Combination Therapy + Radiation for Glioblastoma

Recruiting at 3 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

51 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination therapy including Bevacizumab for treating glioblastoma?

Research shows that adding Bevacizumab to radiation therapy and Temozolomide can prolong the time before glioblastoma progresses, although it may not extend overall survival. This combination has been studied for safety and effectiveness, particularly in certain subgroups of patients. ^{1 2 3 4 5}

Is the combination of Bevacizumab and radiation therapy safe for treating glioblastoma?

Bevacizumab, when combined with radiation therapy, has been linked to safety concerns such as stroke, bleeding, and wound-healing issues, especially in glioblastoma patients. However, studies have shown that while these side effects are known, the combination is generally considered feasible and provides additional safety data for treating high-grade gliomas. ^{2 4 5 6 7}

What makes this treatment for glioblastoma unique?

This treatment combines bevacizumab, which targets blood vessel growth in tumors, with epacadostat and retifanlimab, which are immune-modulating drugs, alongside radiation therapy. This combination aims to enhance the effectiveness of radiation by inhibiting tumor blood supply and boosting the immune response, offering a novel approach compared to standard treatments. ^{1 2 6 8 9}

What is the purpose of this trial?

This trial is testing a combination of treatments including a new drug, radiation therapy, and other medications for patients with aggressive brain cancer that has returned. The goal is to boost the body's immune system to better fight the cancer, shrink tumors, and help patients live longer.

Research Team

Milan Chheda, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Regimen B: Retifanlimab+RT+bevacizumab+epacadostat Experimental Treatment 5 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 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 * 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

Findings from Research

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 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]

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]

References

1. United States 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. [2022]

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

Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. [2022]

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

Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma. [2022]

4. United States 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. [2022]

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

Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. [2022]

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

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. [2022]

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

Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas. [2022]

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

A single-institution phase II trial of radiation, temozolomide, erlotinib, and bevacizumab for initial treatment of glioblastoma. [2022]

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

Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. [2022]