Combination Therapy + Radiation for Glioblastoma

No longer recruiting at 4 trial locations

Overseen By Milan Chheda, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: MAOIs, UGT1A9 inhibitors

Disqualifiers: Autoimmune disease, Active infection, Uncontrolled HIV, others

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: 1

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with glioblastoma, an aggressive brain cancer that has recurred after treatment. It combines radiation with drugs like retifanlimab (an immunotherapy) and bevacizumab, and sometimes adds epacadostat (an IDO inhibitor) to enhance the body's immune response against cancer. The goal is to shrink tumors and extend survival. Those with recurrent glioblastoma who qualify for additional radiation and bevacizumab may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant findings.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but certain drugs are prohibited, especially if you are in regimen B. These include MAOIs, UGT1A9 inhibitors, probiotics, and warfarin. If you are on these, you may need to stop them before joining the trial.

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

Research has shown that using retifanlimab with bevacizumab and radiation therapy is generally safe for people with recurring glioblastoma, a type of brain cancer. Studies have found that this combination, with or without the drug epacadostat, is well-tolerated. Patients in these studies did not experience severe side effects beyond what is typical for cancer treatments.

Bevacizumab is already FDA-approved for other uses, so its safety is well-known. When retifanlimab and epacadostat are combined with bevacizumab and radiation, research has demonstrated their safety in clinical settings. Participants have reported side effects like tiredness and nausea, common with cancer treatments, but serious reactions were rare.

These findings suggest the treatment is generally safe, although individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these glioblastoma treatments because they target the cancer in novel ways. Unlike the standard of care, which typically includes surgery, radiation, and chemotherapy with temozolomide, these experimental regimens combine immunotherapy and targeted therapy. Retifanlimab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. Bevacizumab targets and inhibits blood vessel growth in tumors, potentially starving them of nutrients. Epacadostat, used in one regimen, blocks enzymes that suppress the immune system, further enhancing the body's ability to fight the cancer. This combination approach aims to improve treatment effectiveness and patient outcomes by using multiple mechanisms to tackle the tumor.

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

This trial compares two treatment regimens for recurrent glioblastoma. Studies have shown that combining retifanlimab with bevacizumab and radiation therapy might be more effective than bevacizumab alone. Participants in Regimen A will receive this combination, which has been found safe and shows promise in extending survival and delaying cancer progression. Regimen B adds epacadostat, which enhances the immune system's ability to fight cancer cells and may strengthen these effects. Early research suggests these combinations can boost the body's immune response against tumors. Overall, these treatment combinations are considered safe and show potential for improving outcomes in recurrent glioblastoma. ^{1 2 3 6 7}

Who Is on the Research Team?

Milan Chheda, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults with recurrent grade 4 glioblastoma or gliosarcoma who have measurable disease, normal organ and bone marrow function, and a Karnofsky performance status ≥ 60%. Patients must not be on high doses of steroids or have active infections, uncontrolled HIV/hepatitis B/C, certain heart conditions, autoimmune diseases requiring systemic treatment in the past 2 years (except under specific conditions), or a history of allergic reactions to similar drugs.

Inclusion Criteria

My brain tumor is a high-grade glioblastoma or gliosarcoma.

I have used bevacizumab temporarily for brain swelling or tissue damage.

Prior use of the Optune device is allowed without a washout period

Exclusion Criteria

I am receiving treatment for an autoimmune disease.

Any history of serotonin syndrome after receiving serotonergic drugs

I do not have uncontrolled HIV or active hepatitis B or C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive retifanlimab, radiation therapy, and bevacizumab with or without epacadostat for recurrent glioblastoma

Up to 2 years

Intravenous administration on Days 1 and 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Long-term follow-up

Participants are monitored for progression-free survival and overall survival

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Epacadostat
• Radiation therapy
• Retifanlimab

Trial Overview

The study tests combining retifanlimab with radiation therapy and bevacizumab with/without epacadostat in treating recurrent brain tumors. It aims to enhance anti-tumor immune response and improve survival by leveraging the synergy between radiation therapy and immune modulators.

How Is the Trial Designed?

