Pembrolizumab + Temozolomide + TTFields for Glioblastoma

(2-THE-TOP Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Florida

Must be taking: Temozolomide

Must not be taking: Anti-angiogenics, Immunotherapy

Disqualifiers: Other malignancy, Progressive disease, Autoimmune, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of three treatments—pembrolizumab (an immunotherapy drug), temozolomide (a chemotherapy drug), and TTFields (a device therapy called Optune)—can benefit individuals with newly diagnosed glioblastoma, an aggressive brain cancer. The researchers seek to find out if this combination can extend the time patients live without disease progression. Individuals with confirmed glioblastoma who have begun standard treatment with surgery, radiation, and temozolomide might be suitable candidates. Participants should be prepared to start additional treatments within a specific timeframe after their initial therapies. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive therapy or have a history of certain conditions like active autoimmune disease, you may need to discuss this with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of pembrolizumab, temozolomide, and Optune (Tumor Treating Fields) is under study for safety in treating glioblastoma, a type of brain cancer. Previous studies have found that using Optune with temozolomide is generally safe for patients with newly diagnosed brain cancer. Pembrolizumab is already approved for other cancers, such as lung cancer and melanoma, providing some safety information from those uses.

Pembrolizumab can sometimes cause immune-related reactions because it boosts the immune system. Temozolomide, a chemotherapy drug, may cause common side effects like nausea, tiredness, and a decrease in blood cell counts. Optune, a device worn on the head, is usually well-tolerated, though some people may experience mild skin irritation where the device touches the scalp.

While more information is needed to fully understand the safety of this treatment combination, the individual treatments have been used safely in other situations. This suggests a reasonable expectation of safety, but each person's experience may vary. Always discuss potential risks with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for glioblastoma, which typically involves surgery, radiation, and chemotherapy with drugs like Temozolomide, this treatment combination introduces a novel component: pembrolizumab, an immunotherapy drug. Pembrolizumab works by targeting the PD-1 pathway, reactivating the immune system to recognize and attack cancer cells more effectively. Additionally, the use of TTFields (Tumor Treating Fields) with the Optune System adds a non-invasive treatment modality that disrupts cancer cell division. Researchers are excited about this approach because it combines established therapies with cutting-edge immunotherapy and innovative technology, potentially enhancing treatment efficacy and offering hope for improved outcomes in glioblastoma patients.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that combining Optune, temozolomide, and pembrolizumab may be promising for treating glioblastoma. In this trial, participants will receive this combination. Optune uses special electric fields to target tumors and has helped patients with newly diagnosed glioblastoma live longer when used with temozolomide. Temozolomide, a chemotherapy drug, has been a standard treatment for this type of brain cancer. Pembrolizumab, an immunotherapy drug, has worked well in treating other cancers like lung cancer and melanoma. Early findings suggest that adding pembrolizumab to Optune and temozolomide might enhance the immune system's ability to fight cancer cells. This combination aims to help patients with glioblastoma live longer without the disease worsening. ^{1 2 3 4 6}

Who Is on the Research Team?

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

Adults with newly diagnosed Glioblastoma who've had surgery and radiotherapy can join. They must be healthy enough for further treatment, have a life expectancy of at least 3 months, and use effective contraception. Those with certain other cancers, previous treatments like anti-PD-1 or bevacizumab, implanted electronic brain devices, severe allergies to trial drugs, uncontrolled illnesses or active infections cannot participate.

Inclusion Criteria

I am taking a low dose of steroids, not more than 4mg of dexamethasone daily.

I will start Optune and temozolomide 4-6 weeks after my last cancer treatment.

I am eligible for high dose temozolomide and Optune therapy after my main treatment.

Exclusion Criteria

I have been treated with drugs that target the immune system.

I have previously been treated with medications that stop the formation of new blood vessels.

