Tarlatamab Treatment Before and After Surgery in Surgically Resectable Recurrent High-grade Glioma: a Window of Opportunity Study (TARLAGLIA Study) (TARLAGLIA)
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.
研究概览
研究类型
注册 (估计的)
阶段
- 阶段1
联系人和位置
学习地点
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Catalonia
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Barcelona、Catalonia、西班牙、08035
- Hospital Universitari Vall D Hebron
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接触：
- María Vieito, Dr
- 电话号码：+34932746085
- 邮箱：mvieito@vhio.net
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参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
Inclusion Criteria:
- 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).
- Surgery can be safely delayed for a minimum of 2 weeks following the Day 15 (D15) administration of study immunotherapy.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
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.
- For women of childbearing potential: negative pregnancy test at screening.
- Willingness to use highly effective contraception during treatment during treatment and for at least 60 days after the last dose of tarlatamab,
Exclusion Criteria:
- 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).
Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is permitted.
- Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibodies).
- Known active hepatitis B virus infection (hepatitis B surface antigen reactive).
- Known active hepatitis C virus infection (HCV RNA qualitative positive).
- Receipt of a live vaccine or live-attenuated vaccine within 30 days before the first dose of study treatment.
- 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,
- Pregnant or lactating women.
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的：Recurrent high-grade glioma with DDL-3 positive tumor expression, as assessed by IHC.
Participants with surgically resectable recurrent DLL3-positive high-grade glioma will receive neoadjuvant tarlatamab prior to planned surgery, followed by adjuvant tarlatamab after surgery.
In the neoadjuvant phase, tarlatamab will be administered intravenously using a step-up regimen of 1 mg on Cycle 1 Day 1, followed by 10 mg on Days 8 and 15.
Surgery will be performed after a 2-week washout period following the Day 15 dose.
Approximately 3 weeks after surgery, tarlatamab will be restarted with step-up dosing of 1 mg on Day 1, followed by 10 mg on Days 8 and 15, then continued at 10 mg intravenously every 2 weeks for up to 6 cycles, with each cycle defined as 4 weeks.
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Tarlatamab 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.
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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Number of Participants Completing the DLT Evaluation Period and Undergoing Planned Surgery Without a DLT
大体时间：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.
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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.
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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.
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Number of Participants With Treatment-Emergent Adverse Events
大体时间：From first study intervention through 60 days after cessation of study intervention.
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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.
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From first study intervention through 60 days after cessation of study intervention.
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Number of Participants With Treatment-Related Adverse Events
大体时间：From first study intervention through 60 days after cessation of study intervention.
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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.
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From first study intervention through 60 days after cessation of study intervention.
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Incidence of all treatment-emergent adverse events and treatment-related adverse events.
大体时间：From first study intervention through 60 days after cessation of study intervention.
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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.
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From first study intervention through 60 days after cessation of study intervention.
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Number of Participants With Cytokine Release Syndrome by Maximum ASTCT Grade
大体时间：From first study intervention through 60 days after cessation of study intervention.
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Number of participants with cytokine release syndrome (CRS), categorized according to the maximum CRS grade experienced during the assessment period using the ASTCT consensus grading criteria.
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From first study intervention through 60 days after cessation of study intervention.
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Number of Participants With ICANS by Maximum ASTCT Grade
大体时间：From first study intervention through 60 days after cessation of study intervention.
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Number of participants with immune effector cell-associated neurotoxicity syndrome (ICANS), categorized according to the maximum ICANS grade experienced during the assessment period using the ASTCT consensus grading criteria.
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From first study intervention through 60 days after cessation of study intervention.
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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Response rate according to RANO and iRANO criteria.
大体时间：From treatment initiation; MRI at baseline, pre-surgery, and every 8 weeks thereafter until end of treatment or disease progression, assessed up to approximately 7 months.
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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.
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From treatment initiation; MRI at baseline, pre-surgery, and every 8 weeks thereafter until end of treatment or disease progression, assessed up to approximately 7 months.
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Progression-free survival (PFS)
大体时间：From treatment initiation to the first documented disease progression per RANO/iRANO criteria or death from any cause, whichever occurs first, assessed up to 24 months.
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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.
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From treatment initiation to the first documented disease progression per RANO/iRANO criteria or death from any cause, whichever occurs first, assessed up to 24 months.
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Overall survival (OS)
大体时间：From treatment initiation until death from any cause, assessed up to 12 months.
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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.
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From treatment initiation until death from any cause, assessed up to 12 months.
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EORTC QLQ-C30 questionnaires.
大体时间：Baseline, after surgery, and every 3 months thereafter through end of treatment or disease progression.
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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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Baseline, after surgery, and every 3 months thereafter through end of treatment or disease progression.
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EORTC QLQ-BN20 questionnaires
大体时间：Baseline, after surgery, and every 3 months thereafter through end of treatment or disease progression.
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Assessment of brain tumor-specific symptoms and functioning using the 20-item EORTC QLQ-BN20 questionnaire.
Scores will be calculated according to the published EORTC scoring guidelines to assess brain tumor-related symptoms and functional impairment.
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Baseline, after surgery, and every 3 months thereafter through end of treatment or disease progression.
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Incidence, severity (graded per CTCAE v5.0 and ASTCT criteria for CRS and ICANS), and type of treatment-emergent adverse events occurring during the adjuvant treatment period.
大体时间：From first postoperative adjuvant tarlatamab dose through 60 days after completion of adjuvant treatment; up to 6 cycles (each cycle is 4 weeks), for an estimated total of approximately 33 weeks.
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Assessment of treatment-emergent adverse events during adjuvant tarlatamab treatment.
Events will be summarized by incidence, type, and severity.
Severity will be graded using CTCAE v5.0, except CRS and ICANS, which will be graded using ASTCT criteria.
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From first postoperative adjuvant tarlatamab dose through 60 days after completion of adjuvant treatment; up to 6 cycles (each cycle is 4 weeks), for an estimated total of approximately 33 weeks.
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合作者和调查者
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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