Combination Immunotherapy + Chemoradiation for Glioblastoma

Recruiting at 20 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Inovio Pharmaceuticals

Must not be taking: PD-1 inhibitors, Idelalisib

Disqualifiers: Autoimmune disease, Immunodeficiency, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Phase 1/2 trial to evaluate safety, immunogenicity and preliminary efficacy of INO-5401 and INO-9012 in combination with cemiplimab (REGN2810), with radiation and chemotherapy, in subjects with newly-diagnosed glioblastoma (GBM).

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 have had certain immune treatments or investigational agents within 28 days before starting the trial, and you must be on a stable or decreasing dose of dexamethasone.

Is the combination of immunotherapy and chemoradiation safe for humans?

Research shows that temozolomide, when used with radiation therapy, has a lower toxicity profile compared to older chemotherapy drugs and is generally well-tolerated in patients with glioblastoma. Studies have focused on finding the maximum safe dose of this combination, indicating ongoing efforts to ensure its safety in humans. ^{1 2 3 4 5}

What makes the combination immunotherapy and chemoradiation treatment for glioblastoma unique?

This treatment is unique because it combines immunotherapy (which helps the immune system fight cancer) with chemoradiation (a mix of chemotherapy and radiation therapy) using drugs like Cemiplimab and Temozolomide. This approach aims to enhance the body's immune response while directly targeting cancer cells, potentially offering a more effective treatment for glioblastoma compared to traditional methods. ^{3 6 7 8 9}

What data supports the effectiveness of the treatment for glioblastoma?

Research shows that combining temozolomide (a chemotherapy drug) with radiotherapy can improve outcomes for patients with glioblastoma, a type of brain cancer. Temozolomide is known to be effective in treating high-grade gliomas and is being studied for its potential to enhance the effects of radiotherapy in newly diagnosed cases. ^{3 7 10 11 12}

Who Is on the Research Team?

Jeffrey Skolnik, MD

Principal Investigator

Inovio Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with newly-diagnosed glioblastoma who've recovered from initial surgery, have a Karnofsky Performance Status of 70 or above, can tolerate MRIs, and have stable organ function. They must not be pregnant or fathering children and agree to use effective contraception. Excluded are those with recent autoimmune disease treatment, certain allergies, multifocal brain cancer, immunodeficiency, unstable diseases that could affect the trial's integrity.

Inclusion Criteria

You need to have fully recovered from your previous brain surgery, as determined by the doctor in charge of the study.

Newly-diagnosed brain cancer with histopathological diagnosis of GBM

Karnofsky Performance Status (KPS) rating of >/=70 at baseline

Exclusion Criteria

You have had an autoimmune disease that needed strong medications to control it in the past 5 years.

You have received or are planning to receive certain types of treatments, such as tumor treatment fields or oncolytic viral treatment. You have also taken part in a clinical trial or used an experimental treatment within the past 28 days.

You are allergic to cemiplimab or any of the ingredients in it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive INO-5401 and INO-9012 delivered by electroporation in combination with cemiplimab, radiation, and temozolomide

6 weeks

Chemotherapy

Participants continue to receive temozolomide for up to six additional cycles following radiation therapy, if clinically indicated

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cemiplimab
• INO-5401
• INO-9012
• Radiation Therapy
• Temozolomide

Trial Overview The study tests INO-5401 and INO-9012 combined with cemiplimab (REGN2810), radiation therapy, and temozolomide chemotherapy in patients with new glioblastoma. It aims to assess safety and immune response as well as early signs of effectiveness in treating this aggressive brain cancer.

How Is the Trial Designed?

Group I: Cohort B: Methylated MGMT Promoter Experimental Treatment 5 Interventions

Cohort B will include participants with a glioblastoma tumor with a methylated MGMT promoter or with indeterminate MGMT status. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ), if clinically indicated. Participants will continue to receive TMZ following radiation therapy, for up to six additional cycles, if clinically indicated.

Group II: Cohort A: Unmethylated MGMT Promoter Experimental Treatment 5 Interventions

Cohort A will include participants with a glioblastoma tumor with an unmethylated MGMT promoter. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ; only during radiation therapy), if clinically indicated.

Cemiplimab is already approved in European Union, United States, Canada, Brazil for the following indications:

Approved in European Union as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in United States as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Basal cell carcinoma (BCC)
• Non-small cell lung cancer (NSCLC)

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

Inovio Pharmaceuticals

Lead Sponsor

Trials

54

Recruited

4,800+

Published Research Related to This Trial

Naringenin (NGEN) significantly reduces the migration and invasion of drug-resistant glioma cells, suggesting it can enhance the effectiveness of temozolomide (TMZ) treatment.

The study provides evidence that NGEN can overcome TMZ resistance by modifying protein levels related to cell migration and invasion, making it a promising adjunct therapy for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. J, J., Vanisree, AJ.[2022]

Adding nitrosourea-based chemotherapy to radiotherapy has been shown to increase progression-free survival in patients with grade II and III gliomas, although it does not improve overall survival.

Upcoming phase III trials will investigate whether adding temozolomide to radiotherapy can enhance overall survival in grade II/III gliomas, while also assessing cognitive function and quality of life for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. Schiff, D.[2018]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

In a Phase I clinical trial involving 19 patients with glioblastoma, the maximum tolerated dose of fractionated intensity-modulated radiotherapy (IMRT) combined with temozolomide (TMZ) was determined to be 65 Gy, delivered in 25 fractions over 5 weeks, without any dose-limiting toxicities observed.

The treatment was well tolerated, with only mild to moderate (Grade 1-2) neurologic and skin toxicities reported, and no severe late neurologic toxicities, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. Morganti, AG., Balducci, M., Salvati, M., et al.[2018]

In a study of 128 patients with high-grade gliomas, the combination of radiotherapy and temozolomide showed favorable outcomes, with only 9% experiencing grade 3 hematological toxicity and no grade 4 toxicity reported, indicating a manageable safety profile.

Statistical analysis revealed that factors such as age, tumor histology, and the use of temozolomide were linked to improved 2-year overall survival, supporting the efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas. Corsa, P., Parisi, S., Raguso, A., et al.[2022]

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]

The combination of fractionated radiotherapy and temozolomide (TMZ), followed by autologous formalin-fixed tumor vaccine (AFTV), was well tolerated in 24 patients with newly diagnosed glioblastoma multiforme (GBM), showing promising safety and efficacy.

One-third of the patients experienced progression-free survival (PFS) of 24 months or more, with a median overall survival (OS) of 22.2 months, indicating that this treatment regimen may enhance antitumor immunity and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma. Ishikawa, E., Muragaki, Y., Yamamoto, T., et al.[2023]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

Citations

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

Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: a safety and efficacy analysis. [2022]

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

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. [2018]

4. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability. [2017]

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

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. [2018]

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

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells. [2018]

9. 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]

10. England pubmed.ncbi.nlm.nih.gov

Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. [2023]

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

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma. [2023]

12. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]