Human stem cell derived neuron
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A Multi-Center Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122 for recurrent glioblastoma

Summary

This is a phase 0/I exploratory study to evaluate the safety and toxicity profile of anti-TIGIT AB154 in combination with anti-PD-1 AB122 in patients with recurrent glioblastoma.

AB122 is a monoclonal antibody that targets the human programmed cell death-1 (PD-1) immune checkpoint protein, which normally protects the body from attacking itself. Some cancer cells take advantage of this protection mechanism making the protective signal themselves. Several agents targeting PD-1 have been approved by FDA for the treatment of cancer with activity and efficacy observed in a variety of tumor types.

AB154 is a monoclonal antibody that targets the T cell Ig and ITIM domain (TIGIT). TIGIT is a receptor expressed on a variety of immune cells — including T cells, regulatory T cells (Tregs), and natural killer (NK) cells — that plays an important role in regulating T cell function. TIGIT is highly expressed in glioblastoma and may be essential for Treg suppression after T cell proliferation induced by anti-PD-1 therapy

Inclusion Criteria
  1. Grade IV glioma (glioblastoma and its variants according to the WHO 2016), confirmed in tissue at time of initial diagnosis.
  2. First or second recurrence after treatment. Prior treatment must include at least radiation therapy.
  3. Measurable contrast enhancing tumor by RANO criteria.
  4. Age ≥18 years.
  5. Karnofsky performance status ≥80.
  6. Patients must have adequate organ and marrow function as defined below within 14 days of treatment:
    1. Absolute neutrophil count (ANC) ≥1,500 /mcL
    2. Platelets ≥100,000 / mcL
    3. Hemoglobin ≥9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
    4. Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
    5. Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    6. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
    7. Albumin >2.5 mg/dL
    8. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    9. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  7. An interval of ≥12 weeks from the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiation treatment field.
  8. An interval of ≥3 weeks or 5 half-lives (whichever is longer) after the last administration of any investigational agent or any other treatment prior to first study dose.
  9. Female subjects of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
  10. Ability to understand and the willingness to sign a written informed consent document.
  11. Deemed a candidate for tumor debulking, as determined by the neurosurgeon.
Exclusion Criteria
  1. Patients who have been treated with bevacizumab. Note: Previous use of intra-arterial bevacizumab may be allowed, contingent upon review and approval by study principal investigator and sponsor.
  2. Patients who have not recovered from adverse events due to prior therapy (i.e., > Grade 1) with the exception of alopecia and fatigue.
  3. Patients with multifocal disease.
  4. Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids ( > 10 mg/d of prednisone equivalent or > 2 mg dexamethasone) for control of disease at the time of registration.
  5. Patients receiving previous or current treatment with an immune checkpoint inhibitor.
  6. Patients with a known diagnosis of immunodeficiency, including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS).
  7. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  8. Has a known history of active TB (Bacillus Tuberculosis).
  9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  11. Has known history of, or any evidence of active, non-infectious pneumonitis.
  12. Has an active infection requiring systemic therapy.
  13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  15. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  16. Unable to undergo MRI of the brain with and without contrast enhancement (i.e., pacemaker, allergy to MRI contrast agent or any other contraindication for MRIs).
  17. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Investigator(s)

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