Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: Ph I Personalized NeoAntigen Cancer Vaccine With Radiotherapy for Patients With MGMT Unmethylated, Newly Diagnosed Glioblastoma

Summary: 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.

Eligibility: 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/μL
  -  Absolute lymphocyte count ≥800/μL
  -  Absolute neutrophil count ≥ 1,000/μL
  -  Platelets ≥ 100,000/μL
  -  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/μL
  -  Absolute lymphocyte count ≥ 800/μL
  -  Absolute neutrophil count ≥ 1,000/μL
  -  Platelets ≥ 100,000/μL
  -  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

Relevance to patient case: definitely relevant