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

Trial Summary

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.

What data supports the effectiveness of the drug Cetuximab for newly diagnosed glioblastoma?

A study showed that using Cetuximab with a method to open the blood-brain barrier, combined with standard cancer treatments, helped stabilize a brain tumor in a patient for at least 6 months without signs of it coming back. Another study found that Cetuximab, when used with a special type of radiation therapy, improved survival in rats with brain tumors. ^{1 2 3 4 5}

What is the safety profile of cetuximab in humans?

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. Infusion reactions can be serious, so preventive treatment and careful monitoring are recommended. The skin rash and nail issues are usually mild and manageable with antibiotics. ^{2 3 5 6 7}

How is the drug cetuximab used in treating newly diagnosed glioblastoma different from other treatments?

Cetuximab is unique in treating newly diagnosed glioblastoma because it is delivered directly into the brain's arteries after temporarily opening the blood-brain barrier, allowing the drug to reach the tumor more effectively. This method, combined with standard chemoradiation, may enhance treatment effectiveness for tumors with EGFR amplification. ^{1 2 3 5 8}

What is the purpose of this trial?

Primary brain cancer kills up to 10,000 Americans a year. These brain tumors are typically treated by surgery, radiation therapy and chemotherapy, either individually or in combination. Present therapies are inadequate, as evidenced by the low 5-year survival rate for brain cancer patients, with median survival at approximately 12 months. Glioma is the most common form of primary brain cancer, afflicting approximately 7,000 patients in the United States each year. These highly malignant cancers remain a significant unmet clinical need in oncology. GBM often has a high expression EFGR (Epidermal Growth Factor Receptor) which is blocked by Cetuximab (CTX). The investigators have recently completed a separate Phase I clinical trial using superselective intra-arterial cerebral infusion (SIACI) of CTX after blood brain barrier disruption (BBBD) for recurrent GBM (Chakraborty et al, in revision, Journal of Neurooncology). The investigators found that intra-arterial infusion of CTX is well tolerated with few adverse effects. The investigators hypothesize that in patients with newly diagnosed GBM, repeated SIACI of this drug after BBBD will be safe and efficacious for our patients when combined with standard chemoradiation (STUPP protocol). This trial will be a non-randomized open label Phase I/II clinical trial. In addition to standard chemotherapy and radiation therapy (STUPP protocol) the patient will be given CTX intra-arterially after BBBD for a total of three doses at approximately post surgery days 30, 120 and 210.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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, 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]

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]

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]

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-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]

References

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

Superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with Stupp Protocol for newly diagnosed glioblastoma. [2022]

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

Radioactive EGFR antibody cetuximab in multimodal cancer treatment: stability and synergistic effects with radiotherapy. [2018]

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

Cetuximab. [2020]

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

Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Neutron capture therapy of epidermal growth factor (+) gliomas using boronated cetuximab (IMC-C225) as a delivery agent. [2018]

6. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

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

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

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

Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles. [2018]