Clinical Trials /

Personalized NeoAntigen Cancer Vaccine w RT Plus Pembrolizumab for Patients With MGMT Unmethylated, Newly Diagnosed GBM

NCT02287428

Description:

This research study is studying a new type of vaccine as a possible treatment for patients with MGMT-unmethylated glioblastoma. This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the intervention to use for further studies. "Investigational" means that the intervention is being studied and that research doctors are trying to find more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with glioblastoma. The purpose of this study (Cohort 1) is to determine if it is possible to make and administer safely a vaccine against glioblastoma by using information gained from specific characteristics of the participants tumor. It is known that glioblastomas have mutations (changes in genetic material) that are specific to an individual patient's tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the glioblastoma to come back in the future. Three additional cohorts (1a, 1b, & 1c) were added to the study following completion of accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The rationale for adding cohorts 1a, 1b and 1c includes to: 1) assess the safety and feasibility of NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1 administration impacts the immunogenicity of NeoVax.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Ph I Personalized NeoAntigen <span class="go-doc-concept go-doc-disease">Cancer</span> Vaccine With <span class="go-doc-concept go-doc-intervention">Radiotherapy</span> for Patients With <span class="go-doc-concept go-doc-biomarker">MGMT</span> Unmethylated, Newly Diagnosed <span class="go-doc-concept go-doc-disease">Glioblastoma</span>

Title

  • Brief Title: Ph I Personalized NeoAntigen Cancer Vaccine With Radiotherapy for Patients With MGMT Unmethylated, Newly Diagnosed Glioblastoma
  • Official Title: A Phase I Study of a Personalized NeoAntigen Cancer Vaccine With Radiotherapy Among MGMT Unmethylated, Newly Diagnosed Glioblastoma Patients
  • Clinical Trial IDs

    NCT ID: NCT02287428

    ORG ID: 14-362

    Trial Conditions

    Glioblastoma

    MGMT-unmethylated Glioblastoma

    Gliosarcoma

    Glioblastoma With Oligodendroglial Features

    Giant Cell Glioblastoma

    Glioblastoma Multiforme

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    This research study is studying a new type of vaccine as a possible treatment for patients
    with MGMT-unmethylated glioblastoma. This research study is a Phase I clinical trial, which
    tests the safety of an investigational intervention and also tries to define the appropriate
    dose of the intervention to use for further studies. "Investigational" means that the
    intervention is being studied and that research doctors are trying to find more about it. It
    also means that the FDA (U.S. Food and Drug Administration) has not approved the
    Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with
    glioblastoma.

    The purpose of this study is to determine if it is possible to make and administer safely a
    vaccine against glioblastoma by using information gained from specific characteristics of
    the participants tumor. It is known that glioblastomas have mutations (changes in genetic
    material) that are specific to an individual patient's tumor. These mutations can cause the
    tumor cells to produce proteins that appear very different from the body's own cells. It is
    possible that these proteins used in a vaccine may induce strong immune responses, which may
    help the body fight any tumor cells that could cause the glioblastoma to come back in the
    future.

    Detailed Description

    It is known that glioblastomas have mutations that are specific to an individual patient's
    tumor. These mutations can cause the tumor cells to produce proteins that appear very
    different from the body's own cells. It is possible that these proteins used in a vaccine
    may induce strong immune responses, which may help the body fight any tumor cells that could
    cause glioblastoma to recur.

    Methylguanine methyltransferase (MGMT) is a DNA repair protein which can be increased in
    some cancers, including glioblastoma. MGMT works to repair the DNA of cancer cells that are
    damaged by treatment. If a tumor is found to be "unmethylated", it means there is more MGMT
    present in the tumor than one that is "methylated".

    Methylation of MGMT is believed to make tumor cells more responsive to drugs like
    temozolomide. Studies have shown that temozolomide provides a very small improvement in
    outcome for many patients whose glioblastoma is MGMT-unmethylated. This study is for
    patients with MGMT-unmethylated glioblastoma.

    Patients with glioblastoma usually receive six weeks of radiation with a daily chemotherapy
    called temozolomide after their surgery, followed by six to twelve months of additional
    temozolomide. In this study, participants will not take temozolomide, as their tumors are
    MGMT-unmethylated, and studies have shown that temozolomide provides a very small
    improvement in outcome for many patients whose glioblastoma is MGMT-unmethylated.

    Instead, on this trial, participants will receive the Personalized NeoAntigen Vaccine after
    completing six weeks of radiation:

    - Therapy On This Study:

    - Surgery

    - Followed by six weeks of radiation therapy

    - Followed by a series of vaccine administrations (~ 7 months)

    The study will examine the safety of the vaccine when given at several different time points
    and will examine the participant blood cells for signs that the vaccine induced an immune
    response.

