Personalized Cancer Vaccine + RT + Pembrolizumab for Glioblastoma

Recruiting at 1 trial location

Overseen By Jennifer Stefanik, NP

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must be taking: Pembrolizumab, Temozolomide

Must not be taking: Anticancer agents, Immunosuppressive agents

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new personalized cancer vaccine combined with radiation therapy and the drug pembrolizumab (Keytruda) to treat glioblastoma, a type of brain cancer. Researchers aim to determine the safety of this approach and its potential to enhance the immune system's ability to fight cancer. The trial includes different groups to assess how treatment timing affects effectiveness. This study may suit individuals diagnosed with glioblastoma who have undergone surgery and can receive radiation therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain anti-cancer or immunosuppressive drugs within six months of joining the study, and you should not have received chemotherapy, targeted therapy, or radiation therapy within two weeks before starting the trial.

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

Research has shown that the personalized NeoAntigen Vaccine is safe and enhances the immune response in patients with glioblastoma. This vaccine targets specific tumor proteins, aiding the body in recognizing and combating cancer cells. Studies have found it to be well-tolerated, with most individuals not experiencing severe side effects.

Pembrolizumab, another component of the treatment, is an immunotherapy that assists the immune system in fighting cancer. It has been tested in many patients with various cancer types, including glioblastoma. Research indicates that pembrolizumab is generally safe, though some individuals may experience side effects such as tiredness or skin issues.

Radiation therapy, a common treatment for glioblastoma, is considered safe. It uses high-energy rays to destroy cancer cells. While it can cause side effects like fatigue and skin changes, these are usually manageable.

In one treatment group, temozolomide is used alongside the other therapies. Temozolomide is a standard chemotherapy drug for brain tumors and is generally safe, though it can sometimes lower blood cell counts, increasing the risk of infection.

Overall, each treatment in this study has demonstrated a good safety profile in previous research. However, this clinical trial is crucial to confirm safety when these treatments are used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for glioblastoma, which often rely on surgery followed by chemotherapy and radiation, this new approach combines a personalized cancer vaccine, radiation therapy, and pembrolizumab, an immune checkpoint inhibitor. The personalized NeoAntigen Vaccine, or NeoVax, is tailored specifically to each patient's tumor, potentially enhancing the immune system's ability to recognize and attack cancer cells. Researchers are excited because this method not only targets the cancer more precisely but also includes pembrolizumab, which helps to further unleash the immune response against the tumor. This multi-faceted approach aims to improve outcomes by leveraging the body's own defenses in a more targeted way than current therapies.

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

This trial will evaluate the effectiveness of different treatment combinations for glioblastoma. One arm will study a personalized neoantigen vaccine, which has shown promise in targeting specific markers on tumor cells. In one study, 87.5% of patients did not experience tumor growth for at least 5.4 to 27.3 months after receiving similar vaccines. Another arm will include Pembrolizumab, a drug that boosts the immune system, which has shown a 37.7% rate of patients without tumor growth at 6 months in some studies. Additionally, Temozolomide, a chemotherapy drug known to improve survival rates when used with radiation, will be studied in combination with these treatments. Together, these treatments aim to help the body's immune system fight glioblastoma more effectively, offering new hope. ^{5 6 7 8 9}

Who Is on the Research Team?

David Reardon, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with newly diagnosed glioblastoma who can undergo specific imaging tests, are not pregnant or breastfeeding, and agree to use contraception. They should have a certain performance status indicating they can carry out daily activities and must not be on corticosteroids. Prior cancer treatments other than surgery for glioblastoma are disqualifying.

Inclusion Criteria

I am a woman who can have children and have a negative pregnancy test.

I am able to care for myself but may not be able to do active work.

I have a specific type of brain tumor (glioblastoma) and haven't received treatment other than surgery.

Exclusion Criteria

I had cancer before but have been cancer-free for 3 years or only had certain types of skin or localized cancers.

