Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Temozolomide

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

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.

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

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.

Temozolomide (TMZ)

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

Optune System

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.

Ashley Ghiaseddin, MD

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.

Patients with newly-diagnosed GBM who undergo maximal safe resection (biopsy alone is eligible) followed by standard chemoradiation will be eligible for this trial.

Four weeks after completing chemoradiation, patients will undergo baseline standard of care MRI. Four to six weeks after finishing chemoradiation, patients will start monthly cycles of adjuvant TMZ. A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given. 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.

At first progression, patients will be allowed to continue with Optune therapy combined with any other therapy, which may include pembrolizumab, per standard of care at the discretion of the treating physician. Surgical resection or biopsy of first recurrent tumor for confirmation of recurrence is allowed within the protocol.

All patients will be seen before Cycle 1 of TMZ, before cycle 2 of TMZ, before starting the second dose of pembrolizumab, and every 3 weeks before each subsequent pembrolizumab dose at an outpatient clinic until they complete all 12 cycles of adjuvant TMZ or discontinue TMZ due to toxicity or first progression.

Medical follow-up will continue for 30 days after treatment termination. After this visit, mortality will be assessed based on telephone interviews with the patients or the patients' caregivers every 3 months.

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

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

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.

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting for grade 3 or higher. We will estimate proportions and 95% confidence intervals for patients in the triple combination arm who experience toxicities and other types of AEs and serious AEs.

Time from enrollment to death or censoring, whichever occurs first. We will use the log-rank test to compare OS between the triple combination arm relative to the historical control arm.

We will use mixed effect regression to assess changes in response variables related to glioma-specific immune reaction before, during, and after treatment with pembrolizumab.

NovoCure Ltd.

University of Florida

Adverse event (AE) data for historical controls was reported and presented by Stupp et al. 2017. 466 patients were randomized to treatment in the TMZ+TTFields arm (the comparator for this study); 10 didn't complete treatment. For all cause mortality, we used the intent to treat population (all patients randomized to receive the intended treatment regardless of whether they completed) which was 466. AEs/SAEs were monitored/assessed for the 456 participants who completed the intended treatment.

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.

Temozolomide (TMZ): 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.

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

Pembrolizumab: 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.

Optune System Combined With Temozolomide (TMZ) + Pembrolizumab

Historical control of patients treated with Optune System combined with Temozolomide alone from the EF-14 study based on data published by Stupp et al, 2017.

Historical Control Optune System Combined With Temozolomide (TMZ)

Historical Control

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Thirty-one participants were eligible. Twenty-six participants were treated with the combination of optune, adjuvant temozolomide and pembrolizumab and counted toward the primary outcome measure.

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.

We will use one-sample log-rank test to compare PFS between the triple combination arm relative to the historical control arm.

We took a look at median survival time and CI of our population and we compared it to the median PFS and CI of the historical control descriptively. There is no yielded P value.

Progression-free Survival Between the Groups From Time of Enrollment

Every participant (26/26; 100%) experienced an adverse event.

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

Overall Survival (OS)

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

Historical control data of patients treated with Optune System combined with Temozolomide alone will be compared with the Optune System combined with Temozolomide (TMZ) + Pembrolizumab arm.

Temozolomide (TMZ): 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.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)	NCT03405792	Glioblastoma Glioblastoma, W...	Temozolomide (T... Optune System Pembrolizumab	18 Years - 80 Years	University of Florida
Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)	NCT03405792	Glioblastoma Glioblastoma, W...	Temozolomide (T... Optune System Pembrolizumab	18 Years - 80 Years	University of Florida

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