Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)

NCT03405792 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB201702270OCR16397
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant neoplasm of the central nervous system in adults. Despite an aggressive multimodality treatment approach including surgery, radiation therapy and chemotherapy, overall survival remains poor. Pembrolizumab has recently been approved in the United States for the treatment of patients with advanced and metastatic non-small cell lung cancer, recurrent or metastatic head and neck squamous cell carcinoma, locally advanced urothelial carcinoma, classical Hodgkin lymphoma, unresectable or metastatic melanoma This study is being performed to determine whether the triple combination of pembrolizumab when added to TTFields (Optune®) and adjuvant temozolomide increases progression-free survival (PFS) in patients with newly diagnosed GBM as compared to historical control data.

Conditions

Glioblastoma, WHO Grade IV; Glioblastoma

Keywords

Tumor Treating Electric Fields (TTFields)

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival Between the Groups From Time of Enrollment

  Time from enrollment to progression or death or censoring, whichever occurs first. The study team will use the one-sample log-rank test to compare PFS in the triple combination arm relative to the historical control arm to determine whether the triple combination treatment increases PFS in newly diagnosed GBM patients when compared to TTFields+TMZ historical control patients from the EF-14 study. Evaluability for progression free survival required participants to receive adjuvant TMZ, Optune and at least 1 dose of pembrolizumab.

  Assessed up to 24 months

Secondary Outcomes (3)

• Number of Participants With Toxicities, Serious Adverse Events and/or Other Adverse Events Treated With Triple Combination Treatment

  Assessed up to 24 months

• Overall Survival (OS)

  Assessed up to 5 years

• Augmentation of TTFields-initiated Glioma-specific Immune Reaction by Pembrolizumab

  Assessed up to 24 months

Study Arms (2)

Optune System combined with Temozolomide (TMZ) + Pembrolizumab

EXPERIMENTAL

Patients with newly-diagnosed GBM who undergo maximal safe resection (biopsy alone is eligible) followed by chemoradiation consisting of concomitant TMZ daily and radiation therapy (RT) with minimal RT will be eligible for this trial. Four to six weeks after finishing chemoradiation, patients will start monthly cycles of adjuvant TMZ. Treatment with Optune will start at approximately the same time as the first cycle of adjuvant TMZ and continue until second disease progression or a maximum of 2 years. Within one week after starting Cycle 2 of adjuvant TMZ and Optune therapy, patients will begin open-label treatment with pembrolizumab every 3 weeks until first disease progression or unacceptable toxicities or 2 years, whichever comes first.

Drug: Temozolomide (TMZ); Device: Optune System; Drug: Pembrolizumab

Historical Control

OTHER

Historical control of patients treated with Optune System combined with Temozolomide alone from the EF-14 study will be compared with the Optune System combined with Temozolomide (TMZ) + pembrolizumab

Drug: Temozolomide (TMZ); Device: Optune System

Interventions

Optune System DEVICE

Patients will undergo 24-months of planned treatment with Optune therapy.

Also known as: NovoTTF Therapy

Historical Control; Optune System combined with Temozolomide (TMZ) + Pembrolizumab

Pembrolizumab DRUG

Pembrolizumab will be given intravenously every 3 weeks beginning on Day 1 of Cycle 2 of adjuvant TMZ. Treatment with pembrolizumab every 3 weeks until first disease progression or unacceptable toxicities or 2 years, whichever comes first.

Also known as: Keytruda

Optune System combined with Temozolomide (TMZ) + Pembrolizumab

Temozolomide (TMZ) DRUG

Patients will begin treatment with adjuvant TMZ at least 4 weeks but no more than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given depending on tolerability and toxicity.

Historical Control; Optune System combined with Temozolomide (TMZ) + Pembrolizumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic confirmation of glioblastoma, WHO Grade IV (GBM variants are allowed; Lower grade gliomas that have been transformed to GBM will be considered newly diagnosed GBM if the lower-grade tumor was not previously treated, and the standard treatment for GBM including radiation and temozolomide is now planned).
• MGMT methylation status if available (indeterminate methylation status will be considered unmethylated).
• Karnofsky performance status (KPS) ≥70%.
• Patients must be at least 18 years of age.
• Received maximal safe resection (biopsy only allowed) and radiotherapy concomitant with temozolomide:
• Gliadel wafers placement at the time of surgical resection is allowed.
• Minimum dose for concomitant radiotherapy is 40 Gy.
• Candidate for adjuvant high dose temozolomide and Optune therapy.
• Life expectancy of at least 3 months.
• Adequate bone marrow and organ function as defined below:
• ANC ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (transfusion is allowed)
• Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine \> 1.5 x IULN
• Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin \> 1.5 x IULN

You may not qualify if:

• Prior treatment with anti-angiogenic agents including bevacizumab.
• History of other malignancy that, in the primary oncologist's estimation, has a higher risk of recurrence or death than the study-related cancer at the time of study participation.
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Progressive disease (according to RANO criteria). Advanced imaging is allowed to further investigate suspected pseudoprogression if deemed necessary.
• Actively participating in another clinical treatment trial intended to treat GBM.
• Multifocal gliomas defined as distinct tumors that do not have overlapping T2/FLAIR signal.
• Presence of leptomeningeal metastases.
• Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
• Tumor is entirely located in the infra-tentorial region.
• History of hypersensitivity reactions or allergies to hydrogels and/or compounds of similar chemical or biologic composition to Temozolomide and Pembrolizumab.
• Steroid dose equivalent to \> 4 mg dexamethasone at the time of starting adjuvant therapy.
• History of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (with the exception of daily dexamethasone ≤ 4 mg).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

Sponsors & Collaborators

• University of Florida: lead
• NovoCure Ltd.: collaborator

Study Sites (1)

University of Florida Health

Gainesville, Florida, 32610, United States

Location

Related Publications (1)

• Chen D, Le SB, Ghiaseddin AP, Manektalia H, Li M, O'Dell A, Rahman M, Tran DD. Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study. Med. 2025 Sep 12;6(9):100708. doi: 10.1016/j.medj.2025.100708. Epub 2025 Jun 4.

  PMID: 40466642 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide; pembrolizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Limitation 1: We do not have the distribution of ages for the historical control arm to determine the median for the total population. Limitation 2: Adverse Events for historical controls were monitored/assessed/reported without regard to the specific Adverse Event Term therefore we are not reporting for the historical control arm.

Results Point of Contact

• Title: Ashley Ghiaseddin, MD
• Organization: University of Florida

ashley.ghiaseddin@neurosurgery.ufl.edu

352-273-9000

Study Officials

• Ashley Ghiaseddin, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2018
• First Posted: January 23, 2018
• Study Start: February 23, 2018
• Primary Completion: November 26, 2022
• Study Completion (Estimated): December 1, 2027
• Last Updated: February 6, 2026
• Results First Posted: April 15, 2024

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)