A Pilot Surgical Trial To Evaluate Early Immunologic Pharmacodynamic Parameters For The PD-1 Checkpoint Inhibitor, Pembrolizumab (MK-3475), In Patients With Surgically Accessible Recurrent/Progressive Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- MK-3475
- Conditions
- Brain Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 60
- Locations
- 7
- Primary Endpoint
- Tumor Infiltrating T Lymphocyte (TIL) Density
- Status
- Active, not recruiting
- Last Updated
- last month
Overview
Brief Summary
This research study is studying an immunotherapy as a possible treatment for Glioblastoma.
Detailed Description
PD-1 works to help tumor cells continue to grow and multiply. Pembrolizumab (MK-3475) is a humanized monoclonal antibody. Humanized monoclonal is an antibody that is designed to block the action of the receptor, PD-1. The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for Glioblastoma but it has been approved for other uses.
Investigators
Patrick Wen, MD
Patrick Wen, MD
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Have histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made.
- •Be willing and able to provide written informed consent/assent for the trial.
- •Be 18 years of age on day of signing informed consent.
- •Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A).
- •Previous first line therapy with at least radiotherapy.
- •Be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse.
- •Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.
- •Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 14 days of registration.
- •Table 1 Adequate Organ Function Laboratory Values
- •System Laboratory Value
Exclusion Criteria
- •Current or planned participation in a study of an investigational agent or using an investigational device.
- •Has a diagnosis of immunodeficiency.
- •Has tumor primarily localized to the brainstem or spinal cord.
- •Has presence of diffuse leptomeningeal disease or extracranial disease.
- •Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six months of registration.
- •Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc).
- •Requires treatment with high dose systemic corticosteroids defined as dexamethasone \> 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration.
- •Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery.
- •Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
- •Has a known history of active TB (Bacillus Tuberculosis).
Arms & Interventions
Pre-surgery MK-3475
-After a screening phase of 14 days, eligible subjects will be randomized into two groups. * Pembrolizumab (MK3475) pre-surgery at pre-determine dosage followed by Pembrolizumab at pre-determine dosage every 3 weeks post surgery. * MK-3475 will be administered intravenously
Intervention: MK-3475
No MK-3475 at Pre-Surgery
-After a screening phase of 14 days, eligible subjects will be randomized into two groups. * Pembrolizumab (MK-3475) at pre-determine dosage every 3 weeks post surgery. * MK-3475 will be administered intravenously
Intervention: MK-3475
Outcomes
Primary Outcomes
Tumor Infiltrating T Lymphocyte (TIL) Density
Time Frame: 2 weeks. TIL density is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1.
To measure changes in tumor infiltrating T lymphocyte (TIL) density, defined as % total cells. It will be assessed using pooled Group A and Group B patients.
Incidence of Treatment-Emergent Adverse Events
Time Frame: 5 years. Although there is still 1 patient on active study treatment as of today (4/1/2024), we stopped looking at this information as of 6/2/2022 for study reporting purposes.
Number of Participants who Experienced a Serious Adverse Event (SAE) or Event of Clinical Interest (ECI) Deemed At Least Possibly Related to Pembrolizumab (MK3475). The following are measured as part of safety: laboratory safety assessments, KPS status, vital signs and physical examinations.
Cell Cycle and Cancer Proliferation Genetic Signature
Time Frame: 2 weeks. Cell cycle/cancer proliferation genetic signature is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1.
To measure changes in cell cycle and cancer proliferation genetic signature; these results are reported using Gene Set Variation Analysis (GSVA) absolute enrichment scores (ES). GSVA scores are unit-less scores derived by comparing mRNA expression of a specific gene set to genes outside of the gene set in a sample. In this case, GSVA scores for "Farmers\_breast\_cancer\_cluster\_2, as previously described" were utilized. PMID 30742122 (https://pubmed.ncbi.nlm.nih.gov/30742122/) and PMID 23323831 (https://pubmed.ncbi.nlm.nih.gov/23323831/) It will be assessed using pooled Group A and Group B patients.
Secondary Outcomes
- Progression Free Survival (PFS)(180 Days)