Intra-arterial Cetuximab for Newly Diagnosed Glioblastoma

Overseen By Christopher Filippi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Northwell Health

Must be taking: Chemotherapy, Radiation therapy

Disqualifiers: Pregnancy, Leptomeningeal disease, Allergic to CTX, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 7 months

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating glioblastoma, an aggressive brain cancer. Researchers administer a drug called Cetuximab (an antibody therapy) directly into the brain's blood vessels after opening the blood-brain barrier, combining it with standard chemotherapy and radiation. The goal is to determine if this approach is safe and effective for patients with newly diagnosed glioblastoma. Suitable candidates are those diagnosed with glioblastoma that overexpresses a protein called EGFR and who can tolerate standard cancer treatments. 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 innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop chemotherapy for two weeks and external beam radiation for eight weeks before starting the treatment. Other medications are not specified, so it's best to discuss with the trial team.

Is there any evidence suggesting that intra-arterial Cetuximab is likely to be safe for humans?

Research shows that using Cetuximab directly in the arteries for brain cancer treatment is generally safe and well-tolerated. Earlier studies with children who had brain tumors found this method to have few side effects. Common side effects of Cetuximab include infusion reactions, an acne-like skin rash, and nail problems, which are usually manageable.

Cetuximab has approval for other treatments, supporting its safety. While researchers continue to test this treatment specifically for newly diagnosed glioblastoma (a type of brain cancer), current evidence suggests it could be a promising option. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for glioblastoma, which often include surgery, radiation, and chemotherapy, this approach uses Cetuximab delivered directly into the arteries after disrupting the blood-brain barrier with mannitol. This method allows for a higher concentration of the drug to reach the tumor, potentially increasing its effectiveness. Researchers are excited about this treatment because Cetuximab specifically targets the epidermal growth factor receptor (EGFR), which is overexpressed in many glioblastomas, offering a more targeted attack on the cancer cells.

What evidence suggests that intra-arterial Cetuximab is effective for glioblastoma?

Research has shown that cetuximab might help treat glioblastoma, a common and aggressive brain cancer. Glioblastoma often exhibits high levels of a protein called EGFR, which cetuximab can block. In earlier studies, researchers administered the drug directly to the brain, and it was well tolerated with few side effects. This trial will use intra-arterial infusion, delivering cetuximab straight to the tumor after disrupting the blood-brain barrier with mannitol, potentially enhancing its effectiveness. Although the full results of these studies are still under review, early findings suggest that cetuximab could be a promising addition to current treatments. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with newly diagnosed glioblastoma multiforme (GBM) showing high levels of EGFR. Participants must have good organ function, no recent chemo or radiation, and a life expectancy of at least three months. They should be able to perform daily activities well (Karnofsky score ≥70%) and not be pregnant or breastfeeding. Contraception use during the study and for three months after is required.

Inclusion Criteria

I have been newly diagnosed with glioblastoma multiforme.

My blood counts meet the required levels for treatment.

Patients must agree to use a medically effective method of contraception during and for a period of three months after the treatment period. A pregnancy test will be performed on each premenopausal female of childbearing potential immediately prior to entry into the research study

Exclusion Criteria

Women of childbearing potential and fertile men will be informed as to the potential risk of conception while participating in this research trial and will be advised that they must use effective contraception during and for a period of three months after the treatment period

I am currently pregnant or breastfeeding.

Patients with history of allergic reaction to CTX

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard chemoradiation (STUPP protocol) and intra-arterial Cetuximab after BBBD for three doses at approximately post-surgery days 30, 120, and 210

7 months

3 visits (in-person) for Cetuximab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Mannitol

Trial Overview The trial tests repeated intra-arterial infusions of Cetuximab combined with standard chemoradiation on patients with GBM after disrupting the blood-brain barrier. It's an open-label Phase I/II trial where patients receive three doses post-surgery alongside their regular treatment protocol.

How Is the Trial Designed?

Group I: Intra-arterial Cetuximab after BBBD Experimental Treatment 2 Interventions

Mannitol 20% 12.5ml over two minutes for Blood Brain Barrier (BBB) disruption followed by CTX administered intra-arterially for three doses at a dose of 250mg/m2

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Published Research Related to This Trial

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

This case study presents a novel treatment approach for glioblastoma (GBM) using superselective intraarterial cerebral infusion (SIACI) of cetuximab after temporarily disrupting the blood-brain barrier with mannitol, showing promise for targeting EGFR amplified tumors.

The patient, who received SIACI of cetuximab alongside standard chemoradiation, exhibited stable post-radiation MRI results and no signs of tumor recurrence at 4 and 6 months, suggesting that this combined treatment may enhance therapeutic efficacy for newly diagnosed GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with Stupp Protocol for newly diagnosed glioblastoma. Kulason, KO., Schneider, JR., Chakraborty, S., et al.[2022]

Cetuximab-conjugated iron-oxide nanoparticles (cetuximab-IONPs) effectively target and are internalized by glioblastoma stem-like cells (GSCs), leading to enhanced antitumor effects compared to cetuximab alone.

