Pembrolizumab + Standard Therapy for Glioblastoma

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Antiretrovirals, Immunosuppressants, Corticosteroids, others

Disqualifiers: Pregnancy, HIV, Autoimmune disease, 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

Compensation: Varies

Number of Visits: 5

52 Participants Needed

Trial Summary

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Pembrolizumab + Standard Therapy for Glioblastoma?

Research shows that combining temozolomide (a chemotherapy drug) with radiotherapy can help control glioblastoma, a type of brain cancer. Additionally, immune checkpoint inhibitors like nivolumab, which are similar to pembrolizumab, have been studied for their potential to enhance the effects of standard treatments in glioblastoma. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and standard therapy for glioblastoma safe for humans?

Pembrolizumab (KEYTRUDA) has been approved for use in other conditions like metastatic melanoma, with common side effects including fatigue, cough, nausea, and rash. Temozolomide, used in brain tumors, has a good safety profile and is generally well tolerated. Combining these with radiation therapy has shown to be safe in various studies, although specific safety data for glioblastoma is limited. ^{1 3 6 7 8}

What makes the treatment with pembrolizumab, radiation, and temozolomide unique for glioblastoma?

This treatment combines pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with radiation and temozolomide, a chemotherapy drug that makes cancer cells more sensitive to radiation. This combination aims to enhance the overall effectiveness against glioblastoma, which is typically resistant to standard treatments. ^{1 2 3 9 10}

What is the purpose of this trial?

This phase II trial studies the side effects and how well pembrolizumab works in combination with standard therapy in treating patients with glioblastoma. Immunotherapy with monoclonal antibodies, such as pembrolizumab, 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 the 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. Giving pembrolizumab and standard therapy comprising of temozolomide and radiation therapy may kill tumor cells.

Research Team

Ian F. Parney, MD, PhD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

Adults with confirmed glioblastoma or astrocytoma grade IV, who can provide consent and samples for research. They must have adequate organ function, no severe diseases that could interfere with the trial, not be pregnant or nursing, agree to use contraception if of childbearing potential, and be willing to return for follow-up. Excluded are those with recent heart issues, active autoimmune disease requiring treatment in the past 2 years (except certain conditions), current pneumonitis or infections, HIV on antiretroviral therapy, other cancers being treated within 5 years.

Inclusion Criteria

Albumin >= 2.5 mg/dL (obtained =< 28 days prior to registration)

Provide written informed consent

My cancer is a Grade IV IDH-mutant astrocytoma.

Exclusion Criteria

I have had skin cancer (not melanoma) or early-stage cervical cancer.

You have used or plan to use the Optune device.

I am currently breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant

Patients receive pembrolizumab intravenously over 30 minutes on day 1

1 day

1 visit (in-person)

Surgery

Patients undergo standard of care surgery within days 4-7

1 week

1 visit (in-person)

Concurrent

Patients receive pembrolizumab and temozolomide, and undergo external beam radiation therapy

7 weeks

Multiple visits (in-person)

Adjuvant

Patients receive pembrolizumab and temozolomide in cycles, repeating every 63 days for up to 5 cycles

Up to 10 months

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 months until progressive disease, then every 6 months

Treatment Details

Interventions

• External Beam Radiation Therapy
• Laboratory Biomarker Analysis
• Pembrolizumab
• Radiation Therapy
• Temozolomide
• Therapeutic Conventional Surgery

Trial Overview The trial is testing pembrolizumab combined with standard therapies including temozolomide chemotherapy and radiation therapy against glioblastoma tumors. Pembrolizumab is an immunotherapy drug designed to boost the body's immune response against cancer cells.

Participant Groups

Group I: Group 2 (pembrolizumab, temozolomide, radiation therapy ) Experimental Treatment 5 Interventions

CONCURRENT (CYCLE 1): Starting 21-35 days after surgery, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 8-54. Patients also undergo external beam radiation therapy every 5 days per week on days 8-54. ADJUVANT (CYCLES 2-6): Within 3-5 weeks after completing radiation therapy, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 of cycles 2-5 and 1 and 22 of cycle 6 (up to a total of 17 doses). Patients also receive temozolomide PO daily on days 1-5, 29-33, and 57-61 of cycles 2 and 6, days 22-26 and 50-54 of cycle 3, days 15-19 and 43-47 of cycle 4, days 8-12 and 36-40 of cycle 5. Treatment repeats every 63 days for up to 5 cycles in the absence of disease progression or unexpected toxicity.

Group II: Group 1 (pembrolizumab, surgery, temozolomide, radiation) Experimental Treatment 6 Interventions

NEOADJUVANT (CYCLE 1): Patients receive pembrolizumab IV over 30 minutes on day 1. SURGERY (CYCLE 2): Patients undergo standard of care surgery within days 4-7. CONCURRENT (CYCLE 3): Starting 21-35 days after surgery, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 8-54. Patients also undergo external beam radiation therapy every 5 days per week on days 8-54. ADJUVANT (CYCLE 4-8): Within 3-5 weeks after completing radiation therapy, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 1-5 every 28 days. Treatment repeats every 63 days for up to 5 cycles in the absence of disease progression or unexpected toxicity.

External Beam Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in United States as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Canada as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Japan as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in China as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Switzerland as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 III study involving 716 patients with newly diagnosed glioblastoma, the addition of the immune checkpoint inhibitor nivolumab (NIVO) to standard radiotherapy (RT) and temozolomide (TMZ) did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to placebo, with median OS of 28.9 months for NIVO versus 32.1 months for placebo.

The study found a higher rate of grade 3/4 treatment-related adverse events in the NIVO group (52.4%) compared to the placebo group (33.6%), indicating that while NIVO did not enhance efficacy, it was associated with increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Lim, M., Weller, M., Idbaih, A., et al.[2023]

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 study of 103 glioblastoma patients treated with standard temozolomide and radiotherapy, the median overall survival was found to be 13.7 months, highlighting the effectiveness of this treatment regimen.

Three key prognostic factors were identified that negatively impacted overall survival: age over 65 years, a Medical Research Council (MRC) scale score of 3-4, and the occurrence of postoperative complications, suggesting that these factors can help predict patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. Verlut, C., Mouillet, G., Magnin, E., et al.[2020]

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]

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

In a study of 26 patients with recurrent glioblastoma, pembrolizumab showed an overall response rate of 8%, with two patients experiencing partial responses lasting up to 22.8 months, indicating some durable antitumor activity.

While 73% of patients experienced treatment-related adverse events, most were manageable, suggesting that pembrolizumab has a safety profile that allows for further exploration in combination therapies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. Reardon, DA., Kim, TM., Frenel, JS., et al.[2021]

In a phase II trial involving 15 patients with recurrent glioblastoma, pembrolizumab treatment did not lead to significant immune activation within the tumor microenvironment, which was characterized by a lack of T cells and a predominance of CD68+ macrophages.

Despite no treatment-related deaths and a median overall survival of 20 months, the study found that pembrolizumab alone was insufficient to induce a robust immune response in most patients, suggesting that additional strategies may be needed to enhance its efficacy in glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. de Groot, J., Penas-Prado, M., Alfaro-Munoz, K., et al.[2021]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. [2023]

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

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. [2020]

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

Temozolomide for treating brain metastases. [2019]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. [2021]

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

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. [2021]