, as well as the safety and tolerability of postoperative adjuvant tarlatamab.
Eligible participants will have histologically confirmed recurrent high-grade glioma with DLL3-positive tumor expression and will be candidates for neurosurgical resection in whom surgery can be safely delayed to allow neoadjuvant treatment. Participants will receive tarlatamab intravenously using a step-up dosing regimen during the neoadjuvant phase, followed by planned surgical resection after a washout period. After recovery from surgery, participants will restart tarlatamab with step-up dosing and continue adjuvant treatment every 2 weeks for up to 6 cycles.
The primary objective is to evaluate the feasibility and safety of neoadjuvant tarlatamab, including the number of participants able to complete the dose-limiting toxicity evaluation period and undergo planned surgery without experiencing a dose-limiting toxicity. Safety assessments will include adverse events graded according to CTCAE v5.0, as well as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome graded according to ASTCT criteria.
Secondary objectives include assessment of antitumor activity using RANO and iRANO criteria, progression-free survival, 12-month overall survival, quality of life using EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires, and the incidence, severity, and type of treatment-emergent adverse events during the adjuvant treatment period.
Age ≥18 years.
Ability to provide written informed consent.
Histologically confirmed diagnosis of DLL3 positive high-grade glioma (HGG).
Candidate for neurosurgical resection of HGG, either in the category of supramaximal contrast-enhancing (CE) resection (class 1), maximal CE resection (class 2), or submaximal CE resection (class 3), according to the RANO resect group classification system for extent of resection (EOR).
Candidate for biopsy only (class 4), according to the RANO resect group classification system for EOR.
Ongoing steroid treatment at a dose >4 mg dexamethasone equivalents daily.
Active autoimmune disease that has required systemic treatment in the past 2 years (including disease-modifying agents, corticosteroids, or immunosuppressive drugs).
Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibodies).
Single group
Tarlatamab
Biological/VaccineTarlatamab will be administered by intravenous infusion using a step-up dosing regimen. During the neoadjuvant phase, participants will receive 1 mg on Cycle 1 Day 1, followed by 10 mg on Cycle 1 Day 8 and Day 15. Surgery will be performed after a 2-week washout period following the Day 15 dose. Postoperatively, tarlatamab will be restarted approximately 3 weeks after surgery using step-up dosing with 1 mg on Day 1, followed by 10 mg on Day 8 and Day 15. Thereafter, participants will receive tarlatamab 10 mg intravenously every 2 weeks for up to 6 cycles. Each treatment cycle is defined as 4 weeks. Tarlatamab will be administered as a 60-minute intravenous infusion, followed by a slow bolus flush.
Number of Participants Completing the DLT Evaluation Period and Undergoing Planned Surgery Without a DLT
Number of participants who complete the protocol-defined DLT evaluation period and undergo the planned surgical resection without experiencing a DLT. A participant will be counted only if all criteria are met. DLTs are defined according to protocol-specified criteria.
Number of Participants With Treatment-Emergent Adverse Events
Number of participants with at least one treatment-emergent adverse event (TEAE). AEs will be coded using MedDRA and severity graded according to NCI CTCAE v5.0, except CRS and ICANS, which will be graded according to ASTCT consensus criteria.
Number of Participants With Treatment-Related Adverse Events
Number of participants with at least one adverse event assessed as related to study intervention. AEs will be coded using MedDRA and severity graded according to NCI CTCAE v5.0, except CRS and ICANS, which will be graded according to ASTCT consensus criteria.
Incidence of all treatment-emergent adverse events and treatment-related adverse events.
Number and percentage of participants experiencing treatment-emergent adverse events (TEAEs) and treatment-related adverse events during the study. Events will be summarized by incidence, type, severity, seriousness, and relationship to tarlatamab.
Response rate according to RANO and iRANO criteria.
Percentage of participants achieving a complete response (CR) or partial response (PR) according to RANO and iRANO criteria, as assessed by the investigator using serial MRI examinations.
Progression-free survival (PFS)
Progression-free survival (PFS) is defined as the time from treatment initiation to the first documented disease progression according to RANO/iRANO criteria or death from any cause, whichever occurs first.
Overall survival (OS)
Overall survival (OS) is defined as the time from treatment initiation to death from any cause. Participants alive at the time of analysis will be censored at the last date they were known to be alive.
EORTC QLQ-C30 questionnaires.
Assessment of health-related quality of life using the 30-item EORTC QLQ-C30 questionnaire. Scores will be calculated according to the published EORTC scoring guidelines to assess global health status, functioning, and cancer-related symptoms.
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