Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)
- Conditions
- Glioblastoma
- Interventions
- Registration Number
- NCT03018288
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Glioblastoma (GBM) refers to a specific kind of brain cancer called glioblastoma. The standard treatment for GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune therapy that is now used to treat other cancers. The addition of pembrolizumab to the standard treatment of radiation and temozolomide has been shown to be well tolerated. Researchers want to see if adding a vaccine made from the person's own tumor will improve the effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the time of surgery is called heat shock protein peptide complex-96 (HSPPC-96).
Objectives:
To see if the adding of pembrolizumab and HSPPC-96 improves the standard treatment for glioblastoma.
Eligibility:
Adults at least 18 years old with glioblastoma.
Design:
Participants will be screened with typical cancer tests:
Brain scan
Medical history
Blood and urine tests
Questions about quality of life and symptoms
These tests will be repeated throughout the study.
Participants will have surgery to remove their tumor. A tissue sample from the tumor will be sent to a lab. A vaccine will be made from it.
Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and placebo. Participants will not know which they get.
Participants will get radiation for 6 weeks.
Participants will take temozolomide by mouth before each treatment.
Participants will get pembrolizumab by intravenous (IV) for 30 minutes 3 times over the radiation cycle.
Participants will keep taking the 2 drugs every few weeks for about a year. Some may take pembrolizumab for an additional year.
Most participants will get the vaccine or placebo after radiation. They will get it 5 times over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2 years.
Participants will repeat the screening tests when they stop study treatment. They will also have follow-up phone calls.
- Detailed Description
Background:
* Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these tumors almost always recur.
* Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to standard therapy which consists of concurrent radiation with temozolomide chemotherapy after maximal surgical resection in patients with newly diagnosed disease and salvage chemotherapy with either rechallenge with temozolomide or an alternative alkylating agent such as lomustine (CCNU) or cisplatin. To date, none of the combination strategies have demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT (O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit and salvage therapies have not demonstrated a significant impact in this subject group underscoring the need for more research.
* Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking specific immune responses that may produce a more sustained and less toxic effect than conventional therapy. Heat-shock proteins (HSPs), which function as intracellular chaperones, can be used to deliver a variety of tumor antigens to antigen presenting cells for immune stimulation.
* Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including autologous antigenic peptides (aka vaccine). Heat shock proteins (HSP) are molecules that respond to cellular stress and counteract abnormal protein folding. They are known to modulate immune responses, especially the HSP gp-96. In a stressful environment, such as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the tumor and leads to resistance to therapy. HSP expression is associated with cellular proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.
* Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between Programmed cell death protein 1 (PD-1) and its ligands, programmed death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2). Additionally, pembrolizumab is thought to also have activity in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It is currently Food and Drug Administration (FDA) approved for use in patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor and non-small cell lung cancer (NSCLC) with elevated PD-L1 in the tumor. recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. It is also FDA approved for use with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express a protein called PD-L1 and for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
* This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-1 inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide important data on immune-modulatory effect of this combination. This may be of particular value in patients with high peripheral PD-L1 expression, but also the value of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient s tumor, patients will need to be identified prior to surgery.
Eligibility:
* MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed GBM that has not been treated and would benefit from further surgical resection.
* Tumor must be supratentorial.
* GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed unless there is plan for second surgery to remove greater than or equal to 80% of the tumor) and patients tumors must not have O6-Methylguanine-deoxyribonucleic acid (DNA) Methyltransferase (MGMT) promoter methylation and must be isocitrate Dehydrogenase (IDH) wildtype.
* No prior treatment with radiation or chemotherapy for their GBM.
* Age greater than or equal to 18 years on day of signing informed consent
Objective:
- The primary endpoint is to determine whether the one-year overall survival (OS) rate is improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and are IDH wildtype treated with radiation therapy (RT) + temozolomide (TMZ) + Pembrolizumab followed by TMZ + Pembrolizumab + HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).
Design:
* This will be a randomized, double blind phase II trial of surgery, RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and are IDH wildtype.
* Subjects will be assigned to intervention based on ability to generate vaccine as follows:
* If \>= 80 % of tumor removed, \>=7 g of tumor is resected but HSPPC-96 cannot be generated, subjects will be treated on the ancillary arm of RT+TMZ +Pembrolizumab followed by TMZ+ Pembrolizumab.
