Optune + Temozolomide + Pembrolizumab for Brain Cancer

(EF-41 Trial)

Recruiting at 73 trial locations

Overseen By Uz Stammberger

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: NovoCure GmbH

Must be taking: Temozolomide

Must not be taking: PD-1 inhibitors

Disqualifiers: Immunodeficiency, Pneumonitis, Other malignancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

Duration: 24 months

741 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for patients with newly diagnosed glioblastoma, an aggressive brain cancer. It compares the effectiveness of adding pembrolizumab, an immune therapy drug, to standard treatments, including Optune (a device that uses electric fields to slow tumor growth) and the chemotherapy drug temozolomide. Researchers aim to determine if this combination can extend patients' lives. Individuals with a new glioblastoma diagnosis who have completed surgery and initial treatments, such as chemoradiotherapy, might be eligible to participate. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain cancer therapies or high doses of steroids. It's best to discuss your current medications with the trial team.

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

Research shows that using Optune, Temozolomide, and Pembrolizumab together may help treat brain cancer. In past studies, this combination helped patients with glioblastoma live longer and slow tumor growth.

Regarding safety, patients have generally tolerated the treatment well. The Optune device uses electric fields to stop cancer cells from growing and mainly causes manageable skin irritation. Temozolomide, approved by the FDA for brain tumors, can cause side effects like nausea and tiredness, but these are usually manageable. Pembrolizumab, also FDA-approved for other cancers, can cause tiredness and skin reactions, though serious side effects are rare.

Overall, this combination treatment has demonstrated a good safety record in previous studies, with side effects that patients can usually manage with medical help. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Optune, Temozolomide, and Pembrolizumab for brain cancer because it represents a novel approach to treatment. Unlike traditional treatments like radiation and chemotherapy, this combination targets cancer cells in multiple ways. Optune uses electric fields to disrupt cancer cell division, while Temozolomide is a chemotherapy drug that damages the DNA of cancer cells, and Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. This multi-pronged strategy could potentially improve outcomes by attacking the cancer on different fronts simultaneously.

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

This trial will evaluate the combination of Optune, a device that uses electric fields to stop cancer cells from growing, with pembrolizumab, an immune therapy drug, and temozolomide, a chemotherapy drug, for brain cancer patients. Research has shown that this combination can significantly extend the time patients live without their disease worsening. Adding pembrolizumab to Optune and temozolomide enhances the immune system's ability to fight the tumor. This treatment helps the body recognize cancer cells more effectively, making it a promising option for people with newly diagnosed glioblastoma. Early results suggest this combination could lead to longer survival for patients. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a new diagnosis of Glioblastoma who have recovered from surgery and completed standard chemoradiotherapy. Participants must be in good physical condition (ECOG 0-1) and, if taking corticosteroids, on a stable or decreasing dose. They should agree to use the Optune device alongside maintenance Temozolomide chemotherapy.

Inclusion Criteria

I have recovered from surgery to remove as much of my tumor as possible.

I have been newly diagnosed with GBM as per WHO 2021 standards.

I've finished standard chemoradiotherapy for my condition.

Exclusion Criteria

I haven't had any cancer treatment or experimental drugs in the last 4 weeks.

I have been treated with immunotherapy targeting PD-1, PD-L1, PD-L2, or other T-cell receptors.

My cancer has spread to the lower part of my brain or its lining.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Optune® with maintenance Temozolomide and either pembrolizumab or placebo

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Optune® device
• Pembrolizumab
• Temozolomide

Trial Overview The study tests the combination of the Optune device with Temozolomide chemotherapy and Pembrolizumab versus the same setup but replacing Pembrolizumab with a placebo. The main goal is to see which combination helps patients live longer.

How Is the Trial Designed?

Group I: Treatment Group Experimental Treatment 3 Interventions

Group II: Control Group Placebo Group 3 Interventions

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?

NovoCure GmbH

Lead Sponsor

Trials

16

Recruited

3,700+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

In a Phase II study involving 26 chemotherapy-naive patients with brain metastases from metastatic melanoma, the combination of temozolomide and thalidomide showed activity, with 12% of patients achieving a complete or partial response in brain tumors.

The treatment was associated with significant safety concerns, as 11 patients discontinued due to serious adverse events, including intracranial hemorrhage and pulmonary embolism, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Hwu, WJ., Lis, E., Menell, JH., et al.[2018]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

In a phase II clinical trial involving 23 melanoma patients with untreated brain metastases, pembrolizumab demonstrated a 26% response rate in brain metastases, indicating its potential efficacy in this challenging patient population.

The treatment was associated with acceptable toxicity, as 65% of patients experienced neurologic adverse events, mostly mild (grade 1 or 2), and nearly half of the patients (48%) were alive at 24 months, suggesting durable responses and a need for careful management of brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Kluger, HM., Chiang, V., Mahajan, A., et al.[2020]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a study involving 351 patients with advanced noncolorectal MSI-H/dMMR solid tumors, pembrolizumab showed a significant objective response rate (ORR) of 30.8%, indicating its efficacy in this patient population.

The treatment demonstrated a long median duration of response of 47.5 months and manageable safety, with only 11.1% of patients experiencing severe (grade 3-4) treatment-related adverse events, supporting its use in heavily pretreated cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Maio, M., Ascierto, PA., Manzyuk, L., et al.[2022]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

In a phase II trial involving 19 patients, the combination of temozolomide (TMZ) and pegylated liposomal doxorubicin showed an overall response rate of 36.8%, with three patients achieving a complete response and four a partial response, indicating promising efficacy in treating brain metastases from solid tumors.

The treatment was well tolerated, with manageable toxicities, and resulted in a median overall survival of 10.0 months and a median progression-free survival of 5.5 months, along with significant improvements in quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours. Caraglia, M., Addeo, R., Costanzo, R., et al.[2018]

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]

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]

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]

Citations

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Efficacy and safety of adjuvant TTFields plus ... This study confirms that the use of TTFields in conjunction with pembrolizumab enhances immune recognition and anti-tumor immunity, significantly improving PFS ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.2024

Final analysis of 2-THE-TOP: A phase 2 study of TTFields ... We enrolled 26 newly diagnosed GBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ).

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Efficacy of tumour-treating fields therapy in recurrent ... This review synthesizes the current evidence surrounding the efficacy of TTFields Therapy in the context of recurrent Glioblastoma.

4. novocure.com novocure.com/novocure-announces-presentations-tumor-treating-fields-therapy-including-new-clinical-data-and-real

Novocure Announces Presentations on Tumor Treating ... an oral presentation of data from the 2-THE-TOP trial, suggesting TTFields therapy had an enhanced effect with pembrolizumab in patients with newly diagnosed ...

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NCT03405792 | Study Testing The Safety and Efficacy of ... This study is being performed to determine whether the triple combination of pembrolizumab when added to TTFields (Optune®) and adjuvant temozolomide increases ...

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Recent advances in Tumor Treating Fields (TTFields) therapy ... This article reviews the mechanism, efficacy, safety, and quality of life of Tumor Treating Fields (TTFields) therapy in glioblastoma.

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TTFields Plus Temozolomide/Pembrolizumab Controls ... Patients with newly diagnosed glioblastoma had improved survival when treated with TTFields plus temozolomide and pembrolizumab.

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

KEYNOTE D58 | Optune Gio HCP This clinical study is evaluating the safety and efficacy of Tumor Treating Fields (TTFields, 200 kHz) delivered by the Optune® device concomitant with ...