Pembrolizumab + M032 for Glioblastoma

Overseen By James Markert, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Anti-PD-1, Anti-PD-L1, Anti-PDL2, HSV drugs

Disqualifiers: Pregnancy, Immunodeficiency, Active infection, others

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

Compensation: Varies

Number of Visits: 4

Duration: 9 weeks

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain therapies like chronic systemic steroids or drugs active against HSV. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Pembrolizumab + M032 for treating glioblastoma?

Research shows that pembrolizumab, a part of this treatment, has shown antitumor activity in recurrent glioblastoma, especially in cases where the tumor is PD-L1 positive. Additionally, pembrolizumab has been effective in treating melanoma by helping the immune system attack cancer cells. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and M032 generally safe for humans?

Pembrolizumab, also known as Keytruda, is generally considered safe but can cause immune-related side effects, such as type 1 diabetes in rare cases (0.2% of patients). Safety data specific to the combination with M032 is not available, but Pembrolizumab has been studied in various cancers, showing a manageable safety profile. ^{1 2 6 7 8}

How is the treatment with Pembrolizumab + M032 for glioblastoma different from other treatments?

This treatment combines pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with M032, a modified virus designed to deliver a gene that boosts immune response, offering a novel approach by potentially enhancing the immune system's ability to target glioblastoma. ^{1 2 3 4 5}

What is the purpose of this trial?

This Phase I (Cohort I and Cohort II) and Phase II trial is designed to confirm the safety and tolerability of Pembrolizumab when given in conjunction with M032, an Oncolytic Herpes Simplex Virus (oHSV) that expresses IL-12 and perform the Phase II portion using a Recommended Phase 2 Dose (RP2D) of M032 (provided by the Phase I) when given in conjunction with Pembrolizumab for recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, or glio-sarcoma).

Research Team

James Markert, MD

Principal Investigator

The University of Alabama at Birmingham

Eligibility Criteria

Adults over 18 with specific brain cancers (glioblastoma, astrocytoma, gliosarcoma) who've had prior treatments fail. They must be able to undergo tumor resection, have a life expectancy over 4 weeks, and agree to contraception use. Excluded are those with recent adverse event recovery issues, HSV drug therapy, certain allergies or infections, other active cancers within 3 years, or uncontrolled illnesses.

Inclusion Criteria

I have an MRI indicating a likely malignant brain tumor, with no prior glioma diagnosis or surgery except for a diagnostic biopsy.

I have a type of brain tumor that might be operable again.

I have a specific type of brain tumor and am considered a candidate for surgery to remove it.

Exclusion Criteria

I have been treated with specific immune therapy targeting cancer.

I have a history of encephalitis, multiple sclerosis, or another CNS infection.

I have not received a live vaccine in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical and Initial Treatment

Patients undergo craniotomy and resection, followed by initial administration of M032 directly into the tumor bed.

1 week

1 visit (in-person)

Treatment

Patients receive combined Pembrolizumab and M032 treatments every three weeks for up to three cycles.

9 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including MRI and neurologic evaluation.

6 months

Extension

Patients who are responding to treatment may be considered for additional dosing after the trial period has been completed.

Up to 1 year

Treatment Details

Interventions

• M032
• Pembrolizumab

Trial Overview The trial is testing the safety and effectiveness of Pembrolizumab combined with M032 (an oncolytic virus expressing IL-12) in patients with recurrent malignant gliomas. It's structured in phases to determine the best dose of M032 before assessing its efficacy alongside Pembrolizumab.

Participant Groups

Group I: Recurrent MG Experimental Treatment 2 Interventions

To determine the safety and tolerability of M032 at the doses examined when given in combinations with pembrolizumab in patients with recurrent MG.

Group II: Newly Diagnosed MG Experimental Treatment 2 Interventions

To determine Overall Survival at 12 and 24 months, and Progression Free Survival at 6 months (PFS-6) in patients with newly diagnosed glioblastoma multiforme of M032 when given in combinations with pembrolizumab (while maintaining safety).

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Findings from Research

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]

In a phase II study involving 80 patients with recurrent glioblastoma, pembrolizumab combined with bevacizumab showed a 6-month progression-free survival (PFS-6) of 26% and a median overall survival (OS) of 8.8 months, indicating limited efficacy despite being well tolerated.

Pembrolizumab alone had a much lower PFS-6 of 6.7% and no objective responses, suggesting that while the combination therapy had some durable responses, neither treatment was effective enough for significant clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Nayak, L., Molinaro, AM., Peters, K., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

A patient with a hypermutated glioblastoma showed significant immune responses after treatment with pembrolizumab, including increased lymphocyte infiltration and a positive radiographic response in brain lesions, indicating potential effectiveness of immunotherapy in this context.

The study suggests that glioblastomas with DNA-repair defects may benefit from checkpoint blockade therapy, highlighting a possible new avenue for treatment in patients with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. Johanns, TM., Miller, CA., Dorward, IG., et al.[2022]

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]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

References

1. 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]

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

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. [2022]

5. 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]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

8. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]