Clinical Trials /

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

NCT03014804

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 16-001706
  • SECONDARY ID: NCI-2016-01587
  • SECONDARY ID: 16-001706
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT03014804

Conditions

  • Giant Cell Glioblastoma
  • Gliosarcoma
  • Oligodendroglioma
  • Recurrent Glioblastoma
  • Small Cell Glioblastoma

Interventions

DrugSynonymsArms
autologous dendritic cells pulsed with tumor lysate antigen VaccineDCVax-LungGroup I (DCVax-L)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoGroup II (DCVax-L, nivolumab)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (DCVax-L)ExperimentalPatients 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.
    Group II (DCVax-L, nivolumab)ExperimentalPatients 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.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  PRE-SURGERY SCREENING PROCESS
      
                -  Original diagnosis of glioblastoma multiforme (GBM) confirmed by central review
      
                -  Radiographic evidence of first recurrence per Response Assessment in Neuro-Oncology
                   (RANO) criteria confirmed by central review
      
                -  Surgically accessible, unilateral, recurrent GBM tumor for which extirpative
                   resection, with intent to perform a gross total or near gross total resection, is
                   indicated; a subject may be screened if he or she has had a previous biopsy and is
                   scheduled for a subsequent gross or near gross total resection prior to commencement
                   of other therapies
      
                -  Ability to understand and sign the tumor procurement informed consent form indicating
                   awareness of the investigational nature of this study; the consent for tumor tissue
                   donation may be signed by a legally authorized representative (LAR) if allowed by the
                   institution
      
                -  Life expectancy of >= 12 weeks
      
                -  Absolute lymphocyte count >= 0.6 x 10^3/mm^3 (0.6 x 10^9/L)
      
                -  MGMT promoter methylation status of original tumor is obtainable
      
                -  POST-SURGERY, PRIOR TO PRE-LEUKAPHERESIS
      
                -  Therapy for recurrent disease must have consisted of surgical resection extending
                   beyond biopsy only, with the intent to achieve gross or near-total resection of the
                   contrast-enhancing tumor mass; subjects who underwent resection confirmed beyond
                   biopsy remain eligible for the screening process; subjects undergoing a biopsy only
                   will be excluded; central confirmation is required before the subject can proceed to
                   leukapheresis
      
                -  Patients with recurrent unilateral GBM, confirmed through central pathology (grade
                   IV), without metastases, remain eligible for this protocol
      
                     -  For the purposes of this study, pathology reports for all histologically
                        confirmed GBM includes the recognized variants of glioblastoma (small cell
                        glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with
                        oligodendroglial components)
      
                -  All subjects must have sufficient tumor lysate protein generated from the resected
                   tumor tissue; this determination will be made by the sponsor's contracted
                   manufacturer and communicated to the clinical site through the sponsor or its
                   designee; this confirmation is not required prior to the pre-leukapheresis visit, but
                   is required before the subject can proceed to leukapheresis
      
                -  PRE-LEUKAPHERESIS EVALUATION
      
                -  Hemoglobin > 10 g/dL (100 g/L)
      
                -  White blood cell count 3.6-11.0 x 10^3/mm^3 (3.6-11.0 x 10^9/L)
      
                -  Absolute granulocyte count >= 1.5 x 10^3/mm^3 (1.5 x 10^9/L)
      
                -  Absolute lymphocyte count >= 1.0 x 10^3/mm^3 (1.0 x 10^9/L)
      
                -  Platelet count >= 100 x 10^3/mm^3 (100 x 10^9/L)
      
                -  Eligibility is maintained if these laboratory results are outside of the central
                   laboratory's normal reference ranges or the sample ranges provided above but are not
                   deemed clinically significant by the treating investigator
      
                -  Eligibility level of hemoglobin can be reached by transfusion; these values are
                   determined by a central laboratory
      
                -  Serum glutamate pyruvate transaminase (SGPT) =< 4.0 times upper limits of normal
                   (ULN)
      
