Pembrolizumab + Vaccine for Glioblastoma

Not currently recruiting at 1 trial location

Overseen By Emese Filka

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Pregnancy, Autoimmune disease, Active infection, others

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

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for people with glioblastoma, a type of brain cancer that has returned and can be surgically removed. Researchers aim to evaluate how well pembrolizumab, a drug that helps the immune system fight cancer, works with a vaccine called ATL-DC, which boosts the body's ability to attack cancer cells. Participants will receive either the new treatment combination or a placebo (inactive substance) with the vaccine. Suitable candidates for this trial have recurrent glioblastoma that can be surgically removed and have already undergone initial therapies like radiation or chemotherapy. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should not be on certain therapies like systemic steroids or immunosuppressive drugs within 7 days before starting the study treatment. 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 has shown that pembrolizumab is generally safe. One study used it with another treatment and found no major safety issues. Although it was not very effective on its own for brain cancer, it remained safe.

Studies indicate that the ATL-DC vaccine is also well-tolerated, with patients experiencing manageable side effects. Another study combined it with a specific booster, and the vaccine remained safe.

This trial tests both treatments together. While each has shown safety individually, this combination is new. The trial aims to ensure they work safely together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and the ATL-DC vaccine for glioblastoma because this treatment targets the immune system in a unique way. Pembrolizumab is an immunotherapy that blocks the PD-1 pathway, which can help the immune system recognize and attack cancer cells more effectively. The ATL-DC vaccine, when combined with poly ICLC, is designed to boost the immune response against glioblastoma by priming dendritic cells to recognize tumor antigens. Unlike traditional treatments like surgery, radiation, and chemotherapy, which directly target and kill tumor cells, this approach aims to harness the body's own defenses to fight the cancer more precisely.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research has shown that pembrolizumab may effectively treat glioblastoma, a type of brain cancer. Some studies have found that patients with certain genetic traits responded well to this treatment and experienced fewer side effects. One study reported that 37.7% of patients did not see their cancer worsen for at least 6 months, and the average survival time was 13.1 months. In this trial, participants in Group A will receive a combination of pembrolizumab and the ATL-DC vaccine, which might improve results compared to using the vaccine alone. This combination could help the immune system better fight cancer cells, potentially benefiting patients with recurring glioblastoma. Participants in Group B will receive a placebo with the ATL-DC vaccine. ^{1 3 4 6 7}

Who Is on the Research Team?

Timothy F Cloughesy, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with recurrent glioblastoma that can be surgically removed. They must have a tumor of a certain size, not be on immunosuppressive therapy, and agree to use contraception. Excluded are pregnant or breastfeeding women, those with recent other cancer treatments or live vaccines, severe allergies to pembrolizumab, active infections like HIV or hepatitis B/C, and autoimmune diseases treated within the last 2 years.

Inclusion Criteria

My liver function tests are within the required range.

I am eligible for a surgery to remove at least 2 grams of my tumor safely.

It's been over 12 weeks since my last radiotherapy, or I have confirmed tumor growth since then.

Exclusion Criteria

I have recovered from any major surgery before starting the study treatment.

I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.

You have a severe allergic reaction (grade 3 or higher) to pembrolizumab or any of its ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Patients receive pembrolizumab or placebo intravenously 14 days prior to scheduled surgery

2 weeks

1 visit (in-person)

Surgery

Surgical resection of recurrent glioblastoma

1 day

1 visit (in-person)

Adjuvant Treatment

Post-surgery, patients receive pembrolizumab or placebo every 3 weeks and ATL-DC with poly ICLC every 2 weeks for up to 3 doses

6 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• ATL-DC Vaccine
• Pembrolizumab

Trial Overview The trial tests how well pembrolizumab (an antibody) works alongside an ATL-DC vaccine in treating recurrent glioblastoma compared to the vaccine alone. The study aims to see if this combination helps the immune system better attack cancer cells and prevent their growth.

How Is the Trial Designed?

Group I: Group A (pembrolizumab, ATL-DC, poly ICLC) Experimental Treatment 3 Interventions

Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab IV over 30 minutes. After surgery, patients receive pembrolizumab IV over 30 minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.

Group II: Group B (placebo, ATL-DC, poly ICLC) Active Control 3 Interventions

Beginning 14 days prior to scheduled surgery, patients receive placebo IV. After surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Phase One Foundation

Collaborator

Trials

5

Recruited

180+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Oncovir, Inc.

