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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.

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.

Dendritic Cell Tumor Cell Lysate Vaccine

Placebo Administration

Quan Li, Ph.D.

Emese Filka

Quan li, Ph.D.

Timothy F. Cloughesy

Timothy F Cloughesy

This phase I trial studies the side effects and how well of pembrolizumab and a vaccine therapy (ATL-DC vaccine) work in treating patients with glioblastoma that has come back (recurrent) and can be removed by surgery (surgically accessible). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vaccines, such as ATL-DC vaccine, may help the body build an effective immune response to kill tumor cells. Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone.

PRIMARY OBJECTIVES:

I. To evaluate the influence of pembrolizumab on the cell cycle-related genetic signature within the tumor microenvironment of progressive/recurrent glioblastoma.

II. To evaluate the influence of adjuvant autologous tumor lysatepulsed dendritic cell (ATL-DC) vaccination on peripheral T cell responses.

III. To evaluate the safety and tolerability of pembrolizumab and ATL-DC vaccination in progressive/recurrent glioblastoma.

SECONDARY OBJECTIVES:

I. To estimate the 6 month progression-free survival (PFS6) based on Response Assessment in Neuro-Oncology (RANO) criteria in patients treated on both arms of the clinical trial.

II. To calculate the overall survival of recurrent glioblastoma patients treated on both arms of the clinical trial.

EXPLORATORY OBJECTIVES:

I. To evaluate the associations between exploratory biomarkers, clinical outcomes, and adverse events which include:

Ia. Estimating the correlation of quantitative assessments of tumor infiltrating lymphocyte (TIL) density or the interferon (IFN) gamma-associated genetic signature with clinical responses to pembrolizumab and ATL-DC in recurrent glioblastoma patients.

Ib. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS and overall survival (OS) as defined by RANO.

Ic. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS, and OS as defined by immunotherapy RANO (iRANO).

Id. Exploring whether oligoclonal T cell populations within tumor tissue are similarly expanded in peripheral blood after ATL-DC vaccination and/or pembrolizumab, and correlating with clinical responses.

Ie. Exploring whether changes in specific magnetic resonance imaging (MRI) parameters correlate with tumor and peripheral blood immune responses.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP A: Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab intravenously (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 intradermally (ID) with poly ICLC intramuscularly (IM) every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.

GROUP B: 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.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma

Phase I Surgical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters for the PD-1 Antibody Pembrolizumab With Autologous Tumor Lysate-Pulsed Dendritic Cell Vaccination in Patients With Surgically Accessible Recurrent/Progressive Glioblastoma

The association between biomarkers and clinical outcomes (PFS and OS) will be evaluated using Cox regression. Changes in markers pre- and post- treatment will be assessed using paired t-tests.

The differences of TIL density and TCR Clonality between the archival tumor (pre-treatment) and protocol tumor (post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.

The changes of TIL density and TCR Clonality in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.

The differences of gene expression signature and somatic mutations between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the cell cycle related gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.

The changes of gene expression signature in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.

The changes of T cell subset and activation markers in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in T cell subset/activation markers and clinical outcome (PFS and OS) will be evaluated using Cox regression.

The differences of PD-1, PD-L1, CD3, CD4, CD8, Iba-I, Ki-67 protein expression level between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the protein expression level and clinical outcome (PFS and OS) will be evaluated using Cox regression.

Two-sample T-test with Bonferroni adjustment will be used to compare the increase number of expanded TCR clones after dendritic cell (DC) vaccination with PD-1 blockade in Group A versus (vs) DC vaccination with a placebo in Group B.

Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who receive any amount of pembrolizumab/placebo or ATL-DC vaccination will be evaluable for toxicity, serious adverse events (SAEs), and events of clinical interest (ECIs).

Efficacy will be measured by percent PFS6 as defined by Response Assessment in Neuro-Oncology (RANO) criteria. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Percent PFS6 will be estimated from the KM curves and compared to historical controls.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma	NCT04201873	Recurrent Gliob...	Dendritic Cell ... Pembrolizumab Placebo Adminis... Poly ICLC	18 Years -	Jonsson Comprehensive Cancer Center
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma	NCT04201873	Recurrent Gliob...	Dendritic Cell ... Pembrolizumab Placebo Adminis... Poly ICLC	18 Years -	Jonsson Comprehensive Cancer Center

Spots Global Cancer Trial Database for dendritic cell tumor cell lysate vaccine