Group I: Regimen B: Retifanlimab+RT+bevacizumab+epacadostat Experimental Treatment 4 Interventions

* Retifanlimab will be given intravenously over the course of 30 to 60 minutes at a dose of 500 mg on Day 1 of each 28-day cycle. * Bevacizumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle. * Ten fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction * Retifanlimab and bevacizumab will be started approximately two weeks before the first day of radiation therapy * Epacadostat will be administered orally at 400 mg BID. * Treatment may continue for up to two years.

Group II: Regimen A: Retifanlimab+RT+bevacizumab Experimental Treatment 3 Interventions

* Retifanlimab will be given intravenously over the course of 30 to 60 minutes at a dose of 500 mg on Day 1 of each 28-day cycle. * Bevacizumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle. * Ten fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction * Retifanlimab and bevacizumab will be started approximately two weeks before the first day of radiation therapy * Treatment may continue for up to two years.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

In a retrospective analysis of the AVAglio trial involving 921 glioblastoma patients, those with IDH1 wild-type proneural tumors showed a significant overall survival (OS) benefit from bevacizumab treatment compared to placebo, with an OS of 17.1 months versus 12.8 months.

While patients with mesenchymal and proneural tumors experienced progression-free survival (PFS) benefits from bevacizumab, only the proneural subtype demonstrated a corresponding OS advantage, highlighting the importance of molecular subtypes in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. Sandmann, T., Bourgon, R., Garcia, J., et al.[2022]

In a study of 70 patients with newly diagnosed glioblastoma, combining bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) resulted in improved progression-free survival (PFS) of 13.6 months compared to 7.6 months in a control group, although overall survival (OS) was similar between groups.

The presence of MGMT promoter methylation in tumor tissue was associated with better OS and PFS, suggesting that this biomarker may help identify patients who could benefit more from the treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. Lai, A., Tran, A., Nghiemphu, PL., et al.[2022]

In a phase III trial involving 911 patients with newly diagnosed glioblastoma, those treated with bevacizumab had a longer safety follow-up (12.3 months) and a higher completion rate of maintenance temozolomide (64.6%) compared to placebo (36.9%).

While bevacizumab was associated with a higher incidence of adverse events such as arterial thromboembolic events (5.9% vs 1.6%) and wound-healing complications (6.9% vs 4.7%), these did not hinder patients' ability to receive standard treatment or undergo subsequent surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. Saran, F., Chinot, OL., Henriksson, R., et al.[2022]

In a retrospective study of 14 heavily pretreated patients with recurrent high-grade gliomas, re-irradiation combined with bevacizumab showed a median progression-free survival of 5.1 months and a median overall survival of 9.0 months, indicating potential efficacy for this treatment approach.

The study found that re-irradiation with either conventional 3D-conformal or intensified modulated radiotherapy (IMRT) was feasible and generally safe, with only one case of radionecrosis detected and other side effects being typical of bevacizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas. Hundsberger, T., Brügge, D., Putora, PM., et al.[2022]

In a study involving 25 patients with recurrent glioblastoma and anaplastic gliomas, the combination of bevacizumab and hypofractionated stereotactic radiotherapy (HFSRT) was found to be safe and well tolerated, with no cases of radiation necrosis reported.

The treatment showed promising efficacy, with a 50% overall response rate and a median overall survival of 12.5 months, indicating that this regimen could be an effective option for patients with recurrent malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Gutin, PH., Iwamoto, FM., Beal, K., et al.[2022]

In a Phase II pilot study involving 10 patients with newly diagnosed glioblastoma, the combination of bevacizumab (BV), temozolomide (TMZ), and regional radiation therapy (RT) showed acceptable safety and tolerability, with some patients experiencing serious toxicities like presumed radiation-induced optic neuropathy and high rates of fatigue and myelotoxicity.

Preliminary results indicated encouraging mean progression-free survival, but further research with more patients and longer follow-up is needed before considering routine use of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Lai, A., Filka, E., McGibbon, B., et al.[2022]

Citations

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Combos Deemed Safe, Effective in Recurrent Glioblastoma

Twenty-three patients received retifanlimab (500 mg every 4 weeks), bevacizumab (10 mg/kg every 2 weeks) and HFRT (3.5 Gy/day for 10 days).

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Combos Deemed Safe, Effective in Recurrent Glioblastoma

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