Atezolizumab + Radiation for Glioblastoma

Overseen By Sumbul Yousafi, MS

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Stony Brook University

Must not be taking: Corticosteroids, Immunosuppressive, Immunostimulatory, others

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

Stay on Your Current Meds You can continue your current medications while participating

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm pilot study that will recruit 12 patients with newly diagnosed Glioblastoma, a malignant brain tumor with a poor prognosis. Patients will be treated with fractionated stereotactic radiotherapy (FSRT) for 2 weeks, in addition to two doses of Atezolizumab (Tecentriq), an FDA approved PD- L1 inhibitor drug, 840 mg IV, at the beginning and at the end of the two-week time period, concomitantly with FSRT. After this initial two weeks treatment the patients will undergo craniotomy and maximal safe resection as per normal care for a GB. After surgery patients will follow the normal care for glioblastoma in addition to Atezolizumab 840 mg IV q2 weeks for the duration of adjuvant treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot continue using high-dose corticosteroids or certain immune-related treatments.

What data supports the effectiveness of the treatment Atezolizumab + Radiation for Glioblastoma?

Research shows that combining radiation with drugs that block PD1/PD-L1, like pembrolizumab, can be effective for high-grade brain tumors. Additionally, using precise radiation techniques, such as fractionated stereotactic radiotherapy (FSRT), has shown promise in treating recurrent glioblastoma, suggesting potential benefits for similar treatments. ^{1 2 3 4 5}

Is Atezolizumab safe for use in humans?

Atezolizumab has been studied for safety in patients with glioblastoma, showing clinical activity and being generally safe in humans, as reported in a phase 1a clinical trial. ^{4 5 6 7 8}

How is the treatment Atezolizumab + Radiation for Glioblastoma different from other treatments?

This treatment combines atezolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with fractionated stereotactic radiotherapy (FSRT), a precise form of radiation therapy. Unlike standard treatments, this approach leverages the potential synergy between immunotherapy and targeted radiation to enhance the immune response against glioblastoma, a brain cancer with limited treatment options. ^{1 2 6 7 9}

Research Team

Alexander M. Stessin

Principal Investigator

Stony Brook Cancer Center

Eligibility Criteria

This trial is for patients with a new diagnosis of Glioblastoma Multiforme, a serious brain tumor. They must be candidates for surgery aiming to remove over 80% of the tumor, have good organ function and performance status (ECOG <=2), and not be pregnant. Exclusions include recent other cancers, severe infections or diseases, high steroid use, certain heart conditions, immune system issues like autoimmune disease or prior immunotherapy.

Inclusion Criteria

My organs are working well.

I can take care of myself but might not be able to do heavy physical work.

My tumor is 3.5 cm or smaller.

Exclusion Criteria

I have previously been treated with CD137 agonists or immune checkpoint inhibitors.

My cancer pain is not managed with current treatments.

My brain cancer has spread widely or affects both sides of my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fractionated stereotactic radiotherapy (FSRT) for 2 weeks, along with two doses of Atezolizumab at the beginning and end of the period

2 weeks

2 visits (in-person)

Surgery

Participants undergo craniotomy and maximal safe resection as per normal care for glioblastoma

Adjuvant Treatment

Participants follow normal care for glioblastoma in addition to Atezolizumab 840 mg IV every 2 weeks

Duration of adjuvant treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Atezolizumab
• FSRT radiation

Trial Overview The study tests Atezolizumab combined with FSRT radiation in treating Glioblastoma before and after surgical removal of the tumor. Patients will receive two doses of Atezolizumab along with two weeks of radiotherapy followed by surgery and then continue Atezolizumab every two weeks during adjuvant treatment.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Stony Brook University

Lead Sponsor

Trials

225

Recruited

41,700+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

The combination of pembrolizumab, hypofractionated stereotactic irradiation (HFSRT), and bevacizumab was found to be generally safe and well tolerated in 32 patients with recurrent high-grade gliomas, with manageable treatment-related adverse events such as proteinuria and fatigue.

