TTFields Plus FET-PET-Guided Stereotactic Radiosurgery Versus TTFields Alone for Recurrent Glioblastoma (Tarrget 2.0)

Official title

Tumor Treating Fields (TTFields) Concomitant With Stereotactic Radiosurgery Based on FET-PET vs TTFields Alone for the Treatment of Recurrent, Glioblastoma (Tarrget 2.0)

Overview

This study evaluates whether the addition of FET-PET-guided stereotactic radiosurgery (SRS) to Tumor Treating Fields (TTFields) improves survival outcomes in patients with recurrent IDH-wildtype glioblastoma. Patients with recurrent glioblastoma have limited treatment options and poor prognosis. TTFields is a non-invasive antimitotic therapy that has demonstrated efficacy in recurrent glioblastoma. Stereotactic radiosurgery is commonly used in selected patients with recurrent disease; however, treatment efficacy may be limited by the infiltrative nature of glioblastoma and challenges in accurate target delineation. The study hypothesizes that combining TTFields with FET-PET-guided stereotactic radiosurgery will improve one-year overall survival compared with TTFields alone. Participants will be randomized in a 1:1 ratio to receive either TTFields plus stereotactic radiosurgery or TTFields alone.

Detailed description

Glioblastoma is the most common malignant primary brain tumor in adults and remains associated with poor prognosis despite multimodal treatment. There is currently no established standard therapy for recurrent glioblastoma, and outcomes remain unsatisfactory.

Tumor Treating Fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt mitosis and inhibit tumor growth. TTFields have demonstrated efficacy in recurrent and newly diagnosed glioblastoma with minimal systemic toxicity.

Stereotactic radiosurgery (SRS) is an established local treatment option for selected patients with recurrent glioblastoma. However, MRI-based target delineation may underestimate the true extent of infiltrative tumor growth. FET-PET imaging provides improved visualization of metabolically active tumor tissue and may improve treatment precision.

Preclinical studies suggest synergistic effects between TTFields and radiation therapy through increased radiosensitivity and modulation of DNA repair mechanisms. Additional immunomodulatory effects may further enhance treatment efficacy.

This prospective randomized single-center study will compare TTFields combined with FET-PET-guided stereotactic radiosurgery versus TTFields alone in patients with recurrent IDH-wildtype glioblastoma. The primary objective is to determine whether combined treatment improves the one-year overall survival rate.

Interventions

• Device Tumor Treating Fields (TTFields)
  Tumor Treating Fields (TTFields) therapy delivered using alternating electric fields through transducer arrays placed on the scalp. Treatment is administered continuously according to the study protocol for patients with recurrent IDH-wildtype glioblastoma.
• Radiation FET-PET-Guided Stereotactic Radiosurgery
  Stereotactic radiosurgery planned using MRI and FET-PET imaging for treatment of recurrent IDH-wildtype glioblastoma. Radiosurgery is delivered within 14 days after initiation of TTFields according to protocol-defined target volumes.

Primary outcome measures

• One-Year Overall Survival Rate [Time frame: 12 months after randomization]

Secondary outcome measures (8)

• Overall Survival (OS) [Time frame: From randomization until death from any cause, up to 81 months]
• Progression-Free Survival (PFS) [Time frame: Up to 12 months after randomization]
• Objective Response Rate (ORR) [Time frame: Up to 12 months after randomization]
• Radiation-Induced Contrast Enhancement (RICE) [Time frame: Up to 12 months after randomization]
• Treatment-Related Adverse Events [Time frame: From randomization through 12 months after randomization]
• Patterns of Failure [Time frame: Up to 12 months after randomization]
• Molecular Predictors of overall survival [Time frame: Up to 81 months after randomization]
• Corticosteroid Requirements [Time frame: From randomization until disease progression, up to 12 months after randomization]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• Karnofsky Performance Status ≥70
• Histologically confirmed IDH-wildtype glioblastoma
• First, second, or third recurrence
• Radiological recurrence according to RANO 2.0 criteria
• Prior radiotherapy and temozolomide treatment
• At least 6 months since completion of previous radiotherapy
• Contrast-enhancing recurrent lesion visible on MRI
• Maximum recurrent lesion diameter ≤5 cm
• Available molecular profile including IDH and MGMT status
• Adequate hematologic, renal, and hepatic function
• Written informed consent

Exclusion criteria

• Previous bevacizumab treatment
• Planned chemotherapy or targeted therapy after study intervention
• Previous stereotactic re-irradiation within the planned treatment field
• More than three recurrences
• Significant psychiatric disorders
• Significant unrelated neurological disease
• Implanted pacemaker, defibrillator, deep brain stimulator, or other incompatible electronic device
• Pregnancy or breastfeeding
• Active intracranial hemorrhage
• Uncontrolled hypertension
• Severe renal dysfunction
• Participation in another interventional study likely to interfere with this study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Poland · 1 center

• Department of Neurooncology and Radiosurgery, Franciszek Lukaszczyk Oncology Center — Bydgoszcz

Publications

• Imber BS, Kanungo I, Braunstein S, Barani IJ, Fogh SE, Nakamura JL, Berger MS, Chang EF, Molinaro AM, Cabrera JR, McDermott MW, Sneed PK, Aghi MK. Indications and Efficacy of Gamma Knife Stereotactic Radiosurgery for Recurrent Glioblastoma: 2 Decades of Institutional Experience. Neurosurgery. 2017 Jan 1;80(1):129-139. doi: 10.1227/NEU.0000000000001344. PMID 27428784
• Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, Friedman HS, Willett CG, Kirkpatrick JP. Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):2018-24. doi: 10.1016/j.ijrobp.2010.12.074. Epub 2011 Apr 12. PMID 21489708
• Harat M, Rakowska J, Harat M, Szylberg T, Furtak J, Miechowicz I, Malkowski B. Combining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma. Nat Commun. 2023 Jul 29;14(1):4572. doi: 10.1038/s41467-023-39731-8. PMID 37516762
• Harat M, Blok M, Miechowicz I, Wiatrowska I, Makarewicz K, Malkowski B. Safety and Efficacy of Irradiation Boost Based on 18F-FET-PET in Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res. 2022 Jul 15;28(14):3011-3020. doi: 10.1158/1078-0432.CCR-22-0171. PMID 35552391
• Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, la Fougere C, Pope W, Law I, Arbizu J, Chamberlain MC, Vogelbaum M, Ellingson BM, Tonn JC. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro Oncol. 2016 Sep;18(9):1199-208. doi: 10.1093/neuonc/now058. Epub 2016 Apr 21 PMID 27106405
• Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone o PMID 29260225
• Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus PMID 22608262

Identifiers

NCT: NCT07668869 · Tarrget 2.0

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