This phase II trial studies the side effects of autologous dendritic cells pulsed with tumor lysate antigen vaccine and nivolumab and to see how well they work in treating patients with glioblastoma that has come back. Vaccines made from a person's tumor cells may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving dendritic cell-autologous lung tumor vaccine and nivolumab may work better in treating patients with glioblastoma.
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination treatment of autologous dendritic cells pulsed with tumor lysate antigen vaccine (DCVax-L) and nivolumab. II. To compare overall survival (OS) from the date of surgery in a pooled evaluation of group 1 subjects receiving DCVax-L and group 2 subjects receiving DCVax-L and nivolumab to recent historical standards. III. To compare OS between the two groups. SECONDARY OBJECTIVES: I. Safety. II. Feasibility. III. Tumor response. IV. Immune response. V. Quality of Life (QoL). VI. Overall survival (OS). VII. Overall survival rate at 9, 12, and 18 months. VIII. Progression-free survival (PFS). IX. Evaluation of the safety of the DCVax-L + nivolumab combination regimen. TERTIARY OBJECTIVES: I. Estimate correlation of quantitative assessments of tumor-infiltrating lymphocyte (TIL) proliferation (CD8+/Ki-67+ staining). II. Estimate difference in PD-1 and PD-L1 immunohistochemistry expression between density or clonality with clinical responses to combination therapy in recurrent glioblastoma subjects. III. Estimate differences between outcome groups in monocytic PD-L1 expression at baseline and over time. IV. Estimate differences between outcome groups in circulating tumor DNA, circulating tumor cells, and CD4+ T cells at baseline and over time. V. Estimate difference in PD-1 and PD-L1 immunohistochemical (IHC) expression between archived and study samples. VI. Explore patterns of tumor proteomic profiling. VII. Estimate efficacy of combination therapy by progression-free survival (PFS), rates of contrasted tumor change over time, and overall survival (OS). VIII. Explore effect of nivolumab on TIL proliferation (CD8+/Ki-67+ staining). IX. Explore whether oligoclonal T cell populations within tumor tissue are similarly expanded in peripheral blood after nivolumab, the magnitude of which correlates with clinical responses. X. Explore if changes in specific MRI parameters correlate with tumor and peripheral blood immune responses. XI. Explore if a mesenchymal gene expression signature present in the initial archived tumor sample correlates with T lymphocytic response in tumor after nivolumab. XII. Correlate changes of positron emission tomography (PET) in tumor with the following: TIL density or clonality, clinical outcome, T cell measures in peripheral blood, clinical toxicity. XIII. Correlate changes in PET in lymph nodes with the following: TIL density or clonality, clinical outcome, T cell measures in peripheral blood, clinical toxicity. XIV. Correlate changes in PET in organ tissue with TIL density or clonality. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive dendritic cell-autologous lung tumor vaccine intradermally (ID) on days 0, 7, 14, and weeks 4, 6, 8, 11, 14, 17 and 20. GROUP II: Patients receive dendritic cell-autologous lung tumor vaccine as in Group I, and nivolumab intravenously (IV) over 30 minutes on days 0, 14, and weeks 4, 6, 8, 11, 14, 17, and 20. After completion of study treatment, patients are followed up for up to 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Incidence of adverse events assessed by National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03
Will be compared between groups and to those reported for historical standards, including subjects treated with nivolumab in prior trials.
Time frame: Up to 12 months
Overall Survival (OS)
The overall survival curves will be displayed using a Kaplan-Meier curve for the pooled and individual treatments. A one-sample log-rank test will also be completed as a sensitivity analysis for the same survival rate assumption as the primary efficacy analysis, and a two-sample log-rank test will be used to compare the survival distribution between the two arms.
Time frame: Up to 12 months
Overall Survival rate
The overall survival curves will also be displayed using a Kaplan-Meier curve for the pooled and individual treatments. Estimated proportions of surviving subjects at 9 months will be provided along with the two-sided 95% CIs.
Time frame: 9 months
Overall Survival rate
The overall survival curves will also be displayed using a Kaplan-Meier curve for the pooled and individual treatments. Estimated proportions of surviving subjects at 12 months will be provided along with the two-sided 95% CIs.
Time frame: 12 months
Overall Survival rate
The overall survival curves will also be displayed using a Kaplan-Meier curve for the pooled and individual treatments. Estimated proportions of surviving subjects at 18 months will be provided along with the two-sided 95% CIs.
Time frame: 18 months
Progression Free Survival (PFS)
Kaplan Meier estimates will be provided along with the one-sided 95% lower bound on the survival rate. PFS survival will be compared between groups using a log-rank test.
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Ancillary studies
Ancillary studies
Time frame: From treatment initiation to first progression or death assessed up to 12 months.
Quality of Life (QoL)
Will be summarized descriptively for available subjects, and shifts from day 0 will be summarized for post-baseline assessments using the European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QoL) questionnaire.
Time frame: Up to 12 months
Number of participants with complete response (CR)
Rates of CR will be provided at fixed intervals where tumor size is evaluated. Exact two-sided CIs for the response rate will be provided and the denominator will include subjects with available information or who have previously died or progressed. A Fisher's exact test will be used to compare the test that the number of CR, CR+PR, and CR+PR+SD subjects is homogeneous across the treatment arms.
Time frame: Up to 12 months of follow up after initiation of treatment
Number of participants with partial response (PR)
Rates of PR will be provided at fixed intervals where tumor size is evaluated. Exact two-sided CIs for the response rate will be provided and the denominator will include subjects with available information or who have previously died or progressed. A Fisher's exact test will be used to compare the test that the number of CR, CR+PR, and CR+PR+SD subjects is homogeneous across the treatment arms.
Time frame: Up to 12 months of follow up after initiation of treatment
Number of participants with stable disease (SD)
Rates of SD will be provided at fixed intervals where tumor size is evaluated. Exact two-sided CIs for the response rate will be provided and the denominator will include subjects with available information or who have previously died or progressed. A Fisher's exact test will be used to compare the test that the number of CR, CR+PR, and CR+PR+SD subjects is homogeneous across the treatment arms.
Time frame: Up to 12 months of follow up after initiation of treatment
Number of participants with progressive disease (PD)
Rates of PD will be provided at fixed intervals where tumor size is evaluated. Exact two-sided CIs for the response rate will be provided and the denominator will include subjects with available information or who have previously died or progressed. A Fisher's exact test will be used to compare the test that the number of CR, CR+PR, and CR+PR+SD subjects is homogeneous across the treatment arms.
Time frame: Up to 12 months of follow up after initiation of treatment
Objective response rate (ORR) defined as the percentage of participants with CR + PR
Rates of ORR will be provided at fixed intervals where tumor size is evaluated.
Time frame: Up to 12 months of follow up after initiation of treatment
Response/Stable Disease Rate (RSDR) defined as the percentage of participants demonstrating CR+PR+SD
Rates of RSDR will be provided at fixed intervals where tumor size is evaluated.
Time frame: Up to 12 months of follow up after initiation of treatment