Clinical Trials /

Neo-adjuvant Evaluation of Glioma Lysate Vaccines in WHO Grade II Glioma

NCT02549833

Description:

This is a pilot neoadjuvant vaccine study in adults with WHO grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety and feasibility of the neoadjuvant approach; and 2) whether the regimen increases the level of type-1 chemokine CXCL10 and vaccine-specific (i.e., reactive to GBM6-AD) CD8+ T-cells in tumor-infiltrating leukocytes (TILs) in the surgically resected glioma.

Related Conditions:
  • WHO Grade II Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Neo-adjuvant Evaluation of Glioma Lysate Vaccines in WHO Grade II Glioma
  • Official Title: Pilot Randomized Neo-adjuvant Evaluation of Poly-ICLC-Assisted Tumor Lysate Vaccines in Adult Patients With WHO Grade II Glioma

Clinical Trial IDs

  • ORG STUDY ID: 15-17692
  • SECONDARY ID: CC15103
  • NCT ID: NCT02549833

Conditions

  • Oligodendroglioma
  • Astrocytoma, Grade II
  • Glioma, Astrocytic
  • Glioma
  • Malignant Glioma
  • Oligoastrocytoma, Mixed

Interventions

DrugSynonymsArms
GBM6-AD and poly-ICLC before and after surgeryVaccines before and after surgery
GBM6-AD and poly-ICLC after surgery onlyVaccines after surgery only

Purpose

This is a pilot neoadjuvant vaccine study in adults with WHO grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety and feasibility of the neoadjuvant approach; and 2) whether the regimen increases the level of type-1 chemokine CXCL10 and vaccine-specific (i.e., reactive to GBM6-AD) CD8+ T-cells in tumor-infiltrating leukocytes (TILs) in the surgically resected glioma.

Detailed Description

      Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse
      astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas are a diverse family of
      central nervous system (CNS) neoplasms that occur in children and adults. Based on data from
      the American Cancer Society and Central Brain Tumor Registry of the United States (CBRTUS),
      approximately 1800 LGG were diagnosed in 2006, thus representing approximately 10% of newly
      diagnosed primary brain tumors in the United States. Pilocytic astrocytomas (WHO grade I) are
      the most common brain tumor in children 5 to 19 years of age3. Diffuse astrocytomas,
      oligodendrogliomas, and oligoastrocytomas are all considered WHO grade II low grade gliomas
      (LGG) and are more common in adults. Pilocytic astrocytomas are generally well circumscribed
      histologically and radiographically and amenable to cure with gross total resection. In
      contrast, the diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas are more
      infiltrative and less amenable to complete resection. From a molecular genetics standpoint,
      the most common alterations in LGG are IDH1 mutations6 and mutations in the tumor suppressor
      gene TP53, located on chromosome 17, the gene product of which is a multifunctional protein
      involved in the regulation of cell growth, cell death (apoptosis), and transcription.
      Additionally, several molecular factors are of favorable prognostic significance,
      particularly the presence of 1p/19q co-deletion and IDH1 mutations.

      WHO grade II LGGs are at extremely high risk to undergo malignant transformation into more
      aggressive and lethal WHO grade III or IV high-grade glioma (HGG). Even with a combination of
      available therapeutic modalities (i.e., surgery, radiation therapy [RT], chemotherapy), the
      invasive growth and resistance to therapy exhibited by these tumors results in recurrence and
      death in most patients. Although postoperative RT in LGG significantly improves 5-year
      progression-free survival (PFS), it does not prolong overall survival (OS) compared with
      delayed RT given at the time of progression. Early results from a randomized trial of
      radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy for
      supratentorial adult LGG (RTOG 9802) demonstrated improved PFS in patients receiving PCV plus
      RT compared RT alone. Nonetheless, PCV is considerably toxic and currently not widely used
      for management of glioma patients. Although chemotherapy with temozolomide (TMZ) is currently
      being investigated in LGG patients, it is unknown whether it confers improves OS in these
      patients. Further, our recent study has indicated that 6 of 10 LGG cases treated with TMZ
      progressed to HGG with markedly increased exome mutations and, more worrisome, driver
      mutations in the RB and AKT-mTOR pathways, with predominant C>T/G>A transitions at CpC and
      CpT dinucleotides, strongly suggesting a signature of TMZ-induced mutagenesis; this study
      also showed that in 43% of cases, at least half of the mutations in the initial tumor were
      undetected at recurrence. These data suggests the possibility that treatment of LGG patients
      with TMZ may enhance oncogenic mutations and genetic elusiveness of LGG, therefore calling
      for development of safer and effective therapeutic modalities such as vaccines.

      Taken together, LGG are considered a premalignant condition for HGG, such that novel
      interventions to prevent malignant transformation need to be evaluated in patients with LGG.
      Immunotherapeutic modalities, such as vaccines, may offer a safe and effective option for
      these patients due to the slower growth rate of LGG (in contrast with HGG), which should
      allow sufficient time for multiple immunizations and hence high levels of anti-glioma
      immunity. Because patients with LGGs are generally not as immuno-compromised as patients with
      HGG, they may also exhibit greater immunological response to and benefit from the vaccines.
      Further, the generally mild toxicity of vaccines may improve quality of life compared with
      chemotherapy or RT.
    

