Combination Immunotherapy + Chemoradiation for Glioblastoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for individuals with newly-diagnosed glioblastoma, a type of brain cancer. Researchers aim to assess the safety and effectiveness of these treatments together. Participants will receive a mix of immunotherapy drugs (INO-5401 and INO-9012), cemiplimab (an immunotherapy drug), radiation therapy, and a chemotherapy drug called temozolomide. The trial seeks individuals with glioblastoma who have undergone surgery and are ready to begin radiation soon.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

Research shows that cemiplimab is usually well-tolerated by patients. In a large study with over 1,200 participants, common side effects included muscle pain, tiredness, rash, and diarrhea, while serious side effects were less common.

INO-5401 and INO-9012, when used together, have also proven to be safe. Studies indicate these treatments are tolerable and can help boost the immune system. This combination, along with cemiplimab, was found to be safe for patients with newly diagnosed glioblastoma.

The trial is in its early stages, focusing primarily on ensuring the safety of these treatments. Current safety data suggest these treatments are generally well-tolerated, but further research will provide additional insights. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for glioblastoma rely on approaches like surgery, radiation, and the chemotherapy drug temozolomide. But researchers are excited about combining immunotherapy with chemoradiation because it could enhance the effectiveness of traditional treatments. Cemiplimab, an immune checkpoint inhibitor, works by boosting the body's immune response against cancer cells. INO-5401 and INO-9012 are DNA-based immunotherapies that aim to train the immune system to specifically target and attack the tumor. This approach could potentially offer a more personalized and powerful attack against glioblastoma, especially for patients with different MGMT promoter statuses, which often influence treatment response.

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

This trial will evaluate the combination of INO-5401 and INO-9012 with cemiplimab, alongside radiation and temozolomide, for treating glioblastoma. Participants in Cohort A, with an unmethylated MGMT promoter, will receive this combination, with temozolomide given only during radiation therapy if clinically indicated. Participants in Cohort B, with a methylated MGMT promoter or indeterminate MGMT status, will receive the same combination, with the option to continue temozolomide after radiation therapy for up to six additional cycles if clinically indicated. Research has shown that 70% of patients with a methylated MGMT promoter survived for 18 months, while 50% of those with an unmethylated promoter survived the same period. This treatment can activate the immune system and is generally well-tolerated. Although cemiplimab alone has not been very effective for glioblastoma, combining it with other treatments might be beneficial. These findings offer hope for better outcomes in treating glioblastoma. ^{6 7 8 9 10}

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

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]

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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03491683

Study Details | NCT03491683 | INO-5401 and INO-9012 ... This is a phase 1/2, open-label, multi-center trial to evaluate safety, immunogenicity and preliminary efficacy of INO-5401 and INO-9012 in combination with ...

2. ir.inovio.com ir.inovio.com/news-releases/news-releases-details/2022/INOVIO-Announces-Survival-Results-for-INO-5401--INO-9012-in-Combination-with-Libtayo-cemiplimab-in-Patients-with-Newly-Diagnosed-GBM-at-ASCO-Annual-Meeting-2022/default.aspx

INOVIO Announces Survival Results for INO-5401 + INO-9012 ... INOVIO Announces Survival Results for INO-5401 + INO-9012 in Combination with Libtayo® (cemiplimab) in Patients with Newly Diagnosed GBM at ASCO ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04826393

NCT04826393 | ASP8374 + Cemiplimab in Recurrent Glioma This study is looking at the safety and efficacy of the drug combination of ASP8374 with cemiplimab in people with recurrent malignant glioma.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11674442/

Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment Conclusions: ICI for the treatment of GBM has not demonstrated clear evidence of efficacy thus far. This review serves as a quick reference of ...

5. targetedonc.com targetedonc.com/view/unpacking-the-data-behind-adjuvant-cemiplimab-s-fda-approval

Unpacking the Data Behind Adjuvant Cemiplimab's FDA ... The 24-month DFS rates for cemiplimab and placebo treatment were 87.1% and 64.1%, respectively. This effect was observed across all tumor ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04826393

NCT04826393 | ASP8374 + Cemiplimab in Recurrent Glioma This study is looking at the safety and efficacy of the drug combination of ASP8374 with cemiplimab in people with recurrent malignant glioma.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/761097s014lbl.pdf

LIBTAYO® (cemiplimab-rwlc) injection, for intravenous use In this pooled safety population, the most common adverse reactions (≥15%) were musculoskeletal pain, fatigue, rash, and diarrhea. The most common Grade 3-4 ...

8. libtayohcp.com libtayohcp.com/

LIBTAYO® (cemiplimab-rwlc) | Official HCP Website See Important Safety & full Prescribing Information ... LIBTAYO as a single agent is indicated for the first-line treatment of adult patients with NSCLC whose ...

9. regeneron.com regeneron.com/downloads/libtayo_fpi.pdf

LIBTAYO® Full Prescribing Information Among the 1281 patients, 53% were exposed for 6 months or longer and 26% were exposed for one year or longer. In this pooled safety population, the most common ...

10. ir.inovio.com ir.inovio.com/news-releases/news-releases-details/2020/INOVIOs-INO-5401-in-Combination-with-PD-1-Inhibitor-Libtayo-cemiplimab-Demonstrates-85-of-Newly-Diagnosed-Glioblastoma-Patients-Are-Alive-12-Months-Following-Treatment/default.aspx

INOVIO's INO-5401 in Combination with PD-1 Inhibitor Libtayo ... INO-5401, in combination with INO-9012 and PD-1 inhibitor Libtayo® (cemiplimab), were alive for at least 12 months or more (overall survival at 12 months: OS12 ...