humam stem cell derived neurons

A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

 

Summary

Low-grade gliomas (LGG), which include diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas, are at extremely high risk to undergo malignant transformation into more aggressive high-grade gliomas (HGG; grades III-IV). Because LGG is considered a premalignant condition for HGG, novel interventions to prevent malignant transformation are being evaluated in patients with LGG. 

Vaccine-based immunotherapies may offer a safe and effective option for patients due to the slower growth rate of LGG (in contrast with HGG), which should allow sufficient time for multiple immunizations and therefore 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 radiation therapy.

This clinical trial evaluates the safety and feasibility of IMA950 (a vaccine-based immunotherapy) in combination with varlilumab (an antibody-based immunotherapy) in patients with newly diagnosed or recurrent LGG. 

This vaccine is comprised of 11 molecules that are found on glioblastoma cells. By exposing patients’ immune systems to molecules made by glioblastoma cells, the vaccine may be effective in training the immune system to recognize unique molecules made by gliomas (also called glioma-specific antigens), so that it learn to recognize and specifically attack glioblastoma cells. In this study, IMA950 will also be combined with poly ICLC, which is a compound thought to increase tumor-killing activity in various immune cells.  

Varlilumab is an antibody-based immunotherapy that binds and activates CD27, a protein involved in the immune response and activation of T-cells. In addition to testing the safety and efficacy of IMA950 with poly ICLC, this trial also aims to study whether the addition of varlilumab increases T-cell activity against the glioma-specific antigens introduced by the vaccine. To do so, this Phase I trial will compare the effects of the following two treatment groups:

  • Experimental Group 1: IMA950 + poly ICLC + Varlilumab
  • Experimental Group 2: IMA950 + poly ICLC alone

 

Inclusion Criteria
  1. Patients must be ≥ 18 years old.
  2. Pathological criteria - Participants must have WHO grade II astrocytoma, oligoastrocytoma or oligodendroglioma that has been histologically confirmed by prior biopsy or surgical resection. If patients have already undergone biopsy and have pathological diagnosis in a non-UCSF institute, pathology must be reviewed and confirmed at UCSF.
  3. Patients must be positive for HLA-A2 based on flow-cytometry or genotyping
  4. Before enrollment, patients must show non-enhancing T2-FLAIR lesions that need to be surgically resected and are likely WHO grade II glioma.
  5. Surgical resection of at least 0.5 grams of tumor
  6. Both newly diagnosed (with available pathological diagnosis) and recurrent patients can be eligible. Prior radiation therapy (RT) after the initial diagnosis will be allowed but there must be at least 6 months from the completion of RT (or radiosurgery) to signed informed consent.
  7. Prior chemotherapy and any systemic molecularly targeted anti-tumor therapy will be allowed.
  8. Patients must have a Karnofsky performance status (KPS) of ≥ 70%.
  9. Off or low dose (≤ 4 mg/day by Decadron) corticosteroid at least two weeks before the first pre-surgical vaccine
  10. Adequate organ function within 14 days of study registration including:
    1. Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.0 x 10^9/L, absolute lymphocytes ≥400/μL, platelets ≥100 x 10^9/L; hemoglobin ≥ 8 g/dL
    2. Hepatic: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) and SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN)
    3. Renal: Normal serum creatinine or creatinine clearance ≥60 ml/min/1.73 m^2
  11. 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.
  12. 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.
  13. Patient must sign an informed consent document indicating that they are aware of the investigational nature of this study, which includes an authorization for the release of their protected health information

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Presence of gliomatosis cerebri, cranial or spinal leptomeningeal metastatic disease
  2. Presence of T1 Gadolinium (Gd)-enhancing lesions (on MRI) suggestive of high-grade glioma
  3. Pathological diagnosis for the resected tumor demonstrates transformation to higher grade (i.e. WHO grade III or IV) or gliomas. If a patient who received pre-surgical vaccines is diagnosed as high-grade glioma (HGG), the patient will be withdrawn from the study and considered for therapeutic options for HGG (trials for HGG or standard of care). The tumor tissue of such a case would be brought to the lab before the pathological diagnosis is made; and thus would be processed before the lab is informed of the final HGG diagnosis. Because HGG tissue may still reflect the vaccine effects, we will evaluate the tumor tissue to help us develop future approaches for HGG.
  4. Pregnant women are excluded from this study. Pregnancy testing will be performed on all menstruating females within 14 days prior to study enrollment
  5. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection (e.g. active or chronic hepatitis B and C), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements
  6. History or current status of immune system abnormalities such as hyperimmunity (e.g., autoimmune diseases) that needed to be treated by systemic therapy, such as immuno-suppressants and hypoimmunity (e.g., myelodysplastic disorders, marrow failures, AIDS, transplant immunosuppression).
  7. Receiving ongoing treatment with immunosuppressive drugs, or dexamethasone > 4mg

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

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