I have been diagnosed with HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation

Participants undergo standard chemoradiation with concomitant TMZ and radiation therapy

4-6 weeks

Adjuvant Treatment

Participants receive monthly cycles of adjuvant TMZ and Optune therapy, with pembrolizumab starting within one week after Cycle 2

up to 24 months

Visits every 3 weeks for pembrolizumab dosing

Follow-up

Medical follow-up continues for 30 days after treatment termination, with mortality assessed every 3 months via telephone

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Optune System
• Pembrolizumab
• Temozolomide

Trial Overview The study tests if adding Pembrolizumab (an immunotherapy drug) to Temozolomide chemotherapy and TTFields (Optune®), an electric field therapy, extends the time patients live without their brain cancer getting worse compared to past data.

How Is the Trial Designed?

Group I: Optune System combined with Temozolomide (TMZ) + Pembrolizumab Experimental Treatment 3 Interventions

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.

Group II: Historical Control Experimental Treatment 2 Interventions

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

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

NovoCure Ltd.

Industry Sponsor

Trials

64

Recruited

6,100+

Ashley Cordova

NovoCure Ltd.

Chief Executive Officer

Bachelor of Science in Material Engineering from Ben-Gurion University of the Negev, Israel

Uri Weinberg

NovoCure Ltd.

Chief Medical Officer since 2020

MD from an unspecified institution

Published Research Related to This Trial

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, showing meaningful efficacy in delaying disease progression and maintaining quality of life in a study of 525 patients.

TMZ has a favorable safety profile and does not require liver metabolism for activation, allowing it to rapidly penetrate the cerebrospinal fluid, making it a promising option for treating these aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in malignant gliomas. Yung, WK.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a phase II study involving 42 patients with recurrent glioblastoma multiforme, temozolomide (TMZ) demonstrated a progression-free survival rate of 24% at 6 months, indicating its potential efficacy as a second-line treatment.

The study reported a median time to progression of 11.7 weeks, with a response rate of 19% (including complete and partial responses), suggesting that TMZ can be a valid treatment option for patients who have already undergone extensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study. Brandes, AA., Ermani, M., Basso, U., et al.[2018]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

In a mouse model of glioma, combining temozolomide (TMZ) with anti-PD-1 antibody therapy significantly improved overall survival compared to either treatment alone, indicating a potential synergistic effect.

The combination therapy also resulted in a notable reduction in tumor size and an increase in the infiltration of immune cells (CD4 and CD8 T cells) within the tumor, suggesting enhanced immune response against the glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model. Dai, B., Qi, N., Li, J., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12487835/

Tumor Treating Fields: An Innovative Therapy for ... In this review, we will describe TTFields therapy mechanisms of action, available efficacy and safety data in glioblastoma, administration and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06556563

EF-41/KEYNOTE D58: Phase 3 Study of Optune ... This is a multicenter, two-arm, randomized, double-blind, placebo-controlled study of Optune® (Tumor Treating Fields at 200 kHz) together with maintenance ...

3. va.gov va.gov/COMMUNITYCARE/docs/providers/CDI/IVC-CDI-00002.pdf

Tumor Treating Fields Therapy - Clinical Determinations ... The limited data available for Optune Lua device states that Optune Lua device must be worn for at least 18 hours per day and for four full ...

4. excellusbcbs.com excellusbcbs.com/documents/d/global/exc-prv-tumor-treatment-fields-therapy-effective-on-2025-09-16-

Tumor-Treatment Fields Therapy Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal ...

5. novocuretrials.com novocuretrials.com/cancer-clinical-trials/lung-cancer-clinical-trials-keynote-d58

KEYNOTE D58 | Optune Gio HCP The KEYNOTE D58 study is intended for patients with a newly diagnosed glioblastoma (GBM). This clinical study is evaluating the safety and efficacy of Tumor ...

6. univerahealthcare.com univerahealthcare.com/documents/d/global/uni-prv-tumor-treatment-fields-therapy-effective-2025-09-16-

Tumor-Treatment Fields Therapy ... Optune System (NovoTTF-100A System), which is now called the Optune Lua System (NovoTTF™-100L System), for "treatment of adult patients with unresectable ...