Coh 1a/1b/1c/1d Exclusions: Hypersensitivity to pembrolizumab or any of its excipients, Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used investigational device within 4 weeks of the first dose of treatment. (NOTE: Participation in a clinical trial evaluating interventions for purposes other than GBM therapy is not a basis for exclusion, and may be permitted pending prospective approval of Principal Investigator or designee.), Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., less than or equal to Grade1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

My tumor is mainly in the lower part of my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Participants receive standard radiation therapy (60Gy) over 6 weeks

6 weeks

Weekly visits for radiation sessions

Vaccine Preparation and Recovery

NeoAntigen Vaccine preparation and recovery from radiation therapy

12 weeks

Vaccine Administration

Participants receive NeoAntigen Vaccine with priming and booster doses

7 months

Multiple visits for vaccine administration

Pembrolizumab Administration

Pembrolizumab is administered every 3 weeks for up to 2 years

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Personalized NeoAntigen Vaccine
• Radiation Therapy
• Temozolomide

Trial Overview The trial is testing a new vaccine made from the patient's tumor characteristics combined with radiation therapy and Pembrolizumab (an immunotherapy drug). It aims to see if this personalized vaccine can safely stimulate the immune system to fight brain cancer cells.

How Is the Trial Designed?

Group I: Coh 1d: Std RT+TMZ Followed by 6 Cyc TMZ + NeoVax + Pembro Experimental Treatment 5 Interventions

• RT: Standard RT (60Gy) + concurrent daily temozolomide (TMZ) over 6 weeks. Concurrent TMZ @ 75 mg/m2/day for 6 weeks. Followed by: * 6 cycles of Adjuvant temozolomide (TMZ): Starts 4-6 weeks after completion of RT. TMZ (150-200 mg/m2/day) on days 1-5 of each 28-day cycle for 6 cycles. * Pembrolizumab: Starts 1-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years * NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 \[priming doses\], 78 and 134 \[booster doses\] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing

Group II: Coh 1c: Std RT (+ 1 dose Pembro) Followed by NeoVax & Pembo Experimental Treatment 4 Interventions

* RT: Standard RT (60Gy) over 6 weeks * Pembrolizumab: Single dose of pembrolizumab administered within 2 weeks of start of RT; re-starts 1-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years. * NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 \[priming doses\], 78 and 134 \[booster doses\] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing

Group III: Coh 1b: Std RT Followed by NeoVax + Pembrolizumab Experimental Treatment 4 Interventions

* RT: Standard RT (60Gy) over 6 weeks * Pembrolizumab: Starts 1-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years * NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 \[priming doses\], 78 and 134 \[booster doses\] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing

Group IV: Coh 1a: Pembrolizumab w Std RT Followed by NeoVax + Pembro Experimental Treatment 4 Interventions

* RT: Standard RT (60Gy) over 6 weeks * Pembrolizumab: Starts within 2 weeks of start of RT, and continues every 3 weeks for up to 2 years * NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 \[priming doses\], 78 and 134 \[booster doses\] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing

Group V: Coh 1 (Original Cohort): Standard RT Followed by NeoVax Experimental Treatment 3 Interventions

After the screening procedures confirm participant eligible to participate in the research study (must be registered to within 6 weeks of resection): * \~ 6 weeks of standard radiation therapy (RT) followed by an RT-recovery period. * During that time, participant NeoAntigen Vaccine-Preparation is created (process takes \~ 12 weeks) After participant recovers from RT and vaccine is created, participant will re-screen to confirm participant is eligible to receive study vaccinations. Once registered, participant will proceed to receive study vaccinations: \- NeoAntigen Vaccine: NeoVax will be administered on an individual basis using a dosing schedule that incorporates both priming and boost phases (\~ 7 months total: 5 priming followed by 2 boost vaccine administrations)

Personalized NeoAntigen Vaccine is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer

Approved in United States as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer
• Small cell lung cancer
• Gastric or gastroesophageal junction adenocarcinoma

Approved in Japan as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

The Ben & Catherine Ivy Foundation

Collaborator

Trials

3

Recruited

100+

Accelerate Brain Cancer Cure

Collaborator

Trials

4

Recruited

550+

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

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

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]

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 I trial involving 15 patients with newly diagnosed glioblastoma, a personalized vaccine approach using both unmutated antigens and neoepitopes showed feasibility and safety, with favorable immune responses.