In the bevacizumab-naïve group, 83% of patients showed a complete or partial response, with a median overall survival of 13.45 months, indicating promising preliminary efficacy of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. Sahebjam, S., Forsyth, PA., Tran, ND., et al.[2021]

In a study of 25 patients with recurrent gliomas, the combination of fractionated stereotactic radiotherapy (FSRT) and daily temozolomide (TMZ) demonstrated a median overall survival of 59 months, indicating its effectiveness as a treatment option.

The treatment was well-tolerated, with no severe side effects reported, suggesting that this approach is safe for patients undergoing re-irradiation for recurrent gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiochemotherapy with temozolomide as re-irradiation using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent gliomas. Combs, SE., Bischof, M., Welzel, T., et al.[2022]

In a study of 36 patients with recurrent glioblastoma, both stereotactic single dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) showed radiographic responses in some patients, with median survival times of 8.5 months for SRS and 7.4 months for FSRT, indicating both methods can be effective salvage therapies.

Patients who had a radiographic response or stable disease after treatment had significantly better survival rates (15.8 months) compared to those who did not respond (7.3 months), highlighting the importance of treatment response in predicting outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage reirradiation for recurrent glioblastoma with radiosurgery: radiographic response and improved survival. Patel, M., Siddiqui, F., Jin, JY., et al.[2022]

In a phase II clinical trial involving 158 patients with newly diagnosed glioblastoma, cediranib combined with radiation and temozolomide significantly improved 6-month progression-free survival (PFS) to 46.6% compared to 24.5% for the placebo group (P = 0.005).

Although cediranib showed efficacy in prolonging PFS, it was associated with a higher incidence of grade ≥3 adverse events compared to placebo (P = 0.02), and there was no significant difference in overall survival between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. Batchelor, TT., Won, M., Chakravarti, A., et al.[2023]

Salvage stereotactic radiotherapy (SRT) using CyberKnife for recurrent gliomas showed an acceptable safety profile, with only 11.4% of patients experiencing significant toxicity, specifically radiation-induced brain necrosis.

The treatment resulted in a median overall survival of 9 months and a progression-free survival of 3 months, indicating that SRT can be a viable option for patients with recurrent gliomas after initial treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of Salvage Re-irradiation With Stereotactic Radiotherapy for Recurrent Glioma Using CyberKnife. Adachi, K., Hayashi, K., Kagawa, N., et al.[2019]

Atezolizumab, an immune checkpoint inhibitor, was found to be safe and well tolerated in a phase 1a clinical trial involving 16 patients with recurrent glioblastoma, with no severe treatment-related side effects reported.

The treatment showed some efficacy, with one patient achieving a partial response and three others stabilizing their disease, while median overall survival was 4.2 months, suggesting that certain biomarkers like peripheral CD4+ T cells may help identify patients who could benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. Lukas, RV., Rodon, J., Becker, K., et al.[2020]

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 Phase I clinical trial involving 19 patients with glioblastoma, the maximum tolerated dose of fractionated intensity-modulated radiotherapy (IMRT) combined with temozolomide (TMZ) was determined to be 65 Gy, delivered in 25 fractions over 5 weeks, without any dose-limiting toxicities observed.

The treatment was well tolerated, with only mild to moderate (Grade 1-2) neurologic and skin toxicities reported, and no severe late neurologic toxicities, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. Morganti, AG., Balducci, M., Salvati, M., et al.[2018]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. [2021]

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

Radiochemotherapy with temozolomide as re-irradiation using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent gliomas. [2022]

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

Salvage reirradiation for recurrent glioblastoma with radiosurgery: radiographic response and improved survival. [2022]

4. England pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Feasibility of Salvage Re-irradiation With Stereotactic Radiotherapy for Recurrent Glioma Using CyberKnife. [2019]

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

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. [2020]

7. 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]

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

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]