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

40 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Pembrolizumab + Temozolomide + TTFields for Glioblastoma?

Research shows that Temozolomide, a drug used in this treatment, has been effective in delaying disease progression and maintaining quality of life in patients with malignant gliomas, including glioblastoma. Additionally, combining Temozolomide with anti-PD-1 antibodies, like Pembrolizumab, has shown therapeutic potential in glioma models. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Temozolomide, and TTFields generally safe for humans?

Temozolomide, one of the drugs in the combination, is generally used for treating brain tumors and has been studied for safety in various conditions. However, it has been associated with some serious side effects, including secondary blood disorders like acute lymphoblastic leukemia. Safety data for the combination with Pembrolizumab and TTFields specifically is not detailed in the provided research. ^{4 6 7 8 9}

How is the treatment of Pembrolizumab, Temozolomide, and TTFields for glioblastoma different from other treatments?

This treatment combines Pembrolizumab, an immunotherapy drug, with Temozolomide, a chemotherapy drug, and TTFields, a non-invasive therapy that uses electric fields to disrupt cancer cell division. The unique combination aims to enhance the effectiveness of standard treatments by leveraging the immune system and innovative technology to improve patient outcomes. ^{10 11 12 13 14}

What is the purpose of this trial?

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.

Research Team

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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]

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]

References

1. England 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. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Temozolomide in malignant gliomas. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: high rate of thromboembolic events (CALGB 500102). [2018]

9. Scotland pubmed.ncbi.nlm.nih.gov

Temozolomide-related acute lymphoblastic leukemia with translocation (4;11)(q21;q23) in a glioblastoma patient. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. [2018]

12. Switzerland pubmed.ncbi.nlm.nih.gov

TTFields Prolonged the PFS of Epithelioid Glioblastoma Patient: A Case Report. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Treating Glioblastoma With Tumor-Treating Fields Therapy. [2018]