In rodent models of glioblastoma, treatment with cetuximab-IONPs significantly increased survival, demonstrating their potential as a promising therapeutic strategy for targeting aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles. Kaluzova, M., Bouras, A., Machaidze, R., et al.[2018]

The study demonstrated that radiolabeled cetuximab (131I-Erbi) is stable for up to 72 hours and shows significantly higher uptake in cancer cells with epidermal growth factor receptors, indicating its potential effectiveness in targeting brain metastases.

Combining radiotherapy with 131I-Erbi resulted in a greater inhibition of tumor cell proliferation compared to using cetuximab alone, suggesting a synergistic effect that could enhance treatment outcomes for patients with multiple brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioactive EGFR antibody cetuximab in multimodal cancer treatment: stability and synergistic effects with radiotherapy. Rades, D., Wolff, C., Nadrowitz, R., et al.[2018]

Cetuximab is an effective monoclonal antibody that targets the epidermal growth factor receptor, which is linked to poor outcomes in solid tumors, by blocking its activation and associated oncogenic processes.

While cetuximab can cause infusion reactions and skin-related side effects, its overall safety profile is favorable compared to traditional chemotherapy, and these side effects are generally manageable with appropriate treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: adverse event profile and recommendations for toxicity management. Thomas, M.[2020]

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

Cetuximab, a monoclonal antibody targeting EGFR, effectively delivered boron to brain tumors, achieving significantly higher boron concentrations in gliomas compared to traditional delivery methods, with mean concentrations of 92.3 microg/g in F98(EGFR) gliomas.

Rats treated with boronated cetuximab showed a mean survival time of 45 days, which increased to over 59 days when combined with another boron delivery agent, indicating its potential as an effective treatment for gliomas in neutron capture therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neutron capture therapy of epidermal growth factor (+) gliomas using boronated cetuximab (IMC-C225) as a delivery agent. Barth, RF., Wu, G., Yang, W., et al.[2018]

Cetuximab, when linked to a boronated dendrimer (BD-C225), effectively targets EGFR-positive glioma cells, leading to significantly higher boron retention in tumors compared to receptor-negative cells, which is crucial for boron neutron capture therapy (BNCT).

In vivo studies showed that BNCT using BD-C225 resulted in improved survival times for treated rats (mean survival time of 54.5 days) compared to untreated controls (30.3 days), demonstrating the potential of this targeted therapy for treating brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. Wu, G., Yang, W., Barth, RF., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02800486?term=AREA%5BConditionSearch%5D(Anaplastic%20oligoastrocytoma%20OR%20%22aMOA%22%20OR%20%22%20anaplastic%20mixed%20glioma%22%20OR%20%22%20WHO%20grade%20III%20mixed%20glioma%22)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING)&rank=2

Super Selective Intra-arterial Repeated Infusion of ... Present therapies are inadequate, as evidenced by the low 5-year survival rate for brain cancer patients, with median survival at approximately 12 months.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26945581/

Superselective intraarterial cerebral infusion of cetuximab ... A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma. Keywords: Brain neoplasm; Cetuximab ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/115764

Super Selective Intra-arterial Repeated Infusion of ... Present therapies are inadequate, as evidenced by the low 5-year survival rate for brain cancer patients, with median survival at approximately 12 months.

4. trials.braintumor.org trials.braintumor.org/trials/NCT02861898

Super-selective Intra-arterial Repeated Infusion of Cetuximab ... Present therapies are inadequate, as evidenced by the low 5-year survival rate for brain cancer patients, with median survival at approximately 12 months.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9539841/

A systematic review on intra-arterial cerebral infusions of ... To provide a comprehensive review of intra-arterial cerebral infusions of chemotherapeutics in glioblastoma multiforme treatment and discuss potential research ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01884740

Study Details | NCT01884740 | Intraarterial Infusion Of ... We seek to test the hypothesis that intra-arterial Cetuximab and Bevacizumab is safe and effective in the treatment of relapsed/refractory glioma in patients < ...

7. jnis.bmj.com jnis.bmj.com/content/16/11/1152

Safety and feasibility of intra-arterial delivery of teniposide to ... Conclusion This small series suggests that superselective IA cerebral infusion of teniposide may be a safe and effective therapy in the multimodal treatment of ...

8. withpower.com withpower.com/trial/phase-2-glioblastoma-5-2016-55cd7

Intra-arterial Cetuximab for Newly Diagnosed Glioblastoma Cetuximab is generally considered safe for use in humans, with the most common side effects being infusion reactions, acne-like skin rash, and nail disorders.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34359048/

Intraarterial delivery of bevacizumab and cetuximab ... SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to ...