    Trial Arms

    Name Type Description Interventions
    Personalized NeoAntigen Vaccine Experimental After the screening procedures confirm participant eligible to participate in the research study (must be registered to within 6 weeks of resection): ~ 6 weeks of standard radiation therapy (RT) followed by an RT-recovery period. During that time, participant NeoAntigen Vaccine-Preparation is created (process takes ~ 12 weeks) After participant recovers from RT and vaccine is created, s/he will re-screen to confirm s/he is eligible to receive study vaccinations. Once registered, participant will proceed to receive study vaccinations: - NeoAntigen Vaccine: NeoVax will be administered on an individual basis using a dosing schedule that incorporates both priming and boost phases (~ 7 months total: 5 priming followed by 2 boost vaccine administrations)

    Eligibility Criteria

    NOTE: Eligibility will be confirmed and participants registered on 2 separate, serial
    occasions on this trial: 1.) Initial Study Screening: Shortly after initial resection,
    newly diagnosed patient is identified and screened. Once overall trial eligibility is
    confirmed and participant is registered to study, the creation of the participant's
    vaccine is initiated. 2.) Secondary Screening: As participant's 1st study vaccine dose may
    not be administered until 10-17 weeks from initial study registration, there will be a
    secondary "screen" conducted after participant has completed RT and his/her vaccines have
    been prepared, to ensure s/he meets criteria to receive study treatment. If confirmed
    eligible for this next phase of the study (eligible to treat), participant will proceed to
    receive vaccines on study.

    I. Inclusion Criteria:

    A. Study Eligibility Criteria for Overall Study Participation (for Initial Registration)
    Participants must meet the following criteria on screening examination to be eligible to
    participate in the study (labs/tests/assessments within 14 days prior to initial study
    registration unless otherwise specified)

    - Participant is willing and able to give written informed consent

    - Pathologically confirmed WHO grade IV glioblastoma or variants (gliosarcoma,
    glioblastoma with oligodendroglial features, giant cell glioblastoma) with adequate
    tumor material for genomic sequencing as confirmed by study pathologist Keith Ligon,
    MD, PhD or his designate. Participants will be eligible if the original diagnosis was
    a lower grade glioma and a subsequent histologic diagnosis of glioblastoma or its
    variants was made, and they received no prior therapy other than surgery

    - The tumor must be primarily supratentorial in location as determined by diagnostic
    imaging performed preoperatively

    - Radiographic contrast enhancement attributable to residual tumor on post-operative
    imaging performed within 72 hours of resection must not exceed 4 cm in maximal
    diameter in any plane

    - Age 18 years

    - Karnofsky performance status 70

    - Participant is a candidate for, and agrees to receive conventional external beam
    radiotherapy

    - Normal organ and bone marrow function as defined below

    - Leukocytes 3,000/L

    - Absolute lymphocyte count 800/L

    - Absolute neutrophil count 1,000/L

    - Platelets 100,000/L

    - Hemoglobin 10.0 g/dL

    - Total serum bilirubin 1.5 x institutional upper limit of normal

    - Aspartate aminotransferase (AST/SGOT) / Alanine transaminase (ALT/SGPT) 2.0 x
    institutional upper limit of normal

    - Serum creatinine 1.5 x institutional upper limit of normal

    - Tumor MGMT promoter unmethylated as per clinical Clinical Laboratory Improvement
    Amendments (CLIA) report which will be reviewed and confirmed by study pathologist
    Keith Ligon, MD, PhD, or his designate

    - MGMT Promoter Methylation testing will be performed by BWH's CLIA-approved
    Molecular Diagnostics and Cytogenetics Laboratory in the Center for Advanced
    Molecular Diagnostics (CAMD); there they will utilize their standard clinical
    two-step methylation specific polymerase chain reaction (PCR) assay to detect
    DNA methylation within the promoter region of the MGMT gene. Fully methylated
    and unmethylated control DNAs are run concurrently with each assay to ensure
    quality control

    - Only those results that read "Unmethylated" will be eligible for this trial;
    Results of "Partially Methylated" or "Methylated" will be ineligible for this
    trial

    - Adequate tumor content as determined by study pathologist Keith Ligon, MD, PhD, or
    his designate for nucleic acid extraction and DNA sequence analysis;

    - Patients unable to undergo magnetic resonance (MR) imaging because of non-compatible
    devices can be enrolled, provided CT scans are obtained and are of sufficient
    quality. Patients without non-compatible devices may not have CT scans performed to
    meet this requirement

    - Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum
    sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial, because the
    effects NeoVax on the developing human fetus are unknown

    - Female participants enrolled in the study, who are not free from menses for >2 years,
    post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use
    either 2 adequate barrier methods or a barrier method plus a hormonal method of
    contraception to prevent pregnancy or to abstain from sexual activity throughout the
    study, starting with visit 1 through 4 weeks after the last dose of study therapy.
    Approved contraceptive methods include, for example: intra uterine device, diaphragm
    with spermicide, cervical cap with spermicide, male condoms, or female condom with
    spermicide. Spermicides alone are not an acceptable method of contraception

    - Male participants must agree to use an adequate method of contraception starting with
    the first dose of radiation therapy through 4 weeks after the last dose of study
    therapy