                -  Serum glutamic-oxaloacetic transaminase (SGOT) =< 4.0 times ULN
      
                -  Alkaline phosphatase =< 4.0 times upper limits of normal (ULN)
      
                -  Total bilirubin =< 1.5 mg/dL (25.7 umol/L)
      
                -  Blood urea nitrogen (BUN) =< 1.5 times ULN
      
                -  Creatinine =< 1.5 times ULN
      
                -  Subjects must have a Karnofsky performance status (KPS) rating >= 70 at the
                   pre-leukapheresis visit
      
                -  PRIOR TO DAY 0
      
                -  Subjects may have received steroid therapy as part of their primary treatment;
                   steroid treatment should be stopped or, if continued steroid use is clinically
                   indicated, be tapered down to no more than 2 mg dexamethasone per day (or equivalent)
                   at least 7 days prior to the first immunization
      
                -  White blood cell count >= 2.0 x 10^3/mm^3 (2.0 x 10^9/L)
      
                -  Neutrophils >= 1.5 x 10^3/mm^3 (1.5 x 10^9/L)
      
                -  Platelets >= 100 x 10^3/mm^3 (100 x 10^9/L)
      
                -  Hemoglobin >= 9.0 g/dL (90 g/L)
      
                -  Serum creatinine =< 1.5 x upper limit of normal (ULN)
      
                -  SGOT (aspartate aminotransferase [AST]) =< 3 x ULN
      
                -  SGPT (alanine aminotransferase [ALT]) =< 3 x ULN
      
                -  Total bilirubin =< 1.5 x ULN
      
                     -  Except subjects with Gilbert's syndrome, who must have total bilirubin < 3.0
                        mg/dL
      
                -  Subjects must have a KPS rating a >= 60 at the pre-enrollment evaluation
      
              Exclusion Criteria:
      
                -  PRE-SCREENING
      
                -  Progression on imaging based on RANO criteria within 12 weeks of conclusion of
                   radiotherapy
      
                -  History of other prior malignancy except for adequately treated basal cell or
                   squamous cell skin cancer or in situ cervical cancer or other cancers that were
                   deemed fully resolved 5 or more years prior to surgery
      
                -  History of active, known, or suspected autoimmune or immunodeficiency disease
      
                -  Known human immunodeficiency virus (HIV)-1 or -2 or human T-cell lymphotropic virus
                   (HTLV)-1 or -2 positivity
      
                -  Active uncontrolled infection, such as a sexually transmitted disease (STD), herpes,
                   uncontrolled tuberculosis, malaria, etc
      
                -  Known intolerance to cyclophosphamide or other alkylating agents, or any component of
                   any study drug
      
                -  History of active immunotherapy, including dendritic cell therapy, T cell therapy,
                   immunization with tumor antigens in any form, any anti-PD-1, anti-PD-L1, anti-PD-L2,
                   or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
                   costimulation or immune checkpoint pathways or checkpoint inhibitor therapy such as
                   ipilimumab
      
                -  History of severe infusion-related reaction to any biologics therapy
      
                -  Females who are gravid or breast-feeding
      
                -  Inability to obtain informed consent because of psychiatric or complicating medical
                   problems
      
                -  Any known genetic cancer-susceptibility syndromes
      
                -  Any positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
                   virus ribonucleic acid (HCV antibody) indicative of acute or chronic infection
      
                -  AT OR AROUND SURGERY
      
                -  Bilateral or metastatic glioblastoma detected at diagnosis, during surgery, or at
                   post-surgical magnetic resonance imaging (MRI); tumors may cross into, but not
                   beyond, the corpus callosum
      
                -  Postoperative MRI evidence of biopsy only, without significant tumor resection,
                   confirmed by central reviewer
      
                -  Implantation of Gliadel wafers (polifeprosan 20 with carmustine implant) at surgery
      
