Tarlatamab Treatment Before and After Surgery in Surgically Resectable Recurrent High-grade Glioma: a Window of Opportunity Study (TARLAGLIA Study)

Phase 1Not Yet RecruitingNCT07788677

Vall d'Hebron Institute of Oncology10 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥18 years. 2. Ability to provide written informed consent. 3. Histologically confirmed diagnosis of DLL3 positive high-grade glioma (HGG). 4. 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). 5. Surgery can be safely delayed for a minimum of 2 weeks following the Day 15 (D15) administration of study immunotherapy. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 7. Adequate organ function, defined as follows: a. Hematological function: i. Absolute neutrophil count ≥ 1.5 x 109/L ii. Platelet count ≥ 100 x 109/L iii. Hemoglobin ≥ 9 g/dL (90 g/L) b. Coagulation function: i. prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5 x institutional upper limit of normal (ULN) except for patients receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to study entry. c. Renal function: i. Estimated glomerular filtration rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) calculation \> 30 mL/min/1.73 m2. d. Hepatic function: i. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN (or \< 5 x ULN for patients with liver involvement). ii. total bilirubin (TBL) \< 1.5 x ULN (or \< 2 x ULN for patients with liver involvement), except for patients with Gilbert's disease. e. Pulmonary function i. No oxygen supplementation. f. Cardiac function i. cardiac ejection fraction \>/= 50%, no clinically significant pericardial effusion as determined by an echocardiogram (ECHO) or multigated acquisition (MUGA) scan, and no clinically significant electrocardiogram (ECG) finding. 8. For women of childbearing potential: negative pregnancy test at screening. 9. Willingness to use highly effective contraception during treatment during treatment and for at least 60 days after the last dose of tarlatamab, Exclusion Criteria: 1. Candidate for biopsy only (class 4), according to the RANO resect group classification system for EOR. 2. Ongoing steroid treatment at a dose \>4 mg dexamethasone equivalents daily. 3. Active autoimmune disease that has required systemic treatment in the past 2 years (including disease-modifying agents, corticosteroids, or immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is permitted. 4. Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibodies). 5. Known active hepatitis B virus infection (hepatitis B surface antigen reactive). 6. Known active hepatitis C virus infection (HCV RNA qualitative positive). 7. Receipt of a live vaccine or live-attenuated vaccine within 30 days before the first dose of study treatment. 8. Prior malignancy within the past 3 years, except: except basal cell carcinoma or scaly skin, cervical carcinoma in situ adequately treated or other tumors treated curatively without recurrence for 3 or more years, 9. Pregnant or lactating women.

Outcomes

Primary Outcomes

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.

Time frame: From first neoadjuvant tarlatamab dose through the postoperative safety assessment 7 days after surgery; Cycle 1 is 4 weeks, with dosing on Days 1, 8, and 15 and surgery approximately 2 weeks after Day 15.

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.