Industry Sponsor

Trials

25

Recruited

680+

Published Research Related to This Trial

The AV-GBM-1 vaccine was successfully manufactured for all 63 patients in the trial, demonstrating a high success rate of 97% for tumor cell production and monocyte collection, which is crucial for its effectiveness.

While the treatment was generally well-tolerated, with common side effects including local injection reactions and flu-like symptoms, it also led to significant central nervous system adverse events, such as seizures and headaches, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment. Bota, DA., Taylor, TH., Piccioni, DE., et al.[2023]

Dendritic cell vaccination immunotherapy is showing promising results in clinical trials for glioblastoma, potentially extending patient survival beyond the current median of 15-17 months.

Innovative methods like 'fastDCs' and in-vivo targeting of dendritic cells may enhance the effectiveness of these vaccines compared to traditional approaches, although challenges remain due to T-cell dysfunction caused by glioblastoma's immunosuppressive environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and challenges: dendritic cell vaccination strategies for glioblastoma. Schaller, TH., Sampson, JH.[2021]

In a study involving 34 malignant glioma patients, autologous tumor lysate (ATL)-pulsed dendritic cell (DC) vaccination showed broader patient eligibility compared to glioma-associated antigen (GAA) peptide-pulsed DC vaccination, indicating ATL-DC may be a more accessible treatment option.

The study found that lower ratios of regulatory T lymphocytes (Tregs) after vaccination were significantly correlated with improved overall survival, suggesting that monitoring Treg levels could be an important endpoint for assessing the effectiveness of immunotherapy in glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. Prins, RM., Wang, X., Soto, H., et al.[2021]

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]

Dendritic cell (DC) vaccination has been shown to be safe and non-toxic in early phase trials for treating glioblastoma multiforme (GBM), suggesting a promising new immunotherapy approach.

Pre-clinical studies in mice demonstrated that DCs loaded with glioblastoma proteins significantly increased survival rates, supporting the potential for clinical trials in patients with GBM who do not respond to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dendritic cells pulsed with glioma lysates induce immunity against syngeneic intracranial gliomas and increase survival of tumor-bearing mice. Pellegatta, S., Poliani, PL., Corno, D., et al.[2006]

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]

Dendritic cell (DC) immunotherapy, particularly the DCVax®-L vaccine developed by Northwest Biotherapeutics, shows promise in improving overall survival in patients with glioblastoma multiforme (GBM), based on phase I and II trials.

The side effects associated with DC immunotherapy are generally mild, making it a potentially safe adjunct treatment for patients with newly diagnosed and recurrent GBM, with a phase III trial currently underway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DCVax®-L--developed by Northwest Biotherapeutics. Polyzoidis, S., Ashkan, K.[2018]

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]

In a study of 24 glioblastoma patients undergoing dendritic cell (DC) vaccination, changes in regulatory T cell frequencies were significantly associated with patient survival, indicating their potential as a biomarker for treatment response.

The expression of the negative co-stimulatory molecule CTLA-4 on T cells also correlated with survival outcomes, suggesting that monitoring these immune markers could help predict the effectiveness of DC vaccination in glioblastoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. Fong, B., Jin, R., Wang, X., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10155120/

Current Status and Challenges of Vaccination Therapy for ... Administration of pembrolizumab and the ATL-DC vaccine may be more effective than ATL-DC alone in patients with recurrent GBM[96]. Table 4 summarizes clinical ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04201873

Pembrolizumab and a Vaccine (ATL-DC) for the Treatment ... Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone. PRIMARY OBJECTIVES: I.

3. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2798847

Association of Autologous Tumor Lysate-Loaded Dendritic ... The survival benefit with DCVax-L vs ECP increased over time in the tails of the survival curves, with 13.0% vs 5.7% survival at 60 months in ...

4. biosignaling.biomedcentral.com biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01098-0

Recent advances and future challenges of tumor ... 65 patients with EGFR vIII-positive GBM were recruited, with a median overall survival (OS) of 21.8 months and a 3-year survival rate of 26%, ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39167243/

Dendritic cell vaccine for glioblastoma: an updated meta- ... DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6204866/

Efficacy and safety analysis on dendritic cell-based vaccine ... DC vaccine can significantly improve OS and PFS, with acceptable toxicity, of HGG patients. Nevertheless, further studies are needed to verify this conclusion.

7. nature.com nature.com/articles/s41467-024-48073-y

TLR agonists polarize interferon responses in conjunction ... As such, the addition of a TLR agonist to ATL-DC vaccination in malignant glioma patients was found to be safe and tolerable. Table 2 Adverse ...