    B. Study Eligibility Criteria to Initiate Treatment (for Secondary Registration)
    Participants must meet the following criteria to be eligible to proceed to receive vaccine
    treatment on the study (labs/tests/assessments within 7 days prior to secondary study
    registration and within 14 days of first vaccine administration unless otherwise
    specified)

    - Scan within 14 days prior to initiation of study vaccinations shows no evidence of
    progressive disease prior to study vaccination initiation based on the Response
    Assessment in Neuro-Oncology (RANO) criteria; Participant with progressive disease
    after radiation therapy will not be a candidate for the vaccine despite being
    previously enrolled and will be removed from the study and replaced

    - Normal organ and bone marrow function as defined below

    - Leukocytes 3,000/L

    - Absolute lymphocyte count 800/L

    - Absolute neutrophil count 1,000/L

    - Platelets 100,000/L

    - Total serum bilirubin 1.5 x institutional upper limit of normal

    - AST (SGOT)/ALT (SGPT) 2.0 x institutional upper limit of normal

    - Serum creatinine 1.5 x institutional upper limit of normal

    - Karnofsky performance status 70

    - No new or worsened existing acute medical condition that would require a dose hold or
    delay as noted in protocol

    - No uncontrolled intercurrent illness including, but not limited to ongoing or active
    infection requiring treatment, symptomatic congestive heart failure, unstable angina
    pectoris, cardiac arrhythmia

    - No planned major surgery

    - Requirement of 4 mg/day of dexamethasone (or other corticosteroid bioequivalent)
    within one week of vaccination initiation

    - Participant is neither pregnant nor nursing --- Women of childbearing potential
    (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or
    equivalent of HCG) within 7 days prior to start of study medication, because the
    effects NeoVax on the developing human fetus are unknown. It is the investigators'
    responsibility to repeat the pregnancy test should start of treatment be delayed

    II. Exclusion Criteria:

    Participants who exhibit any of the following conditions at either screening timepoint
    will not be eligible for admission into or continuation on the study

    - Stereotactic biopsy (without further resection)

    - Tumors primarily localized in the infratentorial compartment or spinal cord - tumors
    with limited infratentorial compartment or spinal cord involvement are eligible

    - Radiographic or cytologic evidence of diffuse leptomeningeal extension - tumors with
    limited subependymal involvement are eligible

    - Participants who have received or plan to receive any additional treatment for
    glioblastoma aside from surgical resection and conventional radiotherapy including
    but not limited to temozolomide, stereotactic radiosurgery, placement of Gliadel
    (carmustine; BCNU) wafers, any other intratumoral or intracavitary treatment,
    brachytherapy, bevacizumab, or investigational therapeutic agents

    - Tumor MGMT promoter methylated, partially methylated or methylation status not
    determined

    - Concomitant therapy with any anti-cancer agents, other investigational anti-cancer
    therapies, or immunosuppressive agents including but not limited to methotrexate,
    chloroquine, azathioprine, etc. within six months of study participation

    - History of severe allergic reactions attributed to any vaccine therapy for the
    prevention of infectious diseases

    - Active, known, or suspected autoimmune disease or immunosuppressive conditions with
    the exception of vitiligo, type 1 diabetes, residual autoimmune-related
    hypothyroidism requiring hormone replacement, or psoriasis not requiring systemic
    treatment

    - Known chronic infections with HIV, hepatitis B or C

    - Uncontrolled intercurrent illness including, but not limited to ongoing or active
    infection requiring treatment, symptomatic congestive heart failure, unstable angina
    pectoris, cardiac arrhythmia

    - Any underlying medical condition, psychiatric condition or social situation that in
    the opinion of the investigator would compromise study administration as per protocol
    or compromise the assessment of Adverse Events (AEs)

    - Planned major surgery

    - Pregnant women are excluded from this study because personalized neoantigen peptides
    and poly-ICLC are agents with unknown risks to the developing fetus Because there is
    an unknown but potential risk of adverse events in nursing infants secondary to
    treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing
    women are excluded from this study

    - Individuals with a history of an invasive malignancy are ineligible except for the
    following circumstances: a) individuals with a history of invasive malignancy are
    eligible if they have been disease-free for at least 3 years and are deemed by the
    investigator to be at low risk for recurrence of that malignancy; b) individuals with
    the following cancers are eligible if diagnosed and treated - carcinoma in situ of
    the breast, oral cavity or cervix and basal cell or squamous cell carcinoma of the
    skin

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of participants with Adverse Events as a measure of safety and tolerability

    Number of participants with at least 10 actionable peptides as a measure of study feasibility

    Number of participants who are clinically able to initiate post-RT vaccine therapy within 12 weeks or less from date of surgery as a measure of study feasibility

    Secondary Outcome Measures

    Number of participants who achieve IFN- T-cell response (more than 55 SFU/106 PBMC or 3 times their baseline level) at week 16 via ELISPOT assessments

    Number of participants who are alive without progression at eight months after surgery resection

    Trial Keywords