                -  PRE-LEUKAPHERESIS VISIT
      
                -  Positive HIV-1, -2, or HTLV-1, -2 tests
      
                -  Recipient of organ allografts
      
                -  Allergies to reagents used in this study
      
                -  Unable to stop or taper steroid treatment to no more than 2 mg of dexamethasone per
                   day (or equivalent) prior to leukapheresis; steroid use should be stopped or tapered
                   down to the lowest clinically acceptable dose approximately 7 days prior to
                   leukapheresis; the leukapheresis visit must be scheduled to occur a minimum of 21
                   days before the projected day 0
      
                     -  It is critical to reduce steroid administration to the lowest possible dose, as
                        steroids interfere with DCVax-L manufacturing by hampering the ability of
                        monocytes to adhere to plastic surfaces during purification; leukapheresis
                        should occur at least 21 days prior to the projected date of DCVax-L
                        administration
      
                -  Inability or unwillingness to return for required visits and follow-up exams
      
                -  EXCLUSION PRIOR TO DAY 0
      
                -  Fewer than 6 doses of DCVax-L available for administration
      
                -  Continued requirement for medications that might affect immune function; the
                   following are exceptions: nonprescription strength doses of NSAIDS, acetaminophen
                   (paracetamol), or acetylsalicylic acid (aspirin)
      
                -  Acute infection: any active viral, bacterial, or fungal infection that requires
                   specific therapy; antibiotic therapy must be completed at least 7 days prior to the
                   first DCVax-L/nivolumab administration
      
                -  Fever >= 101.5 degrees Fahrenheit (F) (38.6 degrees Celsius [C]); if considered
                   possibly transient, retesting is allowed
      
                -  Unstable or severe intercurrent medical conditions
      
                -  Women of child-bearing potential (WOCBP) who are pregnant or lactating or who are not
                   using adequate contraception and willing to do so to avoid pregnancy for 5 months
                   after the week 20 visit
      
                -  Males who are sexually active with WOCBP and not willing to use any contraceptive
                   method with a failure rate of less than 1% per year for 7 months after the week 20
                   visit
      
                -  Any dose of steroids exceeding 10 mg/day of prednisone (or equivalent) within 2 weeks
                   prior to study drug administration
            
      Maximum Eligible Age:75 Years
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Incidence of adverse events assessed by National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03
      Time Frame:Up to 12 months
      Safety Issue:
      Description:Will be compared between groups and to those reported for historical standards, including subjects treated with nivolumab in prior trials.

      Secondary Outcome Measures

      Measure:Overall Survival rate
      Time Frame:9 months
      Safety Issue:
      Description: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.
      Measure:Overall Survival rate
      Time Frame:12 months
      Safety Issue:
      Description: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.
      Measure:Overall Survival rate
      Time Frame:18 months
      Safety Issue:
      Description: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.
      Measure:Progression Free Survival (PFS)
      Time Frame:From treatment initiation to first progression or death assessed up to 12 months.
      Safety Issue:
      Description: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.
      Measure:Quality of Life (QoL)
      Time Frame:Up to 12 months
      Safety Issue:
      Description: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.
      Measure:Number of participants with complete response (CR)
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description: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.
      Measure:Number of participants with partial response (PR)
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description: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.
      Measure:Number of participants with stable disease (SD)
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description: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.
      Measure:Number of participants with progressive disease (PD)
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description: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.
      Measure:Objective response rate (ORR) defined as the percentage of participants with CR + PR
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description:Rates of ORR will be provided at fixed intervals where tumor size is evaluated.
      Measure:Response/Stable Disease Rate (RSDR) defined as the percentage of participants demonstrating CR+PR+SD
      Time Frame:Up to 12 months of follow up after initiation of treatment
      Safety Issue:
      Description:Rates of RSDR will be provided at fixed intervals where tumor size is evaluated.

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:Jonsson Comprehensive Cancer Center

      Last Updated

      January 24, 2017