Retifanlimab + Bevacizumab + Radiation for Recurrent Glioblastoma

Recruiting at 2 trial locations

Overseen By Andrea McMahon

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Pregnancy, Autoimmune diseases, Organ transplant, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 31

Duration: Up to 2 years

134 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well retifanlimab with bevacizumab and hypofractionated radiotherapy, compared to bevacizumab and hypofractionated radiotherapy alone, works in treating patients with glioblastoma that has come back after a period of improvement (recurrent). A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as retifanlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving retifanlimab with bevacizumab and hypofractionated radiotherapy may work better in treating patients with recurrent glioblastoma than bevacizumab and hypofractionated radiotherapy alone.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on certain investigational agents or treatments for autoimmune diseases, you may need to stop them before joining the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Retifanlimab + Bevacizumab + Radiation for Recurrent Glioblastoma?

Research suggests that combining bevacizumab (a drug that blocks blood vessel growth) with radiation can improve survival in patients with recurrent glioblastoma, a type of brain cancer. Bevacizumab has been approved for use in recurrent glioblastoma and has shown promise when used with radiation therapy. ^{1 2 3 4 5}

Is the combination of Retifanlimab, Bevacizumab, and Radiation generally safe for humans?

Bevacizumab, when used with radiation and other treatments, has been linked to side effects like stroke, bleeding, and wound-healing issues, especially in brain tumors. However, studies show it is generally feasible and safe when combined with radiation for recurrent high-grade gliomas, though some expected side effects may occur. ^{3 6 7 8 9}

What makes the drug combination of Retifanlimab, Bevacizumab, and Radiation unique for treating recurrent glioblastoma?

This treatment is unique because it combines Retifanlimab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Bevacizumab, which prevents the growth of blood vessels that supply tumors, and radiation therapy, which directly targets and kills cancer cells. This multi-faceted approach aims to enhance the effectiveness of treatment for recurrent glioblastoma, a condition with limited standard treatment options. ^{2 3 5 10 11}

Research Team

Jian L Campian

Principal Investigator

Academic and Community Cancer Research United

Eligibility Criteria

Adults over 18 with recurrent grade IV glioblastoma, who are candidates for radiotherapy and have a Karnofsky performance status of at least 60%. They must have adequate blood counts, organ function, and controlled steroid use. Pregnant or nursing individuals and those not using contraception are excluded. People with severe diseases or conditions that could interfere with the trial or pose risks are also ineligible.

Inclusion Criteria

Measurable disease or non-measurable disease per Response Assessment in Neuro-Oncology (RANO) criteria

I am a candidate for radiation treatment.

Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (obtained ≤ 28 days prior to registration)

Exclusion Criteria

Co-morbid systemic illness or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into the study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

I haven't taken any experimental drugs for my cancer in the last 2 weeks.

I don't have an active, severe autoimmune disease needing strong medication in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive retifanlimab and bevacizumab with hypofractionated radiotherapy or bevacizumab with hypofractionated radiotherapy alone. Treatment repeats every 28 days for up to 2 years.

Up to 2 years

IV administration on day 1 and 15 of each cycle, daily radiotherapy for 10 treatments starting on day 15 of cycle 1

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes survival checks and adverse event monitoring.

4 years

Follow-up at 30 days post-treatment, then every 2 months for the first year, and every 6 months thereafter

Treatment Details

Interventions

• Bevacizumab
• Hypofractionated Radiation Therapy
• Retifanlimab

Trial Overview The trial is testing retifanlimab combined with bevacizumab and hypofractionated radiotherapy versus just bevacizumab and hypofractionated radiotherapy in treating recurrent glioblastoma. Retifanlimab is an immunotherapy drug that may help the immune system fight cancer; bevacizumab aims to stop tumor growth by inhibiting blood vessel formation.

Participant Groups

Group I: Arm B (Bevacizumab and radiation) Experimental Treatment 6 Interventions

Patients receive bevacizumab IV on day 1 and 15 of each cycle. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo HFRT QD, starting in cycle 1 on day 15 for 10 treatments. Patients undergo MRI or CT, as well as blood sample collection throughout the study.