* If\>= 80% of contrasting enhanced tumor removed (based on T1 Post contrast magnetic resonance imaging (MRI) using cross sectional measurement), \>= 7 g of tumor is resected and sufficient HSPPC-96 is generated, subjects will be included in the main cohort and will be randomized on a 1:1 basis to receive:
* RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo
OR
--- RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96
-Subjects whose tumor does not meet the criteria (unmethylated MGMT promoter and IDH wildtype by pathology) and for whom \< 80 % of tumor is removed or \< 7g of tumor is resected are not eligible for further intervention. Approximately 8 potentially eligible patients are screened per month, and it is anticipated that at least 1-2 per month will be accrued per site.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 90
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1/Temozolomide + Pembrolizumab + Radiation Therapy Surgery Standard treatment with experimental treatment (pembro) added. 2/Temozolomide+Pembrolizumab Surgery Temozolomide+Pembrolizumab 3/Temozolomide+Pembrolizumab+ Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine HSPPC-96 Temozolomide+Pembrolizumab+ HSPPC96 Vaccine 4/Temozolomide+Pembrolizumab+ Placebo Placebo Temozolomide+Pembrolizumab+ Placebo 1/Temozolomide + Pembrolizumab + Radiation Therapy Pembrolizumab Standard treatment with experimental treatment (pembro) added. 1/Temozolomide + Pembrolizumab + Radiation Therapy Temozolomide Standard treatment with experimental treatment (pembro) added. 2/Temozolomide+Pembrolizumab Pembrolizumab Temozolomide+Pembrolizumab 2/Temozolomide+Pembrolizumab Temozolomide Temozolomide+Pembrolizumab 3/Temozolomide+Pembrolizumab+ Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine Temozolomide Temozolomide+Pembrolizumab+ HSPPC96 Vaccine 3/Temozolomide+Pembrolizumab+ Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine Pembrolizumab Temozolomide+Pembrolizumab+ HSPPC96 Vaccine 4/Temozolomide+Pembrolizumab+ Placebo Pembrolizumab Temozolomide+Pembrolizumab+ Placebo 4/Temozolomide+Pembrolizumab+ Placebo Temozolomide Temozolomide+Pembrolizumab+ Placebo
- Primary Outcome Measures
Name Time Method One-year Overall Survival (OS) Rate One year One-year overall survival (OS) rate is defined as the percentage of participants who from time of registration survived to one year in newly diagnosed O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) unmethylated Glioblastoma (GBM) participants treated with radiation therapy (RT) + Temozolomide (TMZ) + Pembrolizumab followed by Pembrolizumab + TMZ +/- heat-shock protein peptide complex-96 (HSPPC-96) x 6 cycles (1 cycle is 9 weeks) months. Rate of OS is measured by Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Ancillary Treatment Cohort: Number of Adverse Events Grades 2-5, Unrelated, Unlikely, Possibly, Probably, and/or Definitely Related to Pembrolizumab Start of treatment until participant is off study, approximately 61.5 months Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.
Vaccine Cohort: Number of Adverse Events Grades 2-5, Unrelated, Unlikely, Possibly, Probably, and/or Definitely Related to Pembrolizumab Start of treatment until participant is off study, approximately 61.5 months Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.
Placebo Cohort: Number of Adverse Events Grades 2-5, Unrelated, Unlikely, Possibly, Probably, and/or Definitely Related to Pembrolizumab Start of treatment until participant is off study, approximately 61.5 months Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.
Progression Free Survival (PFS) Time from registration to the time of confirmed progression, an average of 9 months PFS is defined as the time from registration to the time of confirmed progression. Progression was measured by the immunotherapy response assessment for neuro-oncology (iRANO) criteria. Progressive disease is ≥25% increase in the sum of bi-perpendicular diameters of enhancing disease or new lesions or significant worsened T2/fluid-attenuated inversion recovery (FLAIR) or significant clinical decline.
Overall Survival (OS) Time from registration to the time of death or off study up to 26 months OS is defined as the time from registration to the time of death. Kaplan-Meier curves will be used to analyze overall survival.
Mean Symptom Severity Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). Baseline, end of treatment or discontinuation, and 30 days after last dose To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). Participants rate their symptoms on a questionnaire using an 11-point scale (0-10). 0 is "not present" and 10 is "as bad as you can imagine." Differences of at least 2 points will be classified as the minimum clinically meaningful change in the symptom severity measures.
Response Rate After treatment, up to 26 months Response was determined by the Response Assessment in Neuro-Oncology Criteria (RANO) criteria and reported with 95% confidence intervals using exact binomial probability distributions. Complete response is no T1 gadolinium enhancing disease or stable or decreasing T2/fluid-attenuated inversion recovery (FLAIR). Partial response is ≥ 50% decrease in T1 gadolinium enhancing disease or stable or decreasing T2/FLAIR. Stable disease is \<50% decrease but \<25% increase in T1 gadolinium enhancing disease or stable or decreasing T2/FLAIR. Progressive disease is ≥25% incT1 gadolinium enhancing disease, appearance of new lesions or increase in T2/FLAIR.
Overall Survival at 6, 12 and 24 Months, Post-registration 6, 12 and 24 months, post-registration Participants who are alive at 6, 12 and 24 months, post-registration determined from the level of the Kaplan-Meier curves at these time points.
Mean Symptom Interference Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). Baseline, end of treatment or discontinuation, and 30 days after last dose To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). Participants rate their symptoms on a questionnaire using an 11-point scale (0-10) of how much symptoms interfered with different aspects of a patient's life in the last 24 hours such as general activity, mood, work, relations with other people, walking and enjoyment of life. 0 is "not present" and 10 is "as bad as you can imagine." Differences of at least 2 points will be classified as the minimum clinically meaningful change in the symptom severity measures.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States