Trial Arms

NameTypeDescriptionInterventions
Vaccines before and after surgeryExperimentalGBM6-AD lysate protein 1 mg and poly-ICLC 1.4 mg administered as one formulation every week leading up to standard-of-care surgery to remove the WHO grade II glioma (Days -23±2, -16±2, -9±2 and 24-48 hours prior to scheduled surgery), every 3 weeks after surgery (Weeks A1, A4, A7, A10, A13, A16; defining Week A1 as the first post-surgery vaccine), and two booster vaccines (Weeks A32 and A48).
  • GBM6-AD and poly-ICLC before and after surgery
Vaccines after surgery onlyActive ComparatorGBM6-AD lysate protein 1 mg and poly-ICLC 1.4 mg administered as one formulation every 3 weeks after standard-of-care surgery to remove the WHO grade II glioma only (Weeks A1, A4, A7, A10, A13, A16; defining Week A1 as the first post-surgery vaccine) and two booster vaccines (Weeks A32 and A48). Patients will not receive vaccines before surgery.
  • GBM6-AD and poly-ICLC after surgery only

Eligibility Criteria

        Inclusion Criteria:

          -  Pathological criteria - Patients must have newly diagnosed or recurrent WHO grade II
             glioma (defined as an astrocytoma, oligodendroglioma, or oligoastrocytoma) that is to
             be histologically confirmed by clinically indicated resection. If patients have
             already undergone biopsy and have pathological diagnosis of WHO grade II glioma,
             pathology must be reviewed and confirmed at UCSF.

          -  Before enrollment, patients must show supratentorial, non-enhancing T2-FLAIR lesions
             that need to be surgically resected and are likely WHO grade II glioma. Surgical
             resection of at least 500 mg tumor tissue to ensure adequate evaluation of the study
             endpoints.

          -  Prior radiation therapy (RT) after the initial diagnosis will be allowed. Patients
             with prior RT must be at least 6 months from the completion of RT (or radiosurgery)

          -  Prior chemotherapy or molecularly targeted therapy will be allowed. Patients with
             prior chemotherapy must be at least 6 months from the last dose of chemotherapy or
             molecularly targeted therapy

          -  Patients must be ≥ 18 years old

          -  Patients must have a Karnofsky performance status ≥ 70%

          -  Patients must be off corticosteroid for at least for 2 weeks before the first
             neoadjuvant vaccine and for at least 2 weeks prior to the first adjuvant vaccine

          -  Adequate organ function within 14 days of study registration including:

               -  Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count
                  (ANC) ≥1.0 x 10^9/L; absolute lymphocyte count (ALC) ≥0.5 x 10^9/L; platelets
                  ≥100 x 10^9/L; hemoglobin ≥8 g/dL;

               -  Hepatic: - Total bilirubin ≤1.5 x upper limit of normal (ULN) and SGPT (ALT) ≤
                  2.5 x upper limit of normal (ULN), and

               -  Renal: Normal serum creatinine or creatinine clearance ≥60 ml/min/1.73 m^2

          -  Must be free of systemic infection. Subjects with active infections (whether or not
             they require antibiotic therapy) may be eligible after complete resolution of the
             infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days
             before beginning treatment.

          -  Sexually active females of child bearing potential must agree to use adequate
             contraception (diaphragm, birth control pills, injections, intrauterine device [IUD],
             surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration
             of the vaccination period. Sexually active males must agree to use barrier
             contraceptive for the duration of the vaccination period.

        Exclusion Criteria:

          -  History of immune system abnormalities such as hyperimmunity (e.g., autoimmune
             diseases) and hypoimmunity (e.g., myelodysplastic disorders, marrow failures, AIDS,
             transplant immunosuppression)

          -  History or clinical suspicion of neurofibromatosis

          -  Any isolated laboratory abnormality suggestive of a serious autoimmune disease (e.g.
             hypothyroidism)

          -  Any conditions that could potentially alter immune function (AIDS, multiple sclerosis,
             uncontrolled diabetes, renal failure)

          -  Receiving ongoing treatment with immunosuppressive drugs

          -  Currently receiving any investigational agents or registration on another therapy
             based trial

          -  Pregnant or lactating
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety - incidence and severity of adverse events
Time Frame:until disease progression, start of a new therapy, or for a maximum of 18 months from study registration (whichever occurs earlier)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Response rate and magnitude of CD4+ and CD8+ T-cell responses against the GM6-AD lysate in pre- and post-vaccine PBMC using IFN-γ-ELISPOT
Time Frame:at Baseline, At time of surgery (as clinically indicated), Weeks 1, 10 and 16 post-surgery
Safety Issue:
Description:
Measure:Tumor tissue expression of glioma-associated antigens (GAAs) and antigen-presentation machinery (APM) molecules
Time Frame:At the time of clinically indicated surgical resection of the tumor
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:2 years after enrollment
Safety Issue:
Description:
Measure:To tabulate tumor objective response rate (ORR)
Time Frame:2 years after enrollment
Safety Issue:
Description:
Measure:Progression-free survival (PFS)
Time Frame:2 years after enrollment
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • low-grade glioma
  • WHO grade II
  • vaccine
  • immunotherapy
  • glioma

Last Updated

December 3, 2018