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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment combination for brain tumors like glioblastoma. It combines Pembrolizumab, a drug that helps the immune system fight cancer, with M032, a modified virus designed to attack cancer cells. The trial has two parts: one for those whose tumors have returned after treatment and another for those newly diagnosed. People with recurrent brain tumors who have completed prior treatments like radiation and chemotherapy might be a good fit.

As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. Participants have the opportunity to contribute to groundbreaking cancer research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of M032 and pembrolizumab has been studied for safety and tolerability. M032 is a specially designed virus that targets and kills cancer cells. Earlier research has shown that M032 is safe and stable. Studies have tested it in increasing amounts to ensure it is well-tolerated when injected directly into tumors.

Pembrolizumab, a drug already approved for treating other types of cancer, helps the immune system fight cancer cells. Research is exploring how combining it with M032 might offer new ways to treat brain tumors like glioblastoma.

So far, evidence suggests that this combination is generally safe for patients. The current trial aims to confirm this and determine the best dose to use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of M032 and pembrolizumab for glioblastoma because it offers a novel approach to tackling this aggressive brain cancer. Unlike most standard treatments that focus on surgery, radiation, and chemotherapy, M032 utilizes an oncolytic virus designed to selectively target and kill cancer cells while sparing healthy ones. Pembrolizumab, an immune checkpoint inhibitor, further boosts the immune system's ability to recognize and attack tumor cells. This dual-action strategy not only aims to directly eliminate cancer cells but also to enhance the body's natural defenses, potentially leading to improved survival rates and better outcomes for patients with glioblastoma.

What evidence suggests that Pembrolizumab + M032 might be an effective treatment for glioblastoma?

Research has shown that Pembrolizumab may help treat glioblastoma by boosting the immune system to fight cancer cells. Studies have found that it can help patients with recurring glioblastoma live longer. M032, a modified herpes virus, targets and destroys glioma cells. It multiplies inside the tumor, killing cancer cells and producing more virus to continue the attack. In this trial, participants will receive a combination of M032 and Pembrolizumab. Early evidence suggests that using M032 with Pembrolizumab might improve treatment outcomes for glioblastoma patients. ^{1 2 3 6 7}

Who Is on the Research Team?

James Markert, MD

Principal Investigator

The University of Alabama at Birmingham

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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, 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]

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 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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06118

Pembrolizumab and M032 (NSC 733972) in Treating ... Giving M032 and pembrolizumab may work better in treating patients with newly diagnosed or recurrent glioblastoma, anaplastic astrocytoma, or gliosarcoma.

2. grantome.com grantome.com/grant/NIH/R01-CA217179-03

A Phase 1 Study of M032, a Genetically Engineered HSV- ... A Phase 1 Study of M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4932657/

Design of a Phase I Clinical Trial to Evaluate M032, a ... This clinical protocol outlines the dose-escalating phase I study for evaluation of M032 in patients with recurrent or progressive malignant glioma.

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/27/NCT02062827/Prot_SAP_ICF_000.pdf

Phase 1 Study of M032 (NSC 733972), a Genetically ... As M032 represents an excellent vector for evaluation in clinical studies for the treatment of glioblastoma multiforme, the NIH Rapid Access to ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02062827

Genetically Engineered HSV-1 Phase 1 Study for the ... Replication of M032 in the tumor itself not only kills the infected tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus ...

6. grantome.com grantome.com/grant/NIH/R01-CA217179-01

A Phase 1 Study of M032, a Genetically Engineered HSV- ... We created a novel, oncolytic Herpes Simplex Virus (oHSV) termed M032 (NSC 733972) that expresses human Interleukin-12 and the NExT (NCI) program manufactured ...

7. trials.braintumor.org trials.braintumor.org/trials/NCT05084430

Study of Pembrolizumab and M032 (NSC 733972) 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 ...