Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioblastoma

Brain Neoplasms

Gliosarcoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Molgramostim

Sargramostim

Temozolomide

Rindopepimut

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunologic Factors

Antineoplastic Agents, Immunological

Two intradermal injections two weeks apart, followed by monthly injections until tumor progression or intolerance.

Each dose will be 0.8 mL containing approximately 500 mcg CDX-110 and 150 mcg GM CSF.

Rindopepimut (CDX-110) with GM-CSF

150 to 200 mg/m2 for 5 days during each 28-day cycle for a minimum of six cycles or a maximum of 12 cycles, or until intolerance or progression.

Two intradermal injections two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8mL containing approximately 100mcg of KLH.

This 2-arm, randomized, phase III study will investigate the efficacy and safety of the addition of rindopepimut (an experimental cancer vaccine that may act to promote anti-cancer effects in patients who have tumors that express the EGFRvIII protein) to the current standard of care (temozolomide) in patients with recently diagnosed glioblastoma, a type of brain cancer.

All patients will be administered temozolomide, the standard treatment for glioblastoma. Half the patients will be randomly assigned to receive rindopepimut and half the patients will be randomly assigned to receive a control called keyhole limpet hemocyanin.

Patients will be treated in a blinded fashion (neither the patient or the doctor will know which arm of the study the patient is on). Patients will be treated until disease progression or intolerance to therapy and all patients will be followed for survival.

The purpose of this research study is to find out whether adding an experimental vaccine called rindopepimut (also known as CDX-110) to the commonly used chemotherapy drug temozolomide can help improve the life expectancy of patients with newly diagnosed, resected EGFRvIII positive glioblastoma.

The duration of participation in this study may be up to 5 years. After you are screened and enrolled in the study, you will be administered temozolomide and either rindopepimut/GM-CSF or KLH until either disease progression or intolerance to the medications. If your tumor progresses while on this study, your doctor may treat you with other therapies that are not part of the study.

Phase III Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma

An International, Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF With Adjuvant Temozolomide in Patients With Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma

The primary efficacy endpoint of Overall Survival is defined as the number of months from randomization to the date of death (whatever the cause), and will be censored for patients who remain alive at completion of the study for patients with a gross total resection (\~n=374). The overall survival of patients will be monitored and compared between the two study arms until the end of the study.

Compare progression-free survival between the two treatment arms

Safety and tolerability will be measured by comparing the two arms in regards to vital sign measurement, physical and neurological examination, adverse events reporting, ECOG performance status, and EORTC core Quality of Life Questionnaire

Celldex Therapeutics

Symptoms and General Pathology

Recurrence

Oligodendroglioma

Disease Attributes

Antibodies

Vaccines

Nivolumab

Immunoglobulins

Immune Checkpoint Inhibitors

Patients receive autologous dendritic cells pulsed with tumor lysate antigen vaccine ID on days 0, 7, 14, and weeks 4, 6, 8, 11, 14, 17 and 20.

Patients receive autologous dendritic cells pulsed with tumor lysate antigen vaccine as in Group I, and nivolumab IV over 30 minutes on days 0, 14, and weeks 4, 6, 8, 11, 14, 17, and 20.

autologous dendritic cells pulsed with tumor lysate antigen Vaccine

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Questionnaire Administration

Timothy Cloughesy

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.

Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma

A Phase II Clinical Trial Evaluating Combination Therapy Using DCVax-L (Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen) and Nivolumab (an Anti-PD-1 Antibody) for Subjects With Recurrent Glioblastoma Multiforme

Correlated with TIL density or clonality, clinical outcome, T cell measures in peripheral blood and clinical toxicity. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

Correlated with tumor infiltrating lymphocytes (TIL) density or clonality. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

Correlated with T lymphocytic response in tumor after DCVax-L +/- nivolumab. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

The magnitude of morphological changes correlated with clinical responses. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

The difference of PFS and OS between participants with methylated MGMT promotor and participants with unmethylated MGMT promotor enrolled in each treatment group

Difference in expression level on monocytes at baseline and over time (Week 8, the End of Treatment, month 6 and month 18) compared between two groups

Immunohistochemical staining (IHC) will be used to determine the difference in expression between archived tumor tissue samples and on study tumor tissue samples. Archived tumor tissue samples and on study tumor tissue samples are obtained in paraffin blocks or FFPE tissue slides, and are processed by IHC technique for antitumor expression of PD-1 and PD-L1. Multi-plex IHC stained will be performed to assess: 1) the proportion of PD-L1 expression on GFAP+ tumor cells versus myeloid cells (CD68+ or CD163+) within the tumor microenvironment; and 2) the proportion of PD-1 expression on CD4 or CD8 TIL; and 3) the proximity of CD4/8 TIL to PD-L1+ cells in the tumor microenvironment.

Immunohistochemistry will be used to measure the difference in PD-1 and PD-L1 expression between density with clinical responses to combination therapy examined. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

Immunohistochemistry will be used to measure the difference in PD-1 and PD-L1 expression between clonality with clinical responses to combination therapy examined. Descriptive statistics, confidence intervals, or inferential analyses will comprise a set of exploratory analyses.