Group II: Arm A (Retifanlimab, bevacizumab and HFRT) Experimental Treatment 7 Interventions

ARM I: Patients receive retifanlimab IV over 30 minutes on day 1 and bevacizumab IV on day 1 and 15 of each cycle. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo HFRT QD, starting in cycle 1 on day 15 for 10 treatments. Patients undergo MRI or CT, as well as blood sample collection throughout the study.

Retifanlimab is already approved in United States for the following indications:

Approved in United States as Zynyz for:

• Merkel cell carcinoma

Who Is Running the Clinical Trial?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 45 patients with glioblastoma (GBM) treated with gamma knife stereotactic radiosurgery (SRS) and bevacizumab, the combination showed promising results with a median overall survival of 13.3 months after treatment.

The treatment was found to be safe, with no radiation-related adverse events reported, and factors like Karnofsky Performance Score (KPS) and radiation dose significantly influenced progression-free survival (PFS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma Knife Stereotactic Radiosurgery in Combination with Bevacizumab for Recurrent Glioblastoma. Morris, SL., Zhu, P., Rao, M., et al.[2020]

Re-irradiation combined with bevacizumab and temozolomide is a safe and feasible treatment option for patients with bevacizumab-refractory high-grade glioma, showing a median overall survival of 8.5 months across 54 patients.

Patients who were more than 36 months from their initial radiation treatment experienced a significantly longer median overall survival of 13.3 months, suggesting that timing of re-irradiation may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multi-center prospective study of re-irradiation with bevacizumab and temozolomide in patients with bevacizumab refractory recurrent high-grade gliomas. Dixit, KS., Sachdev, S., Amidei, C., 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]

Bevacizumab, an antiangiogenic agent approved in Canada for recurrent glioblastoma, represents a significant advancement in treatment options for this aggressive brain tumor, which typically has a poor prognosis despite initial therapies.

The review discusses how bevacizumab is being used in clinical practice in Canada, along with ongoing debates regarding its effectiveness and application in glioblastoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in recurrent glioblastoma: five informative patient scenarios. Mason, WP.[2016]

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 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]

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]

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 study of 21 patients with recurrent/refractory glioblastoma treated with bevacizumab and irinotecan, the objective response rate was 33.3% and the disease-control rate was 85.7%, indicating that this combination can be an effective salvage treatment.

Factors such as a poor performance status (ECOG PS ≥3) and TP53 loss were linked to worse overall survival, while early clinical improvement after treatment was associated with better outcomes, highlighting the importance of monitoring patient response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Bevacizumab and Irinotecan (BEV+IRI) in Patients With Relapsed/Refractory Glioblastoma (r/rGBM) and its Potential Predictors. Park, JH., Lee, HS., Choi, JW., et al.[2022]

Re-irradiation is a safe treatment option for patients with recurrent glioblastoma, with only 8% experiencing severe acute toxicity, and it resulted in a median overall survival of 7.3 months and progression-free survival of 3.6 months.

Patients who had previously received bevacizumab (BEV) showed a higher rate of marginal recurrences compared to those who had not, indicating that treatment plans may need to include larger volumes of tumor abnormalities to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence. Christ, SM., Youssef, G., Tanguturi, SK., et al.[2023]

References

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

Gamma Knife Stereotactic Radiosurgery in Combination with Bevacizumab for Recurrent Glioblastoma. [2020]

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

A multi-center prospective study of re-irradiation with bevacizumab and temozolomide in patients with bevacizumab refractory recurrent high-grade gliomas. [2022]

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

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

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

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

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

Bevacizumab in recurrent glioblastoma: five informative patient scenarios. [2016]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

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

8. England 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. [2023]

9. 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]

10. Greece pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Bevacizumab and Irinotecan (BEV+IRI) in Patients With Relapsed/Refractory Glioblastoma (r/rGBM) and its Potential Predictors. [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence. [2023]