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

Trial Summary

What is the purpose of this trial?

This research study is studying a new type of vaccine as a possible treatment for patients with glioblastoma. This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the intervention to use for further studies. "Investigational" means that the intervention is being studied and that research doctors are trying to find more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with glioblastoma. The purpose of the initial study cohort (Cohort 1) is to determine if it is possible to make and administer safely a vaccine against glioblastoma by using information gained from specific characteristics of the participants tumor. It is known that glioblastomas have mutations (changes in genetic material) that are specific to an individual patient's tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the glioblastoma to come back in the future. Three additional cohorts (1a, 1b, \& 1c) were added to the study following completion of accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The rationale for adding these new cohorts is: 1) to assess the safety and feasibility of NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1 administration impacts the immunogenicity of NeoVax. An additional sub-study cohort (1d) is being added for patients whose tumor is MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is methylated or partially methylated; patients on cohort 1d will receive standard daily temozolomide during radiation and as adjuvant therapy for up to six cycles following completion of radiation therapy. The rationale for adding cohort 1d is to determine the safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.

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.

What data supports the effectiveness of the treatment Personalized Cancer Vaccine + RT + Pembrolizumab for Glioblastoma?

Research shows that personalized neoantigen vaccines can generate strong immune responses in glioblastoma, potentially improving the immune environment of the tumor. Additionally, pembrolizumab has shown evidence of enhancing immune activity in glioblastoma, suggesting that combining these treatments could be beneficial. ^{1 2 3 4 5}

Is the combination of personalized cancer vaccine, radiation therapy, and pembrolizumab safe for humans?

Research indicates that personalized neoantigen vaccines, when used for glioblastoma, have shown safety and the ability to generate immune responses. Additionally, the combination of stereotactic body radiotherapy and pembrolizumab has been demonstrated to be safe in patients with advanced solid tumors, with some dose-limiting toxicities observed. ^{1 4 6 7 8}

What makes the treatment with Personalized Cancer Vaccine, Radiation Therapy, and Pembrolizumab unique for glioblastoma?

This treatment is unique because it combines a personalized cancer vaccine, which is tailored to the specific mutations in a patient's tumor, with radiation therapy and pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells. This combination aims to enhance the immune response against glioblastoma, a type of brain cancer that is difficult to treat with standard therapies. ^{2 5 9 10 11}

Research Team

David Reardon, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Actively Personalized Neoantigen Vaccination in the Management of Newly Diagnosed Glioblastoma: A Systematic Review. [2022]

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

Actively personalized vaccination trial for newly diagnosed glioblastoma. [2021]

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

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. [2023]

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

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

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

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. [2022]

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

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. [2023]

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

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. [2023]

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

ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. [2022]