Fluorescence-activated cell sorting assay will be used to measure T CD4+/8+ T cell ratios

Fluorescence-activated cell sorting assay will be used to measure T cell subset proliferation and population

Fluorescence-activated cell sorting assay will be used to measure negative costimulatory molecule expression

Will be compared between groups and to those reported for historical standards, including subjects treated with nivolumab in prior trials.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Rates of ORR will be provided at fixed intervals where tumor size is evaluated.

Rates of RSDR will be provided at fixed intervals where tumor size is evaluated.

Northwest Biotherapeutics

Bristol-Myers Squibb

Brain Tumor Funders Collaborative

Jonsson Comprehensive Cancer Center

Bevacizumab

Antibodies, Monoclonal

Angiogenesis Inhibitors

Endothelial Growth Factors

Mitogens

Growth Inhibitors

About half of the patients who have never received treatment with bevacizumab will receive rindopepimut/GM-CSF in a blinded fashion in combination with bevacizumab.

About half of the patients who have never received treatment with bevacizumab will receive KLH in a blinded fashion in combination with bevacizumab.

Patients with progressive disease while currently on or within two months after discontinuing bevacizumab will be administered rindopepimut/GM-CSF while continuing (or restarting if they had stopped bevacizumab).

A vascular endothelial growth factor (VEGF)-specific humanized monoclonal antibody angiogenesis inhibitor. Infusions of 10 mg/kg of bevacizumab will begin on day 1 and will be administered every two weeks until progression of disease or intolerance during the treatment period.

Rindopepimut/GM-CSF will initially be given three times, two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8 mL containing approximately 500 mcg CDX-110 and 150 mcg GM-CSF.

KLH will initially be given three times, two weeks apart, followed by monthly injections until tumor progression or intolerance. Each dose will be 0.8 mL containing approximately 100 mcg of KLH.

The purpose of this research study is to find out whether adding an experimental vaccine called rindopepimut (also known as CDX-110) to the commonly used drug bevacizumab can improve progression free survival (slowing the growth of tumors) of patients with relapsed EGFRvIII positive glioblastoma.

This Phase II study will enroll patients into three groups. Group 1 are patients who have never been treated with bevacizumab. These patients will be randomly assigned to receive either rindopepimut/GM-CSF or KLH, each along with bevacizumab. Treatment assignment for Group 1 will be blinded. Group 2 and Group 2C patients are those who are refractory to bevacizumab (experienced recurrence or progression of glioblastoma while on bevacizumab or within 2 months of discontinuing bevacizumab). These patients will all receive rindopepimut/GM-CSF along with bevacizumab. Patients will be treated until disease progression or intolerance and all patients will be followed for survival. Patients may be treated with other therapies that are not part of the study after discontinuing treatment with the study vaccine.

A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma

A Phase II Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma

Evaluate the antitumor activity of rindopepimut in adult patients with relapsed glioblastoma, as measured by the progression-free survival rate at 6 months post-Day 1 (PFS 6).

Evaluate the anti-tumor activity of rindopepimut in adult patients with relapsed glioblastoma, as measured by the objective response rate (ORR) for patients with measurable disease at study entry.

Safety and tolerability will be evaluated by comparing the treatment regimens in regards to vital sign measurements, physical and neurological examinations, adverse events reporting, and Karnofsky performance status

Evaluated by comparing the treatment regimens for anti-tumor activity, including objective response rate, overall progression free survival (PFS), and overall survival (OS) for Groups 1 and 2; and PFS6, overall PFS, and OS for Group 2C.

Characterize the EGFRvIII specific immune response to rindopepimut.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase III Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma	NCT01480479	Glioblastoma Small Cell Glio... Giant Cell Glio... Gliosarcoma Glioblastoma Wi...	Rindopepimut (C... Temozolomide KLH	18 Years -	Celldex Therapeutics
Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma	NCT03014804	Giant Cell Glio... Gliosarcoma Oligodendroglio... Recurrent Gliob... Small Cell Glio...	autologous dend... Laboratory Biom... Nivolumab Quality-of-Life... Questionnaire A...	18 Years - 75 Years	Jonsson Comprehensive Cancer Center
Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma	NCT03014804	Giant Cell Glio... Gliosarcoma Oligodendroglio... Recurrent Gliob... Small Cell Glio...	autologous dend... Laboratory Biom... Nivolumab Quality-of-Life... Questionnaire A...	18 Years - 75 Years	Jonsson Comprehensive Cancer Center
A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma	NCT01498328	Glioblastoma Small Cell Glio... Giant Cell Glio... Gliosarcoma Glioblastoma Wi... Recurrent Gliob... Relapsed Gliobl...	Bevacizumab Rindopepimut (C... KLH	18 Years -	Celldex Therapeutics
A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma	NCT01498328	Glioblastoma Small Cell Glio... Giant Cell Glio... Gliosarcoma Glioblastoma Wi... Recurrent Gliob... Relapsed Gliobl...	Bevacizumab Rindopepimut (C... KLH	18 Years -	Celldex Therapeutics

Spots Global Cancer Trial Database for small cell glioblastoma