The vaccine strategy elicited strong immunogenicity, with APVAC1 generating sustained central memory CD8+ T cell responses and APVAC2 inducing CD4+ T helper 1 type responses, suggesting a promising avenue for immunotherapy in glioblastoma patients with low mutational loads.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actively personalized vaccination trial for newly diagnosed glioblastoma. Hilf, N., Kuttruff-Coqui, S., Frenzel, K., et al.[2021]

Neoantigen-based personalized vaccines for glioblastoma (GBM) have shown high immunogenicity and safety in clinical trials, with significant T cell responses observed in most patients.

In a review of two trials involving 24 patients, no serious treatment-related adverse events were reported, indicating that these vaccines could be a promising treatment option for newly diagnosed GBM, although larger studies are needed to confirm their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Actively Personalized Neoantigen Vaccination in the Management of Newly Diagnosed Glioblastoma: A Systematic Review. Khan, M., Li, X., Yan, M., et al.[2022]

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

Rindopepimut, an immunotherapy targeting the EGFRvIII mutation, is the first of its kind to enter Phase III clinical trials for treating recurrent glioblastoma, a highly aggressive brain tumor.

The ReACT Phase II trial evaluated the combination of rindopepimut and bevacizumab in patients with EGFRvIII-positive recurrent glioblastoma, highlighting the potential of this approach to activate the immune response against tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. Gatson, NT., Weathers, SP., de Groot, JF.[2018]

In a phase 1 study involving 16 patients with brain metastases from melanoma, ipilimumab combined with stereotactic radiosurgery (SRS) was found to be safe at a maximum dose of 10 mg/kg, with no dose-limiting toxicities reported.

The study showed that while the median progression-free survival was similar for both treatment arms (2.1 months for SRS and 2.5 months for whole brain radiation therapy), the overall survival was not reached for the SRS group, indicating potential benefits of this combination therapy that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. Williams, NL., Wuthrick, EJ., Kim, H., et al.[2022]

Personalized neoantigen vaccination is a feasible strategy for treating glioblastoma, even in tumors with low mutation loads and an immunologically 'cold' environment, as demonstrated in a phase I/Ib study.

Patients who did not receive dexamethasone showed enhanced immune responses, including increased neoantigen-specific T cells that can migrate into glioblastoma tumors, suggesting that this vaccination approach could improve the immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Keskin, DB., Anandappa, AJ., Sun, J., et al.[2023]

The combination of stereotactic body radiotherapy (SBRT) and pembrolizumab (SBRT+P) is safe for patients with large, advanced solid tumors, with only 7.2% experiencing dose-limiting toxicities in a study involving 97 patients.

Patients who showed a positive response to SBRT+P had significantly better overall survival rates, with a 1-year overall survival of 71% for responders, compared to 0% for nonresponders, highlighting the potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. Korpics, MC., Onderdonk, BE., Dadey, RE., et al.[2023]

In a study of 179 patients with non-small cell lung cancer, renal cell carcinoma, or melanoma treated with immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS), the combination showed a low local failure rate of 5.8%, suggesting effective intracranial control when these treatments are used together.

Higher PD-L1 expression (≥50%) was linked to increased rates of grade 2+ radiation necrosis (17% vs. 3%), indicating that while the combination therapy is generally safe, patients with high PD-L1 levels may need closer monitoring for potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. Hall, J., Lui, K., Tan, X., et al.[2023]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

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