Immunotherapy + Chemotherapy + Radiation for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Immunostimulants

Disqualifiers: Autoimmune disease, Active infection, Others

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: 8

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I/II trial studies the side effects and how well atezolizumab works in combination with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. It is not yet known how well atezolizumab works in combination with temozolomide and radiation therapy in treating patients with glioblastoma.

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 receive other chemotherapy, hormonal therapy, immunotherapy, or radiotherapy while participating. It's best to discuss your specific medications with the trial team.

Is the combination of immunotherapy, chemotherapy, and radiation therapy safe for treating glioblastoma?

The combination of temozolomide (a chemotherapy drug) with radiotherapy has been studied for safety in glioblastoma patients. Common side effects include myelosuppression (a decrease in bone marrow activity), nausea, and constipation. Safety data from studies involving similar treatments suggest that while there are risks of side effects, these treatments are generally considered safe for use in humans. ^{1 2 3 4 5}

How is the treatment of Atezolizumab, Radiation Therapy, and Temozolomide for glioblastoma different from other treatments?

This treatment combines immunotherapy (Atezolizumab) with chemotherapy (Temozolomide) and radiation therapy, which is unique because it uses the body's immune system to help fight the cancer while also using traditional methods to kill cancer cells. Temozolomide is known to make cancer cells more sensitive to radiation, potentially improving the effectiveness of the treatment. ^{1 6 7 8 9}

What data supports the effectiveness of the treatment for glioblastoma?

Research shows that combining Temozolomide (a chemotherapy drug) with intensity-modulated radiation therapy (a precise form of radiation) improves the overall response rate and strengthens immune function in glioma patients compared to radiation alone. Additionally, Temozolomide has been shown to enhance the effectiveness of radiation therapy by making cancer cells more sensitive to it. ^{1 8 9 10 11}

Who Is on the Research Team?

Shiao-Pei S. Weathers

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with newly diagnosed glioblastoma who have had surgery but no other treatment. They must start treatment within 6 weeks of surgery, have adequate blood counts and organ function, not be pregnant or breastfeeding, agree to use contraception, and have a performance status indicating they can care for themselves.

Inclusion Criteria

Ability and willingness to comply with the requirements of the study protocol

I had surgery for my condition and have not received any treatment since.

Absolute neutrophil count (ANC) >= 1,500 /mcL

Exclusion Criteria

I have not taken any antibiotics in the last 2 weeks.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

I am not receiving any other cancer treatments while on this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Concurrent Phase

Patients receive temozolomide daily and atezolizumab on specific days, along with radiation therapy 5 days per week for 6 weeks

6 weeks

5 visits per week (in-person) for radiation therapy

Adjuvant Phase

Patients receive temozolomide and atezolizumab with treatment repeating every 28 days for up to 12 courses

Up to 12 months

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

1 visit every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Radiation Therapy
• Temozolomide

Trial Overview The study tests how well the combination of atezolizumab (an immune system-boosting drug), temozolomide (a chemotherapy drug), and radiation therapy works in treating glioblastoma. It's a phase I/II trial to assess side effects and effectiveness.

How Is the Trial Designed?

Group I: Concurrent phase (temozolomide, atezolizumab, RT) Experimental Treatment 3 Interventions

Patients receive temozolomide PO daily on days 1-42 and atezolizumab IV over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo RT 5 days per week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Adjuvant phase (temozolomide, atezolizumab) Experimental Treatment 2 Interventions

Patients receive temozolomide PO on days 1-5 and atezolizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

The study determined that the maximum tolerated dose (MTD) of hypofractionated SIB-IMRT combined with temozolomide (TMZ) for treating high-grade gliomas is 3.6 Gy per fraction, with tolerable adverse reactions observed in 16 patients.

Patients treated with this regimen showed promising survival outcomes, with a median overall survival of 19 months and a 1-year overall survival rate of 86.7%, suggesting potential benefits of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. Ge, X., Xue, X., Liu, H., et al.[2022]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

In a study of 165 glioblastoma patients, the extent of tumor resection was the only factor associated with longer survival, indicating that surgical removal of the tumor is crucial for improving outcomes.

The use of Gliadel wafers significantly increased the risk of adverse events, especially in patients with recurrent tumors, with those receiving eight wafers facing a 3-fold higher risk of adverse events and a 5.6-fold higher risk of site-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. De Bonis, P., Anile, C., Pompucci, A., et al.[2018]

In a study of 78 patients with gliomas, combining 3-dimensional conformal radiotherapy with temozolomide resulted in a significantly higher 3-year survival rate of 41.38% compared to 20.83% for temozolomide alone and 20.00% for radiotherapy alone.

The combination therapy also improved progression-free survival time to 23.29 months and overall survival time to 25.75 months, while adverse reactions were reported to be mild and tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of 3-dimensional conformal radiotherapy combined with temozolomide for glioma]. Wang, L., Tu, Q., Zhou, W., et al.[2018]

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]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

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 51 patients with newly diagnosed glioblastoma, concurrent treatment with temozolomide (TMZ) and radiotherapy was found to be the new standard of care.

The occurrence of early necrosis in 14% of patients, without signs of tumor recurrence, suggests that TMZ may enhance the effectiveness of radiotherapy by acting as a radiosensitizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. Chamberlain, MC., Glantz, MJ., Chalmers, L., et al.[2022]

Citations

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

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. [2018]

2. India pubmed.ncbi.nlm.nih.gov

Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. [2022]

3. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

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

Effect of Temozolomide Combined with Intensity Modulated Radiation Therapy on Serum Factor, Immune Function and Clinical Efficacy in Postoperative Glioma Patients. [2023]

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

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. [2018]

6. Austria pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. [2018]

7. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of 3-dimensional conformal radiotherapy combined with temozolomide for glioma]. [2018]

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. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

10. 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]

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

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. [2022]